Feature

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

In 2024, the Guttmacher Institute reported that eight states enacted or proposed limits on contraceptive access. Currently, more than 19 million women aged 13-44 years in the United States live in “contraceptive deserts” or places that lack access to a full range of birth control methods. About 1.2 million of those women live in counties that don’t have a single health center that has complete birth control services.

Providing contraceptive care in primary care settings has long been deemed a best practice by the Centers for Disease Control and Prevention (CDC). But the percentage of primary care physicians (PCPs) prescribing contraception or offering contraceptive procedures is strikingly low.

 

Only Half of Family Physicians (FPs) Prescribe Contraceptives

Research by Candice Chen, MD, MPH, and colleagues found that while 73.1% of obstetrician-gynecologists (OB/GYNs) and 72.6% of nurse-midwives prescribed the pill, patch, or vaginal ring; only 51% of FPs, 32.4% of pediatricians, and 19.8% of internal medicine physicians did so. And while 92.8% of OB/GYNs provided intrauterine device (IUD) services, only 16.4% of FPs, 2.6% of internists, and 0.6% of pediatricians did so.

One reason primary care is positioned so well to fill contraception gaps is found in the sheer numbers of PCPs. Chen and colleagues found that while the percentage of FPs prescribing contraception was much smaller (51.4%) than the percentage of OB/GYN prescribers (72.6%), the numbers translate to 72,725 FPs prescribing contraceptives, which is nearly double the number of OB/GYNs prescribing them (36,887).

Access to contraception services took a big hit with the COVID-19 pandemic as did access to healthcare in general. And the 2022 Supreme Court ruling that struck down Roe V. Wade has shaken up the landscape for reproductive services with potential consequences for contraceptive access.

 

Why Aren’t More PCPs Offering Contraceptive Services?

Reasons for the relatively low numbers of PCPs prescribing contraceptives include lack of training in residency, health systems’ financial choices, insurance barriers, and expectation by some physicians and many patients that birth control belongs in the OB/GYN sector. Access, patient awareness that PCPs can provide the care, expectations, and options vary by states and regions.

Angeline Ti, MD, an FP who teaches in a residency program at Wellstar Douglasville Medical Center in Douglasville, Georgia, told this news organization that the awareness issue might be the easiest change for PCPs as many patients aren’t aware you can get contraceptive services in primary care.

 

Things PCPs ‘Could Do Tomorrow’

Those physicians who want to add those services might want to start with universal screening, Ti said — having conversations with patients about contraceptive needs and letting them know they don’t have to get those prescriptions from an OB/GYN. The conversations could center on laying out the options and counseling on risks and benefits of various options and providing referrals, if that is the best option. “There are definitely things that you could do tomorrow,” she said.

PCPs should be familiar with the CDC’s Contraceptive Guidance for Health Care Providers and the federal Office of Population Affairs’ Quality Family Planning Recommendations for providers, which offer practice-level information, Ti said.

PCPs should not feel they need to be able to provide same-day contraceptive care to get started. Having nurses and medical assistants and practice managers on board who are passionate about adding the services can also help bring about change with a team approach, she said.

Even when the provider is enthusiastic about providing the care and is trained to do so, however, insurance barriers may exist, Ti acknowledged. For example, at her clinic a common IUD insertion requires prior authorization.

 

Including Other Providers

Julia Strasser, DrPH, MPH, a member of the core faculty at the Fitzhugh Mullan Institute for Health Workforce Equity in Washington, DC, told this news organization that including other clinicians could help expand contraceptive services in primary care. Her research showed that the proportion of the contraception workforce that is made up of advanced practice clinicians and nurse practitioners is increasing, whereas the proportion that includes physicians is either static or declining.

A paper by her team found that although OB/GYNs and nurse-midwives were more likely to prescribe the pill, patch, or ring, the largest numbers of contraception prescribers were FPs (72,725) and advanced practice nurses (70,115).

“We also know that pharmacists can safely prescribe contraception, and some states have authorized this practice, but uptake is low and policies vary by state,” she said. “Some health systems have pharmacists embedded in their practice — for example in federally qualified health centers and others.”

It’s important, she said, not to frame the gaps in contraceptive care as a failure on the part of individual clinicians but rather as: “How can we change some of the system-level factors that have gotten us to this point?”

Yalda Jabbarpour, MD, an FP and director of the Robert Graham Center of the American Academy of Family Physicians, said sometimes it’s the health center’s cost analysis that stands in the way. She gave an example from her own health system.

“The health system doesn’t want to pay for us to have the IUDs stored in our offices and provide that procedure because they feel it’s more cost effective if the OB/GYNs do it.” IUD insertions take more appointment time than the standard appointment, which also goes into the cost analysis. “Even though you’re trained to do it, you can’t necessarily do it when you get to the real world,” Jabbarpour said.

She said the thinking is that while OB/GYNs focus on women, FPs cover all ages and family members, so having the equipment and the storage space is best left to the OB/GYNs. She said that thinking may be short sighted.

“We have good data that the highest number of office visits in the United States actually happen in the family physician’s office,” she said. Not providing the services injects a barrier into the system as women are being referred for a simple procedure to a physician they’ve never seen. “That’s not very patient centered,” Jabbarpour noted.

In systems that refer contraceptive procedures to OB/GYNs, doctors also can’t practice skills they learned in residency and then may not feel comfortable performing the procedures when they enter a health system that offers the procedures in primary care.

 

Number of FPs Prescribing Long-Acting Contraception Growing

Jabbarpour said there has been some improvement in that area in terms of long-acting reversible contraception.

She pointed to a study of recertifying FPs that found that the percent of FPs who offer either IUDs or implants increased from 23.9% in 2018 to 30% in 2022. The share of FPs providing implant insertion increased from 12.9% to 20.8%; those providing IUDs also increased from 22.9% to 25.5% from 2018 to 2022.

FPs also have the advantage of being more widely distributed in rural and remote areas than OB/GYNs, she noted. “They are in almost every county in the United States.”

Jabbarpour said the education must start with health system leaders. If they deem it important to offer these services in primary care, then residency programs will see that their residents must be appropriately trained to provide it.

“Right now, it’s not an expectation of many of the employers that primary care physicians should do this,” she said.

Ti said that expectation should change. The value proposition for all PCPs and health systems, she said, is this: “Most of contraceptive care is well within the scope of primary care providers. This is care that we can do, and it’s care that we should be doing. So why aren’t we doing it?”

Ti, Strasser, and Jabbarpour reported no relevant financial disclosures.

A version of this article appeared on Medscape.com.

In 2024, the Guttmacher Institute reported that eight states enacted or proposed limits on contraceptive access. Currently, more than 19 million women aged 13-44 years in the United States live in “contraceptive deserts” or places that lack access to a full range of birth control methods. About 1.2 million of those women live in counties that don’t have a single health center that has complete birth control services.

Providing contraceptive care in primary care settings has long been deemed a best practice by the Centers for Disease Control and Prevention (CDC). But the percentage of primary care physicians (PCPs) prescribing contraception or offering contraceptive procedures is strikingly low.

 

Only Half of Family Physicians (FPs) Prescribe Contraceptives

Research by Candice Chen, MD, MPH, and colleagues found that while 73.1% of obstetrician-gynecologists (OB/GYNs) and 72.6% of nurse-midwives prescribed the pill, patch, or vaginal ring; only 51% of FPs, 32.4% of pediatricians, and 19.8% of internal medicine physicians did so. And while 92.8% of OB/GYNs provided intrauterine device (IUD) services, only 16.4% of FPs, 2.6% of internists, and 0.6% of pediatricians did so.

One reason primary care is positioned so well to fill contraception gaps is found in the sheer numbers of PCPs. Chen and colleagues found that while the percentage of FPs prescribing contraception was much smaller (51.4%) than the percentage of OB/GYN prescribers (72.6%), the numbers translate to 72,725 FPs prescribing contraceptives, which is nearly double the number of OB/GYNs prescribing them (36,887).

Access to contraception services took a big hit with the COVID-19 pandemic as did access to healthcare in general. And the 2022 Supreme Court ruling that struck down Roe V. Wade has shaken up the landscape for reproductive services with potential consequences for contraceptive access.

 

Why Aren’t More PCPs Offering Contraceptive Services?

Reasons for the relatively low numbers of PCPs prescribing contraceptives include lack of training in residency, health systems’ financial choices, insurance barriers, and expectation by some physicians and many patients that birth control belongs in the OB/GYN sector. Access, patient awareness that PCPs can provide the care, expectations, and options vary by states and regions.

Angeline Ti, MD, an FP who teaches in a residency program at Wellstar Douglasville Medical Center in Douglasville, Georgia, told this news organization that the awareness issue might be the easiest change for PCPs as many patients aren’t aware you can get contraceptive services in primary care.

 

Things PCPs ‘Could Do Tomorrow’

Those physicians who want to add those services might want to start with universal screening, Ti said — having conversations with patients about contraceptive needs and letting them know they don’t have to get those prescriptions from an OB/GYN. The conversations could center on laying out the options and counseling on risks and benefits of various options and providing referrals, if that is the best option. “There are definitely things that you could do tomorrow,” she said.

PCPs should be familiar with the CDC’s Contraceptive Guidance for Health Care Providers and the federal Office of Population Affairs’ Quality Family Planning Recommendations for providers, which offer practice-level information, Ti said.

PCPs should not feel they need to be able to provide same-day contraceptive care to get started. Having nurses and medical assistants and practice managers on board who are passionate about adding the services can also help bring about change with a team approach, she said.

Even when the provider is enthusiastic about providing the care and is trained to do so, however, insurance barriers may exist, Ti acknowledged. For example, at her clinic a common IUD insertion requires prior authorization.

 

Including Other Providers

Julia Strasser, DrPH, MPH, a member of the core faculty at the Fitzhugh Mullan Institute for Health Workforce Equity in Washington, DC, told this news organization that including other clinicians could help expand contraceptive services in primary care. Her research showed that the proportion of the contraception workforce that is made up of advanced practice clinicians and nurse practitioners is increasing, whereas the proportion that includes physicians is either static or declining.

A paper by her team found that although OB/GYNs and nurse-midwives were more likely to prescribe the pill, patch, or ring, the largest numbers of contraception prescribers were FPs (72,725) and advanced practice nurses (70,115).

“We also know that pharmacists can safely prescribe contraception, and some states have authorized this practice, but uptake is low and policies vary by state,” she said. “Some health systems have pharmacists embedded in their practice — for example in federally qualified health centers and others.”

It’s important, she said, not to frame the gaps in contraceptive care as a failure on the part of individual clinicians but rather as: “How can we change some of the system-level factors that have gotten us to this point?”

Yalda Jabbarpour, MD, an FP and director of the Robert Graham Center of the American Academy of Family Physicians, said sometimes it’s the health center’s cost analysis that stands in the way. She gave an example from her own health system.

“The health system doesn’t want to pay for us to have the IUDs stored in our offices and provide that procedure because they feel it’s more cost effective if the OB/GYNs do it.” IUD insertions take more appointment time than the standard appointment, which also goes into the cost analysis. “Even though you’re trained to do it, you can’t necessarily do it when you get to the real world,” Jabbarpour said.

She said the thinking is that while OB/GYNs focus on women, FPs cover all ages and family members, so having the equipment and the storage space is best left to the OB/GYNs. She said that thinking may be short sighted.

“We have good data that the highest number of office visits in the United States actually happen in the family physician’s office,” she said. Not providing the services injects a barrier into the system as women are being referred for a simple procedure to a physician they’ve never seen. “That’s not very patient centered,” Jabbarpour noted.

In systems that refer contraceptive procedures to OB/GYNs, doctors also can’t practice skills they learned in residency and then may not feel comfortable performing the procedures when they enter a health system that offers the procedures in primary care.

 

Number of FPs Prescribing Long-Acting Contraception Growing

Jabbarpour said there has been some improvement in that area in terms of long-acting reversible contraception.

She pointed to a study of recertifying FPs that found that the percent of FPs who offer either IUDs or implants increased from 23.9% in 2018 to 30% in 2022. The share of FPs providing implant insertion increased from 12.9% to 20.8%; those providing IUDs also increased from 22.9% to 25.5% from 2018 to 2022.

FPs also have the advantage of being more widely distributed in rural and remote areas than OB/GYNs, she noted. “They are in almost every county in the United States.”

Jabbarpour said the education must start with health system leaders. If they deem it important to offer these services in primary care, then residency programs will see that their residents must be appropriately trained to provide it.

“Right now, it’s not an expectation of many of the employers that primary care physicians should do this,” she said.

Ti said that expectation should change. The value proposition for all PCPs and health systems, she said, is this: “Most of contraceptive care is well within the scope of primary care providers. This is care that we can do, and it’s care that we should be doing. So why aren’t we doing it?”

Ti, Strasser, and Jabbarpour reported no relevant financial disclosures.

A version of this article appeared on Medscape.com.

In 2024, the Guttmacher Institute reported that eight states enacted or proposed limits on contraceptive access. Currently, more than 19 million women aged 13-44 years in the United States live in “contraceptive deserts” or places that lack access to a full range of birth control methods. About 1.2 million of those women live in counties that don’t have a single health center that has complete birth control services.

Providing contraceptive care in primary care settings has long been deemed a best practice by the Centers for Disease Control and Prevention (CDC). But the percentage of primary care physicians (PCPs) prescribing contraception or offering contraceptive procedures is strikingly low.

 

Only Half of Family Physicians (FPs) Prescribe Contraceptives

Research by Candice Chen, MD, MPH, and colleagues found that while 73.1% of obstetrician-gynecologists (OB/GYNs) and 72.6% of nurse-midwives prescribed the pill, patch, or vaginal ring; only 51% of FPs, 32.4% of pediatricians, and 19.8% of internal medicine physicians did so. And while 92.8% of OB/GYNs provided intrauterine device (IUD) services, only 16.4% of FPs, 2.6% of internists, and 0.6% of pediatricians did so.

One reason primary care is positioned so well to fill contraception gaps is found in the sheer numbers of PCPs. Chen and colleagues found that while the percentage of FPs prescribing contraception was much smaller (51.4%) than the percentage of OB/GYN prescribers (72.6%), the numbers translate to 72,725 FPs prescribing contraceptives, which is nearly double the number of OB/GYNs prescribing them (36,887).

Access to contraception services took a big hit with the COVID-19 pandemic as did access to healthcare in general. And the 2022 Supreme Court ruling that struck down Roe V. Wade has shaken up the landscape for reproductive services with potential consequences for contraceptive access.

 

Why Aren’t More PCPs Offering Contraceptive Services?

Reasons for the relatively low numbers of PCPs prescribing contraceptives include lack of training in residency, health systems’ financial choices, insurance barriers, and expectation by some physicians and many patients that birth control belongs in the OB/GYN sector. Access, patient awareness that PCPs can provide the care, expectations, and options vary by states and regions.

Angeline Ti, MD, an FP who teaches in a residency program at Wellstar Douglasville Medical Center in Douglasville, Georgia, told this news organization that the awareness issue might be the easiest change for PCPs as many patients aren’t aware you can get contraceptive services in primary care.

 

Things PCPs ‘Could Do Tomorrow’

Those physicians who want to add those services might want to start with universal screening, Ti said — having conversations with patients about contraceptive needs and letting them know they don’t have to get those prescriptions from an OB/GYN. The conversations could center on laying out the options and counseling on risks and benefits of various options and providing referrals, if that is the best option. “There are definitely things that you could do tomorrow,” she said.

PCPs should be familiar with the CDC’s Contraceptive Guidance for Health Care Providers and the federal Office of Population Affairs’ Quality Family Planning Recommendations for providers, which offer practice-level information, Ti said.

PCPs should not feel they need to be able to provide same-day contraceptive care to get started. Having nurses and medical assistants and practice managers on board who are passionate about adding the services can also help bring about change with a team approach, she said.

Even when the provider is enthusiastic about providing the care and is trained to do so, however, insurance barriers may exist, Ti acknowledged. For example, at her clinic a common IUD insertion requires prior authorization.

 

Including Other Providers

Julia Strasser, DrPH, MPH, a member of the core faculty at the Fitzhugh Mullan Institute for Health Workforce Equity in Washington, DC, told this news organization that including other clinicians could help expand contraceptive services in primary care. Her research showed that the proportion of the contraception workforce that is made up of advanced practice clinicians and nurse practitioners is increasing, whereas the proportion that includes physicians is either static or declining.

A paper by her team found that although OB/GYNs and nurse-midwives were more likely to prescribe the pill, patch, or ring, the largest numbers of contraception prescribers were FPs (72,725) and advanced practice nurses (70,115).

“We also know that pharmacists can safely prescribe contraception, and some states have authorized this practice, but uptake is low and policies vary by state,” she said. “Some health systems have pharmacists embedded in their practice — for example in federally qualified health centers and others.”

It’s important, she said, not to frame the gaps in contraceptive care as a failure on the part of individual clinicians but rather as: “How can we change some of the system-level factors that have gotten us to this point?”

Yalda Jabbarpour, MD, an FP and director of the Robert Graham Center of the American Academy of Family Physicians, said sometimes it’s the health center’s cost analysis that stands in the way. She gave an example from her own health system.

“The health system doesn’t want to pay for us to have the IUDs stored in our offices and provide that procedure because they feel it’s more cost effective if the OB/GYNs do it.” IUD insertions take more appointment time than the standard appointment, which also goes into the cost analysis. “Even though you’re trained to do it, you can’t necessarily do it when you get to the real world,” Jabbarpour said.

She said the thinking is that while OB/GYNs focus on women, FPs cover all ages and family members, so having the equipment and the storage space is best left to the OB/GYNs. She said that thinking may be short sighted.

“We have good data that the highest number of office visits in the United States actually happen in the family physician’s office,” she said. Not providing the services injects a barrier into the system as women are being referred for a simple procedure to a physician they’ve never seen. “That’s not very patient centered,” Jabbarpour noted.

In systems that refer contraceptive procedures to OB/GYNs, doctors also can’t practice skills they learned in residency and then may not feel comfortable performing the procedures when they enter a health system that offers the procedures in primary care.

 

Number of FPs Prescribing Long-Acting Contraception Growing

Jabbarpour said there has been some improvement in that area in terms of long-acting reversible contraception.

She pointed to a study of recertifying FPs that found that the percent of FPs who offer either IUDs or implants increased from 23.9% in 2018 to 30% in 2022. The share of FPs providing implant insertion increased from 12.9% to 20.8%; those providing IUDs also increased from 22.9% to 25.5% from 2018 to 2022.

FPs also have the advantage of being more widely distributed in rural and remote areas than OB/GYNs, she noted. “They are in almost every county in the United States.”

Jabbarpour said the education must start with health system leaders. If they deem it important to offer these services in primary care, then residency programs will see that their residents must be appropriately trained to provide it.

“Right now, it’s not an expectation of many of the employers that primary care physicians should do this,” she said.

Ti said that expectation should change. The value proposition for all PCPs and health systems, she said, is this: “Most of contraceptive care is well within the scope of primary care providers. This is care that we can do, and it’s care that we should be doing. So why aren’t we doing it?”

Ti, Strasser, and Jabbarpour reported no relevant financial disclosures.

A version of this article appeared on Medscape.com.

For millennia in medicine, alcohol, particularly red wine, carried a health halo; in small doses, it has historically been thought to have cardioprotective benefits. Michael Farkouh, MD, a professor of cardiology at Cedars-Sinai, estimates half the physicians still accept people having a drink or two a day. “That is still in practice, though the numbers are reducing,” he said.

But Farkouh no longer drinks alcohol, a position he has come to after getting more involved in research into the substance and his realization that many of the studies touting alcohol’s health benefits were flawed.

Today, alcohol sits alongside asbestos and tobacco as class 1 carcinogens. According to the World Health Organization, it has no known safe ingestible amount. In 2018, a blockbuster report in The Lancet found no amount of any kind of alcohol improves health. In early January, US Surgeon General Vivek Murthy called for adding cancer warnings to alcohol labels.

But the way doctors drink is far from black and white. For physicians, drinking habits are tied up in personal values, professional understanding of a substance with a confusing research history, and the fact alcohol is deeply ingrained in the social fabric of society — and in medicine. As thinking on alcohol shifts, this news organization spoke with physicians about their own drinking habits, how they counsel patients on it, and alcohol’s place in a field that works to keep people healthy.

 

Cultural Currency

From the days of Hippocrates, who believed alcohol could cure virtually every ailment, alcohol has held a large role in medicine. Through much of the 19th century, patent remedies like Hamlin’s Wizard Oil and the Seven Sutherland Sisters Hair Grower, contained alcohol — sometimes in concentrations exceeding 50%.

The first American Pharmacopoeia, published in 1820, even contained nine wine-based medicines. Throughout the second half of the 19th century, physicians largely debated alcohol’s role in medicine. However, a 1922 poll of members of the American Medical Association found that physicians were still using alcohol as a medicine for everything from heart attacks to animal bites.

Today, alcohol’s presence in medicine is, in some ways, representative of a realized cognitive dissonance.

“In my mind, alcohol has completely lost any illusion of benefit. It is a poison to almost every single organ in our body. Yet I’m currently engaged in a duel of being a physician who drinks in moderation and constantly judging myself for it,” said Tyra Fainstad, MD, an internist and an associate professor at CU Medicine in Denver.

Fainstad said every academic national conference she has attended has had a reception with multiple cash bars — and professional recruitment dinners regularly include at least the offering of alcohol. Private hospitals often have open bars at events.

“Drinking has historically been a way that people unwind, even in medicine,” said addiction psychiatrist Alexis Ritvo, MD. Ritvo — who said she drinks occasionally but much less than she used to after paying attention to how alcohol makes her feel and the harm alcohol can cause — noted that some occasions where alcohol is present socially in medicine don’t bother her. Alcohol is even an option at the addiction psychiatry conference, where attendees can exchange tickets for drinks. But last year, the event provided separate bars for alcoholic and nonalcoholic drinks.

“Our life is full of things that are contradictory or at odds,” Ritvo said. “We want things to either be wrong or right, appropriate or inappropriate, but just like all things, everything’s pretty nuanced.”

But there are examples of alcohol being a part of an event that are downright inappropriate, such as when she attended a fundraiser for a recovery facility that had an open bar.

Farkouh said alcohol at events can exclude others. (He recommends that instead of calling a social gathering “going out for drinks,” someone might say, “We’re getting together.”) He drinks mocktails or nonalcoholic beer at work events where alcohol is served.

Brian Dwinnell, MD, associate dean of student life at CU Medicine, said alcohol can quickly become the focus of an event — something he noticed at an annual kickball game between first- and second-year students that has historically served beer.

In recent years, school leadership has removed alcohol from his institution’s match day celebration and the kickball game. “Initially, there was some pushback from students,” he said of making these events dry, “but now, it’s just sort of accepted, and the events have been just as great as they were when we did provide alcohol.”

 

How Doctors Drink

Physicians may have a greater understanding of alcohol’s health harms. Still, they don’t necessarily drink less because of it, and whether they should becomes a question not just of health but also of the standards to which society holds medical professionals.

Data suggest physicians tend to drink at rates similar to those among the general population. A recent Medscape Medical News survey found nearly 60% of physicians have started drinking less.

Dwinnell said he is a long-time “wine connoisseur” and drinks on occasion. But he admitted that while he thinks about the health implications of alcohol more — and he has nixed it from various events for medical students — he does not believe his drinking habits have changed much.

Navya Mysore, MD, a family physician in New York City, said she has become interested in wine over the past few years, even taking classes to learn more about it. “I like understanding how it’s made, the regions it’s from, and how to pair it with food,” she said. Mysore admits she drank a little more than usual throughout the pandemic, yet today, she said her relationship with alcohol in moderation is related to family, community, and connection.

Fainstad, who drinks socially, said: “I think there’s an immeasurable quality to the social ritual of it. I think for better or worse — probably for worse — for many generations, alcohol has been a part of many meaningful traditions and rituals that we hold.”

Farkouh was quick to underscore the importance of social connection, and that alcohol reduces stress for some people. “I don’t want to take that away from people,” he said. But he also stated the importance of finding other ways to find social fulfillment and enjoyment — and said it’s essential for societal norms to shift to reflect this.

With emerging data, alcohol’s image in society is shifting. Ireland recently became the first country to pass regulation requiring all alcohol sold there to come with a cancer warning. All the clinicians interviewed for this article spoke about the increased acceptability of choosing not to drink for whatever reason.

In the context of alcohol, Dwinnell often asks his students, “What if you were out at a restaurant and you saw your mother’s surgeon there and they were intoxicated? Are you going to feel comfortable with that individual operating on your mother tomorrow or any time?” He added: “Physicians are held to a higher professional standard than those in other fields — and they should be. This is a high-stakes business.”

Dwinnell’s hypothetical question to students is a good one, albeit perhaps not always a fair one. “It’s important for people to realize that physicians are humans,” Mysore said. “We are people, we have lives, and we may choose to have habits that are not necessarily the healthiest for us.”

Fainstad said there’s no shame in medical professionals drinking on occasion. “You can’t be held accountable for something you don’t know about,” she said, acknowledging the known harms of alcohol and that there is still more to learn. But she does wonder how doctors who drank might be perceived in years to come. “I can imagine in a couple of decades, people could say, ‘Even doctors used to have a glass of wine with dinner.’”

 

‘Physicians Should Tighten Their Stances on Alcohol’

The 2020-2025 Dietary Guidelines suggest limiting intake to two alcoholic drinks or less daily for men and one drink or less for women or to choose not to drink. Farkouh said he skews toward the latter, encouraging patients to drink as little as possible or nothing at all. “If you take a holistic approach, physicians should tighten their stances on alcohol,” he said.

Ultimately, he said a randomized trial is warranted to address the risk for cardiovascular disease, in particular.

Of course, physicians vary in how they discuss the topic with patients.

Mysore said she regularly educates patients about pour size and ways to swap out alcoholic drinks with nonalcoholic ones. Outside of cases of addiction, she favors the idea of moderation. “I don’t really subscribe to all-or-nothing mindsets. If there’s something that you enjoy having as a part of your life, I don’t think there’s any reason why you need to eliminate it,” she said. “You just need to figure out what moderation looks like for you.”

Ritvo favors motivational interviewing and tries to understand someone’s relationship with alcohol.

Fainstad provides the Dietary Guidelines’ cutoffs to patients and educates them on the poisonous nature of the substance.

Clearer guidance from large governing bodies — potential changes around alcohol in the 2025-230 revision of the US Dietary Guidelines or cancer warnings on booze sold in the United States — are coming and could help streamline messaging.

And although he speaks with urgency about alcohol’s dangers, Farkouh emphasized the need for a judgment-free and patient-centered approach to conversations around drinking: “People have grown up with alcohol being acceptable, and it’s going to take time to change that.”

A version of this article first appeared on Medscape.com.

For millennia in medicine, alcohol, particularly red wine, carried a health halo; in small doses, it has historically been thought to have cardioprotective benefits. Michael Farkouh, MD, a professor of cardiology at Cedars-Sinai, estimates half the physicians still accept people having a drink or two a day. “That is still in practice, though the numbers are reducing,” he said.

But Farkouh no longer drinks alcohol, a position he has come to after getting more involved in research into the substance and his realization that many of the studies touting alcohol’s health benefits were flawed.

Today, alcohol sits alongside asbestos and tobacco as class 1 carcinogens. According to the World Health Organization, it has no known safe ingestible amount. In 2018, a blockbuster report in The Lancet found no amount of any kind of alcohol improves health. In early January, US Surgeon General Vivek Murthy called for adding cancer warnings to alcohol labels.

But the way doctors drink is far from black and white. For physicians, drinking habits are tied up in personal values, professional understanding of a substance with a confusing research history, and the fact alcohol is deeply ingrained in the social fabric of society — and in medicine. As thinking on alcohol shifts, this news organization spoke with physicians about their own drinking habits, how they counsel patients on it, and alcohol’s place in a field that works to keep people healthy.

 

Cultural Currency

From the days of Hippocrates, who believed alcohol could cure virtually every ailment, alcohol has held a large role in medicine. Through much of the 19th century, patent remedies like Hamlin’s Wizard Oil and the Seven Sutherland Sisters Hair Grower, contained alcohol — sometimes in concentrations exceeding 50%.

The first American Pharmacopoeia, published in 1820, even contained nine wine-based medicines. Throughout the second half of the 19th century, physicians largely debated alcohol’s role in medicine. However, a 1922 poll of members of the American Medical Association found that physicians were still using alcohol as a medicine for everything from heart attacks to animal bites.

Today, alcohol’s presence in medicine is, in some ways, representative of a realized cognitive dissonance.

“In my mind, alcohol has completely lost any illusion of benefit. It is a poison to almost every single organ in our body. Yet I’m currently engaged in a duel of being a physician who drinks in moderation and constantly judging myself for it,” said Tyra Fainstad, MD, an internist and an associate professor at CU Medicine in Denver.

Fainstad said every academic national conference she has attended has had a reception with multiple cash bars — and professional recruitment dinners regularly include at least the offering of alcohol. Private hospitals often have open bars at events.

“Drinking has historically been a way that people unwind, even in medicine,” said addiction psychiatrist Alexis Ritvo, MD. Ritvo — who said she drinks occasionally but much less than she used to after paying attention to how alcohol makes her feel and the harm alcohol can cause — noted that some occasions where alcohol is present socially in medicine don’t bother her. Alcohol is even an option at the addiction psychiatry conference, where attendees can exchange tickets for drinks. But last year, the event provided separate bars for alcoholic and nonalcoholic drinks.

“Our life is full of things that are contradictory or at odds,” Ritvo said. “We want things to either be wrong or right, appropriate or inappropriate, but just like all things, everything’s pretty nuanced.”

But there are examples of alcohol being a part of an event that are downright inappropriate, such as when she attended a fundraiser for a recovery facility that had an open bar.

Farkouh said alcohol at events can exclude others. (He recommends that instead of calling a social gathering “going out for drinks,” someone might say, “We’re getting together.”) He drinks mocktails or nonalcoholic beer at work events where alcohol is served.

Brian Dwinnell, MD, associate dean of student life at CU Medicine, said alcohol can quickly become the focus of an event — something he noticed at an annual kickball game between first- and second-year students that has historically served beer.

In recent years, school leadership has removed alcohol from his institution’s match day celebration and the kickball game. “Initially, there was some pushback from students,” he said of making these events dry, “but now, it’s just sort of accepted, and the events have been just as great as they were when we did provide alcohol.”

 

How Doctors Drink

Physicians may have a greater understanding of alcohol’s health harms. Still, they don’t necessarily drink less because of it, and whether they should becomes a question not just of health but also of the standards to which society holds medical professionals.

Data suggest physicians tend to drink at rates similar to those among the general population. A recent Medscape Medical News survey found nearly 60% of physicians have started drinking less.

Dwinnell said he is a long-time “wine connoisseur” and drinks on occasion. But he admitted that while he thinks about the health implications of alcohol more — and he has nixed it from various events for medical students — he does not believe his drinking habits have changed much.

Navya Mysore, MD, a family physician in New York City, said she has become interested in wine over the past few years, even taking classes to learn more about it. “I like understanding how it’s made, the regions it’s from, and how to pair it with food,” she said. Mysore admits she drank a little more than usual throughout the pandemic, yet today, she said her relationship with alcohol in moderation is related to family, community, and connection.

Fainstad, who drinks socially, said: “I think there’s an immeasurable quality to the social ritual of it. I think for better or worse — probably for worse — for many generations, alcohol has been a part of many meaningful traditions and rituals that we hold.”

Farkouh was quick to underscore the importance of social connection, and that alcohol reduces stress for some people. “I don’t want to take that away from people,” he said. But he also stated the importance of finding other ways to find social fulfillment and enjoyment — and said it’s essential for societal norms to shift to reflect this.

With emerging data, alcohol’s image in society is shifting. Ireland recently became the first country to pass regulation requiring all alcohol sold there to come with a cancer warning. All the clinicians interviewed for this article spoke about the increased acceptability of choosing not to drink for whatever reason.

In the context of alcohol, Dwinnell often asks his students, “What if you were out at a restaurant and you saw your mother’s surgeon there and they were intoxicated? Are you going to feel comfortable with that individual operating on your mother tomorrow or any time?” He added: “Physicians are held to a higher professional standard than those in other fields — and they should be. This is a high-stakes business.”

Dwinnell’s hypothetical question to students is a good one, albeit perhaps not always a fair one. “It’s important for people to realize that physicians are humans,” Mysore said. “We are people, we have lives, and we may choose to have habits that are not necessarily the healthiest for us.”

Fainstad said there’s no shame in medical professionals drinking on occasion. “You can’t be held accountable for something you don’t know about,” she said, acknowledging the known harms of alcohol and that there is still more to learn. But she does wonder how doctors who drank might be perceived in years to come. “I can imagine in a couple of decades, people could say, ‘Even doctors used to have a glass of wine with dinner.’”

 

‘Physicians Should Tighten Their Stances on Alcohol’

The 2020-2025 Dietary Guidelines suggest limiting intake to two alcoholic drinks or less daily for men and one drink or less for women or to choose not to drink. Farkouh said he skews toward the latter, encouraging patients to drink as little as possible or nothing at all. “If you take a holistic approach, physicians should tighten their stances on alcohol,” he said.

Ultimately, he said a randomized trial is warranted to address the risk for cardiovascular disease, in particular.

Of course, physicians vary in how they discuss the topic with patients.

Mysore said she regularly educates patients about pour size and ways to swap out alcoholic drinks with nonalcoholic ones. Outside of cases of addiction, she favors the idea of moderation. “I don’t really subscribe to all-or-nothing mindsets. If there’s something that you enjoy having as a part of your life, I don’t think there’s any reason why you need to eliminate it,” she said. “You just need to figure out what moderation looks like for you.”

Ritvo favors motivational interviewing and tries to understand someone’s relationship with alcohol.

Fainstad provides the Dietary Guidelines’ cutoffs to patients and educates them on the poisonous nature of the substance.

Clearer guidance from large governing bodies — potential changes around alcohol in the 2025-230 revision of the US Dietary Guidelines or cancer warnings on booze sold in the United States — are coming and could help streamline messaging.

And although he speaks with urgency about alcohol’s dangers, Farkouh emphasized the need for a judgment-free and patient-centered approach to conversations around drinking: “People have grown up with alcohol being acceptable, and it’s going to take time to change that.”

A version of this article first appeared on Medscape.com.

For millennia in medicine, alcohol, particularly red wine, carried a health halo; in small doses, it has historically been thought to have cardioprotective benefits. Michael Farkouh, MD, a professor of cardiology at Cedars-Sinai, estimates half the physicians still accept people having a drink or two a day. “That is still in practice, though the numbers are reducing,” he said.

But Farkouh no longer drinks alcohol, a position he has come to after getting more involved in research into the substance and his realization that many of the studies touting alcohol’s health benefits were flawed.

Today, alcohol sits alongside asbestos and tobacco as class 1 carcinogens. According to the World Health Organization, it has no known safe ingestible amount. In 2018, a blockbuster report in The Lancet found no amount of any kind of alcohol improves health. In early January, US Surgeon General Vivek Murthy called for adding cancer warnings to alcohol labels.

But the way doctors drink is far from black and white. For physicians, drinking habits are tied up in personal values, professional understanding of a substance with a confusing research history, and the fact alcohol is deeply ingrained in the social fabric of society — and in medicine. As thinking on alcohol shifts, this news organization spoke with physicians about their own drinking habits, how they counsel patients on it, and alcohol’s place in a field that works to keep people healthy.

 

Cultural Currency

From the days of Hippocrates, who believed alcohol could cure virtually every ailment, alcohol has held a large role in medicine. Through much of the 19th century, patent remedies like Hamlin’s Wizard Oil and the Seven Sutherland Sisters Hair Grower, contained alcohol — sometimes in concentrations exceeding 50%.

The first American Pharmacopoeia, published in 1820, even contained nine wine-based medicines. Throughout the second half of the 19th century, physicians largely debated alcohol’s role in medicine. However, a 1922 poll of members of the American Medical Association found that physicians were still using alcohol as a medicine for everything from heart attacks to animal bites.

Today, alcohol’s presence in medicine is, in some ways, representative of a realized cognitive dissonance.

“In my mind, alcohol has completely lost any illusion of benefit. It is a poison to almost every single organ in our body. Yet I’m currently engaged in a duel of being a physician who drinks in moderation and constantly judging myself for it,” said Tyra Fainstad, MD, an internist and an associate professor at CU Medicine in Denver.

Fainstad said every academic national conference she has attended has had a reception with multiple cash bars — and professional recruitment dinners regularly include at least the offering of alcohol. Private hospitals often have open bars at events.

“Drinking has historically been a way that people unwind, even in medicine,” said addiction psychiatrist Alexis Ritvo, MD. Ritvo — who said she drinks occasionally but much less than she used to after paying attention to how alcohol makes her feel and the harm alcohol can cause — noted that some occasions where alcohol is present socially in medicine don’t bother her. Alcohol is even an option at the addiction psychiatry conference, where attendees can exchange tickets for drinks. But last year, the event provided separate bars for alcoholic and nonalcoholic drinks.

“Our life is full of things that are contradictory or at odds,” Ritvo said. “We want things to either be wrong or right, appropriate or inappropriate, but just like all things, everything’s pretty nuanced.”

But there are examples of alcohol being a part of an event that are downright inappropriate, such as when she attended a fundraiser for a recovery facility that had an open bar.

Farkouh said alcohol at events can exclude others. (He recommends that instead of calling a social gathering “going out for drinks,” someone might say, “We’re getting together.”) He drinks mocktails or nonalcoholic beer at work events where alcohol is served.

Brian Dwinnell, MD, associate dean of student life at CU Medicine, said alcohol can quickly become the focus of an event — something he noticed at an annual kickball game between first- and second-year students that has historically served beer.

In recent years, school leadership has removed alcohol from his institution’s match day celebration and the kickball game. “Initially, there was some pushback from students,” he said of making these events dry, “but now, it’s just sort of accepted, and the events have been just as great as they were when we did provide alcohol.”

 

How Doctors Drink

Physicians may have a greater understanding of alcohol’s health harms. Still, they don’t necessarily drink less because of it, and whether they should becomes a question not just of health but also of the standards to which society holds medical professionals.

Data suggest physicians tend to drink at rates similar to those among the general population. A recent Medscape Medical News survey found nearly 60% of physicians have started drinking less.

Dwinnell said he is a long-time “wine connoisseur” and drinks on occasion. But he admitted that while he thinks about the health implications of alcohol more — and he has nixed it from various events for medical students — he does not believe his drinking habits have changed much.

Navya Mysore, MD, a family physician in New York City, said she has become interested in wine over the past few years, even taking classes to learn more about it. “I like understanding how it’s made, the regions it’s from, and how to pair it with food,” she said. Mysore admits she drank a little more than usual throughout the pandemic, yet today, she said her relationship with alcohol in moderation is related to family, community, and connection.

Fainstad, who drinks socially, said: “I think there’s an immeasurable quality to the social ritual of it. I think for better or worse — probably for worse — for many generations, alcohol has been a part of many meaningful traditions and rituals that we hold.”

Farkouh was quick to underscore the importance of social connection, and that alcohol reduces stress for some people. “I don’t want to take that away from people,” he said. But he also stated the importance of finding other ways to find social fulfillment and enjoyment — and said it’s essential for societal norms to shift to reflect this.

With emerging data, alcohol’s image in society is shifting. Ireland recently became the first country to pass regulation requiring all alcohol sold there to come with a cancer warning. All the clinicians interviewed for this article spoke about the increased acceptability of choosing not to drink for whatever reason.

In the context of alcohol, Dwinnell often asks his students, “What if you were out at a restaurant and you saw your mother’s surgeon there and they were intoxicated? Are you going to feel comfortable with that individual operating on your mother tomorrow or any time?” He added: “Physicians are held to a higher professional standard than those in other fields — and they should be. This is a high-stakes business.”

Dwinnell’s hypothetical question to students is a good one, albeit perhaps not always a fair one. “It’s important for people to realize that physicians are humans,” Mysore said. “We are people, we have lives, and we may choose to have habits that are not necessarily the healthiest for us.”

Fainstad said there’s no shame in medical professionals drinking on occasion. “You can’t be held accountable for something you don’t know about,” she said, acknowledging the known harms of alcohol and that there is still more to learn. But she does wonder how doctors who drank might be perceived in years to come. “I can imagine in a couple of decades, people could say, ‘Even doctors used to have a glass of wine with dinner.’”

 

‘Physicians Should Tighten Their Stances on Alcohol’

The 2020-2025 Dietary Guidelines suggest limiting intake to two alcoholic drinks or less daily for men and one drink or less for women or to choose not to drink. Farkouh said he skews toward the latter, encouraging patients to drink as little as possible or nothing at all. “If you take a holistic approach, physicians should tighten their stances on alcohol,” he said.

Ultimately, he said a randomized trial is warranted to address the risk for cardiovascular disease, in particular.

Of course, physicians vary in how they discuss the topic with patients.

Mysore said she regularly educates patients about pour size and ways to swap out alcoholic drinks with nonalcoholic ones. Outside of cases of addiction, she favors the idea of moderation. “I don’t really subscribe to all-or-nothing mindsets. If there’s something that you enjoy having as a part of your life, I don’t think there’s any reason why you need to eliminate it,” she said. “You just need to figure out what moderation looks like for you.”

Ritvo favors motivational interviewing and tries to understand someone’s relationship with alcohol.

Fainstad provides the Dietary Guidelines’ cutoffs to patients and educates them on the poisonous nature of the substance.

Clearer guidance from large governing bodies — potential changes around alcohol in the 2025-230 revision of the US Dietary Guidelines or cancer warnings on booze sold in the United States — are coming and could help streamline messaging.

And although he speaks with urgency about alcohol’s dangers, Farkouh emphasized the need for a judgment-free and patient-centered approach to conversations around drinking: “People have grown up with alcohol being acceptable, and it’s going to take time to change that.”

A version of this article first appeared on Medscape.com.

Could an artificial intelligence (AI)–driven tool that mines medical records for suspected cases of osteoporosis be so successful that it becomes a potential liability? Yes, according to Christopher White, PhD, executive director of Maridulu Budyari Gumal, the Sydney Partnership for Health, Education, Research, and Enterprise, a research translation center in Liverpool, Australia.

In a thought-provoking presentation at the Endocrine Society’s AI in Healthcare Virtual Summit, White described the results after his fracture liaison team at Prince of Wales Hospital in Randwick, Australia, tried to plug the “osteoporosis treatment gap” by mining medical records to identify patients with the disorder.

 

‘Be Careful What You Wish For’

White and colleagues developed a robust standalone database over 20 years that informed fracture risk among patients with osteoporosis in Sydney. The database included all relevant clinical information, as well as bone density measurements, on about 30,000 patients and could be interrogated for randomized controlled trial recruitment.

However, a “crisis” occurred around 2011, when the team received a recruitment request for the first head-to-head comparison of alendronate with romosozumab. “We had numerous postmenopausal women in the age range with the required bone density, but we hadn’t captured the severity of their vertebral fracture or how many they actually had,” White told the this news organization. For recruitment into the study, participants must have had at least two moderate or severe vertebral fractures or a proximal vertebral fracture that was sustained between 3 and 24 months before recruitment.

White turned to his hospital’s mainframe, which had coding data and time intervals for patients who were admitted with vertebral or hip fractures. He calculated how many patients who met the study criteria had been discharged and how many of those he thought he’d be able to capture through the mainframe. He was confident he would have enough, but he was wrong. He underrecruited and could not participate in the trial.

Determined not to wind up in a similar situation in the future, he investigated and found that other centers were struggling with similar problems. This led to a collaboration with four investigators who were using AI and Advanced Encryption Standard (AES) coding to identify patients at risk for osteoporotic fractures. White, meanwhile, had developed a natural language processing tool called XRAIT that also identified patients at fracture risk. A study comparing the two electronic search programs, which screen medical records for fractures, found that both reliably identified patients who had had a fracture. White and his colleagues concluded that hybrid tools combining XRAIT and AES would likely improve the identification of patients with osteoporosis who would require follow-up or might participate in future trials.

Those patients were not being identified sooner for multiple reasons, White explained. Sometimes, the radiologist would report osteoporosis, but it wouldn’t get coded. Or, in the emergency department, a patient with a fracture would be treated and then sent home, and the possibility of osteoporosis wasn’t reported.

“As we went deeper and deeper with our tools into the medical record, we found more and more patients who hadn’t been coded or reported but who actually had osteoporosis,” White said. “It was incredibly prevalent.”

But the number of patients identified was more than the hospital could comfortably handle.

Ironically, he added, “To my relief and probably not to the benefit of the patients, there was a system upgrade of the radiology reporting system, which was incompatible with the natural language processing technology that I had installed. The AI was turned off at that point, but I had a look over the edge and into the mine pit.”

“The lesson learned,” White told this news organization, is “If you mine the medical record for unidentified patients before you know what to do with the output, you create a medico-legal minefield. You need to be careful what you wish for with technology, because it may actually come true.”

 

Grappling With the Treatment Gap

An (over)abundance of patients is likely contributing to the “osteoporosis treatment gap” that Australia’s fracture liaison services, which handle many of these patients, are grappling with. One recent meta-analysis showed that not all eligible patients are treated and that not all patients who are treated actually start treatment. Another study showed that only a minority of patients — anywhere between 20% and 40% — who start are still persisting at about 3 years, White said.

Various types of fracture liaison services exist, he noted. The model that has been shown to best promote adherence is the one requiring clinicians to “identify, educate [usually, the primary care physician], evaluate, start treatment, continue treatment, and follow-up at 12 months for to confirm that there is adherence.”

What’s happening now, he said, is that the technology is identifying a high number of vertebral crush fractures, and there’s no education or evaluation. “The radiologist just refers the patient to a primary care physician and hopes for the best. AI isn’t contributing to solving the treatment gap problem; it’s amplifying it. It’s ahead of the ability of organizations to accommodate the findings.”

Solutions, he said, would require support at the top of health systems and organizations, and funding to proceed; data surveys concentrating on vertical integration of the medical record to follow patients wherever they are — eg, hospital, primary care — in their health journeys; a workflow with synchronous diagnosis and treatment planning, delivery, monitoring, and payment; and clinical and community champions advocating and “leading the charge in health tech.”

Furthermore, he advised, organizations need to be “very, very careful with safety and security — that is, managing the digital risks.”

“Oscar Wilde said there are two tragedies in life: One is not getting what one wants, and the other is getting it,” White concluded. “In my career, we’ve moved on from not knowing how to treat osteoporosis to knowing how to treat it. And that is both an asset and a liability.”

A version of this article first appeared on Medscape.com.

Could an artificial intelligence (AI)–driven tool that mines medical records for suspected cases of osteoporosis be so successful that it becomes a potential liability? Yes, according to Christopher White, PhD, executive director of Maridulu Budyari Gumal, the Sydney Partnership for Health, Education, Research, and Enterprise, a research translation center in Liverpool, Australia.

In a thought-provoking presentation at the Endocrine Society’s AI in Healthcare Virtual Summit, White described the results after his fracture liaison team at Prince of Wales Hospital in Randwick, Australia, tried to plug the “osteoporosis treatment gap” by mining medical records to identify patients with the disorder.

 

‘Be Careful What You Wish For’

White and colleagues developed a robust standalone database over 20 years that informed fracture risk among patients with osteoporosis in Sydney. The database included all relevant clinical information, as well as bone density measurements, on about 30,000 patients and could be interrogated for randomized controlled trial recruitment.

However, a “crisis” occurred around 2011, when the team received a recruitment request for the first head-to-head comparison of alendronate with romosozumab. “We had numerous postmenopausal women in the age range with the required bone density, but we hadn’t captured the severity of their vertebral fracture or how many they actually had,” White told the this news organization. For recruitment into the study, participants must have had at least two moderate or severe vertebral fractures or a proximal vertebral fracture that was sustained between 3 and 24 months before recruitment.

White turned to his hospital’s mainframe, which had coding data and time intervals for patients who were admitted with vertebral or hip fractures. He calculated how many patients who met the study criteria had been discharged and how many of those he thought he’d be able to capture through the mainframe. He was confident he would have enough, but he was wrong. He underrecruited and could not participate in the trial.

Determined not to wind up in a similar situation in the future, he investigated and found that other centers were struggling with similar problems. This led to a collaboration with four investigators who were using AI and Advanced Encryption Standard (AES) coding to identify patients at risk for osteoporotic fractures. White, meanwhile, had developed a natural language processing tool called XRAIT that also identified patients at fracture risk. A study comparing the two electronic search programs, which screen medical records for fractures, found that both reliably identified patients who had had a fracture. White and his colleagues concluded that hybrid tools combining XRAIT and AES would likely improve the identification of patients with osteoporosis who would require follow-up or might participate in future trials.

Those patients were not being identified sooner for multiple reasons, White explained. Sometimes, the radiologist would report osteoporosis, but it wouldn’t get coded. Or, in the emergency department, a patient with a fracture would be treated and then sent home, and the possibility of osteoporosis wasn’t reported.

“As we went deeper and deeper with our tools into the medical record, we found more and more patients who hadn’t been coded or reported but who actually had osteoporosis,” White said. “It was incredibly prevalent.”

But the number of patients identified was more than the hospital could comfortably handle.

Ironically, he added, “To my relief and probably not to the benefit of the patients, there was a system upgrade of the radiology reporting system, which was incompatible with the natural language processing technology that I had installed. The AI was turned off at that point, but I had a look over the edge and into the mine pit.”

“The lesson learned,” White told this news organization, is “If you mine the medical record for unidentified patients before you know what to do with the output, you create a medico-legal minefield. You need to be careful what you wish for with technology, because it may actually come true.”

 

Grappling With the Treatment Gap

An (over)abundance of patients is likely contributing to the “osteoporosis treatment gap” that Australia’s fracture liaison services, which handle many of these patients, are grappling with. One recent meta-analysis showed that not all eligible patients are treated and that not all patients who are treated actually start treatment. Another study showed that only a minority of patients — anywhere between 20% and 40% — who start are still persisting at about 3 years, White said.

Various types of fracture liaison services exist, he noted. The model that has been shown to best promote adherence is the one requiring clinicians to “identify, educate [usually, the primary care physician], evaluate, start treatment, continue treatment, and follow-up at 12 months for to confirm that there is adherence.”

What’s happening now, he said, is that the technology is identifying a high number of vertebral crush fractures, and there’s no education or evaluation. “The radiologist just refers the patient to a primary care physician and hopes for the best. AI isn’t contributing to solving the treatment gap problem; it’s amplifying it. It’s ahead of the ability of organizations to accommodate the findings.”

Solutions, he said, would require support at the top of health systems and organizations, and funding to proceed; data surveys concentrating on vertical integration of the medical record to follow patients wherever they are — eg, hospital, primary care — in their health journeys; a workflow with synchronous diagnosis and treatment planning, delivery, monitoring, and payment; and clinical and community champions advocating and “leading the charge in health tech.”

Furthermore, he advised, organizations need to be “very, very careful with safety and security — that is, managing the digital risks.”

“Oscar Wilde said there are two tragedies in life: One is not getting what one wants, and the other is getting it,” White concluded. “In my career, we’ve moved on from not knowing how to treat osteoporosis to knowing how to treat it. And that is both an asset and a liability.”

A version of this article first appeared on Medscape.com.

Could an artificial intelligence (AI)–driven tool that mines medical records for suspected cases of osteoporosis be so successful that it becomes a potential liability? Yes, according to Christopher White, PhD, executive director of Maridulu Budyari Gumal, the Sydney Partnership for Health, Education, Research, and Enterprise, a research translation center in Liverpool, Australia.

In a thought-provoking presentation at the Endocrine Society’s AI in Healthcare Virtual Summit, White described the results after his fracture liaison team at Prince of Wales Hospital in Randwick, Australia, tried to plug the “osteoporosis treatment gap” by mining medical records to identify patients with the disorder.

 

‘Be Careful What You Wish For’

White and colleagues developed a robust standalone database over 20 years that informed fracture risk among patients with osteoporosis in Sydney. The database included all relevant clinical information, as well as bone density measurements, on about 30,000 patients and could be interrogated for randomized controlled trial recruitment.

However, a “crisis” occurred around 2011, when the team received a recruitment request for the first head-to-head comparison of alendronate with romosozumab. “We had numerous postmenopausal women in the age range with the required bone density, but we hadn’t captured the severity of their vertebral fracture or how many they actually had,” White told the this news organization. For recruitment into the study, participants must have had at least two moderate or severe vertebral fractures or a proximal vertebral fracture that was sustained between 3 and 24 months before recruitment.

White turned to his hospital’s mainframe, which had coding data and time intervals for patients who were admitted with vertebral or hip fractures. He calculated how many patients who met the study criteria had been discharged and how many of those he thought he’d be able to capture through the mainframe. He was confident he would have enough, but he was wrong. He underrecruited and could not participate in the trial.

Determined not to wind up in a similar situation in the future, he investigated and found that other centers were struggling with similar problems. This led to a collaboration with four investigators who were using AI and Advanced Encryption Standard (AES) coding to identify patients at risk for osteoporotic fractures. White, meanwhile, had developed a natural language processing tool called XRAIT that also identified patients at fracture risk. A study comparing the two electronic search programs, which screen medical records for fractures, found that both reliably identified patients who had had a fracture. White and his colleagues concluded that hybrid tools combining XRAIT and AES would likely improve the identification of patients with osteoporosis who would require follow-up or might participate in future trials.

Those patients were not being identified sooner for multiple reasons, White explained. Sometimes, the radiologist would report osteoporosis, but it wouldn’t get coded. Or, in the emergency department, a patient with a fracture would be treated and then sent home, and the possibility of osteoporosis wasn’t reported.

“As we went deeper and deeper with our tools into the medical record, we found more and more patients who hadn’t been coded or reported but who actually had osteoporosis,” White said. “It was incredibly prevalent.”

But the number of patients identified was more than the hospital could comfortably handle.

Ironically, he added, “To my relief and probably not to the benefit of the patients, there was a system upgrade of the radiology reporting system, which was incompatible with the natural language processing technology that I had installed. The AI was turned off at that point, but I had a look over the edge and into the mine pit.”

“The lesson learned,” White told this news organization, is “If you mine the medical record for unidentified patients before you know what to do with the output, you create a medico-legal minefield. You need to be careful what you wish for with technology, because it may actually come true.”

 

Grappling With the Treatment Gap

An (over)abundance of patients is likely contributing to the “osteoporosis treatment gap” that Australia’s fracture liaison services, which handle many of these patients, are grappling with. One recent meta-analysis showed that not all eligible patients are treated and that not all patients who are treated actually start treatment. Another study showed that only a minority of patients — anywhere between 20% and 40% — who start are still persisting at about 3 years, White said.

Various types of fracture liaison services exist, he noted. The model that has been shown to best promote adherence is the one requiring clinicians to “identify, educate [usually, the primary care physician], evaluate, start treatment, continue treatment, and follow-up at 12 months for to confirm that there is adherence.”

What’s happening now, he said, is that the technology is identifying a high number of vertebral crush fractures, and there’s no education or evaluation. “The radiologist just refers the patient to a primary care physician and hopes for the best. AI isn’t contributing to solving the treatment gap problem; it’s amplifying it. It’s ahead of the ability of organizations to accommodate the findings.”

Solutions, he said, would require support at the top of health systems and organizations, and funding to proceed; data surveys concentrating on vertical integration of the medical record to follow patients wherever they are — eg, hospital, primary care — in their health journeys; a workflow with synchronous diagnosis and treatment planning, delivery, monitoring, and payment; and clinical and community champions advocating and “leading the charge in health tech.”

Furthermore, he advised, organizations need to be “very, very careful with safety and security — that is, managing the digital risks.”

“Oscar Wilde said there are two tragedies in life: One is not getting what one wants, and the other is getting it,” White concluded. “In my career, we’ve moved on from not knowing how to treat osteoporosis to knowing how to treat it. And that is both an asset and a liability.”

A version of this article first appeared on Medscape.com.

The woman, in severe pain from hip and knee osteoarthritis, was confined to a wheelchair and had been told that would likely be for life. To qualify for hip replacement surgery, she needed to lose 100 pounds, a seemingly impossible goal. But she wanted to try.

“We tried a couple of medicines — oral medicines off-label — topiramate, phentermine,” said Leslie Golden, MD, MPH, DABM, a family medicine physician and obesity medicine specialist in Watertown, Wisconsin, 42 miles northeast of Madison.

They weren’t enough. But then Golden turned to glucagon-like peptide 1 (GLP-1) receptor agonists, and they delivered.

“She did lose a significant amount of weight and was able to get the hip replacement,” said Golden.

It took a couple of years. However, seeing her walk into her office, rather than wheel in, “is still one of the joys of my practice,” Golden said. “She’s so grateful. She felt everyone else had written her off.”

As she told Golden: “If I fell and broke my leg today, they would take me to surgery without concern.”

Because her hip replacement was viewed as a nonemergency procedure, the accepted threshold for elective safe surgery was a body mass index (BMI) < 40. That BMI cutoff can vary from provider to provider and medical facility to medical facility but is often required for other surgeries as well, including kidney and lung transplants, gender-affirming surgery, bariatric surgery, hernia surgery, and in vitro fertilization procedures.

Golden is at the forefront of a growing trend — obesity medicine physicians collaborating with surgeons to prescribe the more effective GLP-1s and get surgery candidates to the starting line. She worked with Rajit Chakravarty, MD, an adult reconstructive surgeon who practices in Watertown and nearby Madison, to oversee the weight loss.

 

High BMIs & Surgery Issues

High BMIs have long been linked with postsurgery complications, poor wound healing, and other issues, although some research now is questioning some of those associations. Even so, surgeons have long stressed weight loss for their patients with obesity before orthopedic and other procedures.

These days, surgeons are more likely to need to have that talk. In the last decade, the age-adjusted prevalence of severe obesity — a BMI of ≥ 40 — has increased from 7.7% to 9.7% of US adults. The number of joint replacements is also rising — more than 700,000 total knee arthroplasty (TKA) and more than 450,000 total hip arthroplasty (THA), according to the American Academy of Orthopaedic Surgeons. As the population ages, those numbers are expected to increase.

 

Making the GLP-1 Choice

GLP-1s aren’t the only choice, of course. But they’re often more effective, as Golden found, than other medications. And when his patients with obesity are offered bariatric surgery or GLP-1s, “people definitely want to avoid the bariatric surgery,” Chakravarty said.

With the Food and Drug Administration (FDA) approval of semaglutide (Wegovy) in June 2021 for chronic weight management and then tirzepatide (Zepbound) in November 2023, interest has boomed, he said, among his surgery candidates with a high BMI.

The FDA approved Wegovy based on clinical trials, including one in which participants lost an average of 12.4% of initial body weight compared with those on placebo. It approved Zepbound based on clinical trials, including one in which those on Zepbound lost an average of 18% of their body weight, compared with those on placebo.

The wheelchair-bound woman, now 65, began with a BMI of 63, Golden said. She negotiated a cutoff of 45 with the surgeon and got the go-ahead. Currently, her BMI is 36 as she stayed on the medications.

Beyond the benefit of GLP-1s helping patients meet the BMI cutoff, some research finds fewer postoperative infections and readmissions with their use. This study found the medications did lower both, and another found reduced readmissions and complications.

 

Growing Partnerships, Increasing Success

Helping patients lose weight isn’t just about lowering the BMI, Chakravarty pointed out. The aim is to improve nutritional health — to teach patients how to eat healthfully for their needs, in turn improving other health barometers. Referring them to an obesity medicine physician helps to meet those goals.

When Daniel Wiznia, MD, a Yale Medicine orthopedic surgeon and codirector of the Avascular Necrosis Program, has a patient who must delay a TKA or THA until they meet a BMI cutoff, he refers that patient to the Yale Medicine Center for Weight Management, New Haven, Connecticut, to learn about weight loss, including the options of anti-obesity medications or bariatric surgery.

Taking the GLP-1s can be a game changer, according to Wiznia and John Morton, MD, MPH, FACS, FASMBS, Yale’s medical director of Bariatric Surgery and professor and vice chair of surgery, who is a physician-director of the center. The program includes other options, such as bariatric surgery, and emphasizes diet and other lifestyle measures. GLP-1s give about a 15% weight loss, Morton said, compared with bariatric surgery providing up to 30%.

Sarah Stombaugh, MD, a family medicine and obesity medicine physician in Charlottesville, Virginia, often gets referrals from two orthopedic surgeons in her community. One recent patient in her early 60s had a BMI of 43.2, too high to qualify for the TKA she needed. On GLP-1s, the initial goal was to decrease a weight of 244 to 225, bringing the BMI to 39.9. The woman did that, then kept losing before her surgery was scheduled, getting to a weight of 210 or a BMI of 37 and staying there for 3 months before the surgery.

She had the TKA, and 5 months out, she is doing well, Stombaugh said. “We do medical weight loss primarily with the GLP-1s because they’re simply the best, the most effective,” Stombaugh said. She does occasionally use oral medications such as naltrexone/bupropion (Contrave).

Stombaugh sees the collaborating trend as still evolving. When she attends obesity medicine conferences, not all her colleagues report they are partnering with surgeons. But she predicts the practice will increase, saying the popularization of what she terms the more effective GLP-1 medications Wegovy and Zepbound is driving it. Partnering with the surgeon requires a conversation at the beginning, when the referral is made, about goals. After that, she sees her patient monthly and sends progress notes to the surgeon.

Golden collaborates with three orthopedic groups in her area, primarily for knee and hip surgeries, but has also helped patients meet the BMI cutoff before spine-related surgeries. She is helping a lung transplant patient now. She has seen several patients who must meet BMI requirements before starting in vitro fertilization, due to the need for conscious sedation for egg retrieval. She has had a few patients who had to meet a BMI cutoff for nonemergency hernia repair.

 

Insurance Issues

Insurance remains an issue for the pricey medications. “Only about a third of patients are routinely covered with insurance,” Morton said.

However, it’s improving, he said. Golden also finds about a third of private payers cover the medication but tries to use manufacturers’ coupons to help defray the costs (from about $1000 or $1400 to about $500 a month). She has sometimes gotten enough samples to get patients to their BMI goal

Morton consulted for Novo Nordisk, Eli Lilly, Olympus, Teleflex, and Johnson & Johnson.

A version of this article appeared on Medscape.com.

The woman, in severe pain from hip and knee osteoarthritis, was confined to a wheelchair and had been told that would likely be for life. To qualify for hip replacement surgery, she needed to lose 100 pounds, a seemingly impossible goal. But she wanted to try.

“We tried a couple of medicines — oral medicines off-label — topiramate, phentermine,” said Leslie Golden, MD, MPH, DABM, a family medicine physician and obesity medicine specialist in Watertown, Wisconsin, 42 miles northeast of Madison.

They weren’t enough. But then Golden turned to glucagon-like peptide 1 (GLP-1) receptor agonists, and they delivered.

“She did lose a significant amount of weight and was able to get the hip replacement,” said Golden.

It took a couple of years. However, seeing her walk into her office, rather than wheel in, “is still one of the joys of my practice,” Golden said. “She’s so grateful. She felt everyone else had written her off.”

As she told Golden: “If I fell and broke my leg today, they would take me to surgery without concern.”

Because her hip replacement was viewed as a nonemergency procedure, the accepted threshold for elective safe surgery was a body mass index (BMI) < 40. That BMI cutoff can vary from provider to provider and medical facility to medical facility but is often required for other surgeries as well, including kidney and lung transplants, gender-affirming surgery, bariatric surgery, hernia surgery, and in vitro fertilization procedures.

Golden is at the forefront of a growing trend — obesity medicine physicians collaborating with surgeons to prescribe the more effective GLP-1s and get surgery candidates to the starting line. She worked with Rajit Chakravarty, MD, an adult reconstructive surgeon who practices in Watertown and nearby Madison, to oversee the weight loss.

 

High BMIs & Surgery Issues

High BMIs have long been linked with postsurgery complications, poor wound healing, and other issues, although some research now is questioning some of those associations. Even so, surgeons have long stressed weight loss for their patients with obesity before orthopedic and other procedures.

These days, surgeons are more likely to need to have that talk. In the last decade, the age-adjusted prevalence of severe obesity — a BMI of ≥ 40 — has increased from 7.7% to 9.7% of US adults. The number of joint replacements is also rising — more than 700,000 total knee arthroplasty (TKA) and more than 450,000 total hip arthroplasty (THA), according to the American Academy of Orthopaedic Surgeons. As the population ages, those numbers are expected to increase.

 

Making the GLP-1 Choice

GLP-1s aren’t the only choice, of course. But they’re often more effective, as Golden found, than other medications. And when his patients with obesity are offered bariatric surgery or GLP-1s, “people definitely want to avoid the bariatric surgery,” Chakravarty said.

With the Food and Drug Administration (FDA) approval of semaglutide (Wegovy) in June 2021 for chronic weight management and then tirzepatide (Zepbound) in November 2023, interest has boomed, he said, among his surgery candidates with a high BMI.

The FDA approved Wegovy based on clinical trials, including one in which participants lost an average of 12.4% of initial body weight compared with those on placebo. It approved Zepbound based on clinical trials, including one in which those on Zepbound lost an average of 18% of their body weight, compared with those on placebo.

The wheelchair-bound woman, now 65, began with a BMI of 63, Golden said. She negotiated a cutoff of 45 with the surgeon and got the go-ahead. Currently, her BMI is 36 as she stayed on the medications.

Beyond the benefit of GLP-1s helping patients meet the BMI cutoff, some research finds fewer postoperative infections and readmissions with their use. This study found the medications did lower both, and another found reduced readmissions and complications.

 

Growing Partnerships, Increasing Success

Helping patients lose weight isn’t just about lowering the BMI, Chakravarty pointed out. The aim is to improve nutritional health — to teach patients how to eat healthfully for their needs, in turn improving other health barometers. Referring them to an obesity medicine physician helps to meet those goals.

When Daniel Wiznia, MD, a Yale Medicine orthopedic surgeon and codirector of the Avascular Necrosis Program, has a patient who must delay a TKA or THA until they meet a BMI cutoff, he refers that patient to the Yale Medicine Center for Weight Management, New Haven, Connecticut, to learn about weight loss, including the options of anti-obesity medications or bariatric surgery.

Taking the GLP-1s can be a game changer, according to Wiznia and John Morton, MD, MPH, FACS, FASMBS, Yale’s medical director of Bariatric Surgery and professor and vice chair of surgery, who is a physician-director of the center. The program includes other options, such as bariatric surgery, and emphasizes diet and other lifestyle measures. GLP-1s give about a 15% weight loss, Morton said, compared with bariatric surgery providing up to 30%.

Sarah Stombaugh, MD, a family medicine and obesity medicine physician in Charlottesville, Virginia, often gets referrals from two orthopedic surgeons in her community. One recent patient in her early 60s had a BMI of 43.2, too high to qualify for the TKA she needed. On GLP-1s, the initial goal was to decrease a weight of 244 to 225, bringing the BMI to 39.9. The woman did that, then kept losing before her surgery was scheduled, getting to a weight of 210 or a BMI of 37 and staying there for 3 months before the surgery.

She had the TKA, and 5 months out, she is doing well, Stombaugh said. “We do medical weight loss primarily with the GLP-1s because they’re simply the best, the most effective,” Stombaugh said. She does occasionally use oral medications such as naltrexone/bupropion (Contrave).

Stombaugh sees the collaborating trend as still evolving. When she attends obesity medicine conferences, not all her colleagues report they are partnering with surgeons. But she predicts the practice will increase, saying the popularization of what she terms the more effective GLP-1 medications Wegovy and Zepbound is driving it. Partnering with the surgeon requires a conversation at the beginning, when the referral is made, about goals. After that, she sees her patient monthly and sends progress notes to the surgeon.

Golden collaborates with three orthopedic groups in her area, primarily for knee and hip surgeries, but has also helped patients meet the BMI cutoff before spine-related surgeries. She is helping a lung transplant patient now. She has seen several patients who must meet BMI requirements before starting in vitro fertilization, due to the need for conscious sedation for egg retrieval. She has had a few patients who had to meet a BMI cutoff for nonemergency hernia repair.

 

Insurance Issues

Insurance remains an issue for the pricey medications. “Only about a third of patients are routinely covered with insurance,” Morton said.

However, it’s improving, he said. Golden also finds about a third of private payers cover the medication but tries to use manufacturers’ coupons to help defray the costs (from about $1000 or $1400 to about $500 a month). She has sometimes gotten enough samples to get patients to their BMI goal

Morton consulted for Novo Nordisk, Eli Lilly, Olympus, Teleflex, and Johnson & Johnson.

A version of this article appeared on Medscape.com.

The woman, in severe pain from hip and knee osteoarthritis, was confined to a wheelchair and had been told that would likely be for life. To qualify for hip replacement surgery, she needed to lose 100 pounds, a seemingly impossible goal. But she wanted to try.

“We tried a couple of medicines — oral medicines off-label — topiramate, phentermine,” said Leslie Golden, MD, MPH, DABM, a family medicine physician and obesity medicine specialist in Watertown, Wisconsin, 42 miles northeast of Madison.

They weren’t enough. But then Golden turned to glucagon-like peptide 1 (GLP-1) receptor agonists, and they delivered.

“She did lose a significant amount of weight and was able to get the hip replacement,” said Golden.

It took a couple of years. However, seeing her walk into her office, rather than wheel in, “is still one of the joys of my practice,” Golden said. “She’s so grateful. She felt everyone else had written her off.”

As she told Golden: “If I fell and broke my leg today, they would take me to surgery without concern.”

Because her hip replacement was viewed as a nonemergency procedure, the accepted threshold for elective safe surgery was a body mass index (BMI) < 40. That BMI cutoff can vary from provider to provider and medical facility to medical facility but is often required for other surgeries as well, including kidney and lung transplants, gender-affirming surgery, bariatric surgery, hernia surgery, and in vitro fertilization procedures.

Golden is at the forefront of a growing trend — obesity medicine physicians collaborating with surgeons to prescribe the more effective GLP-1s and get surgery candidates to the starting line. She worked with Rajit Chakravarty, MD, an adult reconstructive surgeon who practices in Watertown and nearby Madison, to oversee the weight loss.

 

High BMIs & Surgery Issues

High BMIs have long been linked with postsurgery complications, poor wound healing, and other issues, although some research now is questioning some of those associations. Even so, surgeons have long stressed weight loss for their patients with obesity before orthopedic and other procedures.

These days, surgeons are more likely to need to have that talk. In the last decade, the age-adjusted prevalence of severe obesity — a BMI of ≥ 40 — has increased from 7.7% to 9.7% of US adults. The number of joint replacements is also rising — more than 700,000 total knee arthroplasty (TKA) and more than 450,000 total hip arthroplasty (THA), according to the American Academy of Orthopaedic Surgeons. As the population ages, those numbers are expected to increase.

 

Making the GLP-1 Choice

GLP-1s aren’t the only choice, of course. But they’re often more effective, as Golden found, than other medications. And when his patients with obesity are offered bariatric surgery or GLP-1s, “people definitely want to avoid the bariatric surgery,” Chakravarty said.

With the Food and Drug Administration (FDA) approval of semaglutide (Wegovy) in June 2021 for chronic weight management and then tirzepatide (Zepbound) in November 2023, interest has boomed, he said, among his surgery candidates with a high BMI.

The FDA approved Wegovy based on clinical trials, including one in which participants lost an average of 12.4% of initial body weight compared with those on placebo. It approved Zepbound based on clinical trials, including one in which those on Zepbound lost an average of 18% of their body weight, compared with those on placebo.

The wheelchair-bound woman, now 65, began with a BMI of 63, Golden said. She negotiated a cutoff of 45 with the surgeon and got the go-ahead. Currently, her BMI is 36 as she stayed on the medications.

Beyond the benefit of GLP-1s helping patients meet the BMI cutoff, some research finds fewer postoperative infections and readmissions with their use. This study found the medications did lower both, and another found reduced readmissions and complications.

 

Growing Partnerships, Increasing Success

Helping patients lose weight isn’t just about lowering the BMI, Chakravarty pointed out. The aim is to improve nutritional health — to teach patients how to eat healthfully for their needs, in turn improving other health barometers. Referring them to an obesity medicine physician helps to meet those goals.

When Daniel Wiznia, MD, a Yale Medicine orthopedic surgeon and codirector of the Avascular Necrosis Program, has a patient who must delay a TKA or THA until they meet a BMI cutoff, he refers that patient to the Yale Medicine Center for Weight Management, New Haven, Connecticut, to learn about weight loss, including the options of anti-obesity medications or bariatric surgery.

Taking the GLP-1s can be a game changer, according to Wiznia and John Morton, MD, MPH, FACS, FASMBS, Yale’s medical director of Bariatric Surgery and professor and vice chair of surgery, who is a physician-director of the center. The program includes other options, such as bariatric surgery, and emphasizes diet and other lifestyle measures. GLP-1s give about a 15% weight loss, Morton said, compared with bariatric surgery providing up to 30%.

Sarah Stombaugh, MD, a family medicine and obesity medicine physician in Charlottesville, Virginia, often gets referrals from two orthopedic surgeons in her community. One recent patient in her early 60s had a BMI of 43.2, too high to qualify for the TKA she needed. On GLP-1s, the initial goal was to decrease a weight of 244 to 225, bringing the BMI to 39.9. The woman did that, then kept losing before her surgery was scheduled, getting to a weight of 210 or a BMI of 37 and staying there for 3 months before the surgery.

She had the TKA, and 5 months out, she is doing well, Stombaugh said. “We do medical weight loss primarily with the GLP-1s because they’re simply the best, the most effective,” Stombaugh said. She does occasionally use oral medications such as naltrexone/bupropion (Contrave).

Stombaugh sees the collaborating trend as still evolving. When she attends obesity medicine conferences, not all her colleagues report they are partnering with surgeons. But she predicts the practice will increase, saying the popularization of what she terms the more effective GLP-1 medications Wegovy and Zepbound is driving it. Partnering with the surgeon requires a conversation at the beginning, when the referral is made, about goals. After that, she sees her patient monthly and sends progress notes to the surgeon.

Golden collaborates with three orthopedic groups in her area, primarily for knee and hip surgeries, but has also helped patients meet the BMI cutoff before spine-related surgeries. She is helping a lung transplant patient now. She has seen several patients who must meet BMI requirements before starting in vitro fertilization, due to the need for conscious sedation for egg retrieval. She has had a few patients who had to meet a BMI cutoff for nonemergency hernia repair.

 

Insurance Issues

Insurance remains an issue for the pricey medications. “Only about a third of patients are routinely covered with insurance,” Morton said.

However, it’s improving, he said. Golden also finds about a third of private payers cover the medication but tries to use manufacturers’ coupons to help defray the costs (from about $1000 or $1400 to about $500 a month). She has sometimes gotten enough samples to get patients to their BMI goal

Morton consulted for Novo Nordisk, Eli Lilly, Olympus, Teleflex, and Johnson & Johnson.

A version of this article appeared on Medscape.com.

Do patients with early-stage non–small cell lung cancer (NSCLC) benefit from continuing immunotherapy beyond surgery?

The short answer: Oncologists don’t know for sure.

Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.

But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.

That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease. 

Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.

But that may soon change.

In July, an FDA advisory committee met to discuss the pending approval of durvalumab.

During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.

The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.

“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.

But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?

 

Treating Patients Without Clear Evidence

Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.

A month later, in August, the FDA approved durvalumab for this indication.

Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.

No trial, however, identified when patients benefited from the drug.

Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.

“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”

So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.

A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.

According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.

Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”

This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.

Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.

When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.

For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.

With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.

All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”

When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.

That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”

If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.

 

But Will FDA Follow ODAC’s Recommendation?

“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”

Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.

An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”

Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.

“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”

In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.

Still, getting answers may be a challenge.

Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.

And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.

According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.

For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.

Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.

A version of this article appeared on Medscape.com.

Do patients with early-stage non–small cell lung cancer (NSCLC) benefit from continuing immunotherapy beyond surgery?

The short answer: Oncologists don’t know for sure.

Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.

But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.

That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease. 

Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.

But that may soon change.

In July, an FDA advisory committee met to discuss the pending approval of durvalumab.

During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.

The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.

“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.

But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?

 

Treating Patients Without Clear Evidence

Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.

A month later, in August, the FDA approved durvalumab for this indication.

Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.

No trial, however, identified when patients benefited from the drug.

Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.

“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”

So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.

A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.

According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.

Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”

This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.

Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.

When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.

For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.

With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.

All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”

When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.

That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”

If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.

 

But Will FDA Follow ODAC’s Recommendation?

“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”

Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.

An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”

Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.

“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”

In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.

Still, getting answers may be a challenge.

Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.

And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.

According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.

For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.

Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.

A version of this article appeared on Medscape.com.

Do patients with early-stage non–small cell lung cancer (NSCLC) benefit from continuing immunotherapy beyond surgery?

The short answer: Oncologists don’t know for sure.

Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.

But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.

That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease. 

Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.

But that may soon change.

In July, an FDA advisory committee met to discuss the pending approval of durvalumab.

During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.

The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.

“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.

But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?

 

Treating Patients Without Clear Evidence

Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.

A month later, in August, the FDA approved durvalumab for this indication.

Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.

No trial, however, identified when patients benefited from the drug.

Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.

“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”

So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.

A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.

According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.

Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”

This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.

Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.

When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.

For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.

With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.

All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”

When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.

That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”

If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.

 

But Will FDA Follow ODAC’s Recommendation?

“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”

Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.

An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”

Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.

“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”

In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.

Still, getting answers may be a challenge.

Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.

And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.

According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.

For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.

Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

For over 200 years, researchers have been captivated by axolotl salamanders (Ambystoma mexicanum) and their remarkable regenerative abilities, seeking to uncover secrets that could revolutionize regenerative medicine, including the scarless healing of wounds.

“The axolotl salamander is the most studied animal ever in science for its neotenic ability to regenerate,” Jill S. Waibel, MD, dermatologist and researcher in Miami, Florida, said in an interview. Neotenic tissue retains a juvenile or immature state throughout an organism’s life. In the case of the axolotl, “it can regenerate limbs, part of its heart, even its brain.”

 

A 2019 review of several studies on the regenerative abilities of axolotls highlights the importance of gene activity in controlling its skin regeneration. Specifically, growth factors such as fibroblast growth factors, transforming growth factor beta, and Wnt play a key role in guiding how the creature’s skin cells behave during healing and regrowth. The immune response , particularly the actions of macrophages and neutrophils, is also crucial in the early stages of regeneration, as these cells clear away dead tissue and kickstart the healing process.

After studying the axolotl for the past 8 years, including mapping its genetic makeup, Waibel and researchers at RegenX Science are developing a line of cosmeceutical and over-the-counter products containing urodele collagen extract derived from the creature’s neotenic tissue, without harming the animal. In axolotls, Waibel explained, damaged neotenic tissue “still thinks it’s in fetal mode, so if it injures its muscle, bone, nerves, collagen, or skin, everything will redevelop. After a few months in utero, that process stops in humans, but it never stops in the axolotl. The axolotl has scarless healing and immunity because of antimicrobial properties found in the neotenic tissue.”

RegenX scientists have developed a proprietary decellularization process that renders the urodele collagen extract safe and effective for use in humans. “We then harnessed a reservoir of bioactive peptides, which are small proteins that come from the axolotl, but they don’t contain any RNA or DNA that could confer the risk of any diseases or cancer,” she added.

According to Waibel, who is also subsection chief of dermatology at Baptist Hospital and past medical director of the Miami Cancer Institute’s Multidisciplinary Skin Cancer Clinic, genetic analysis of the axolotl revealed genes that have not been seen in humans. The urodele collagen extract also has anti-inflammatory and analgesic properties. “It decreases TNF [tumor necrosis factor] and IL [interleukin]–23 and stimulates regenerative pathways like FETUB (Fetuin-B), which is a gene involved in tissue regeneration,” she said. “We’re exploring these for some products.”

Institutional Review Board–approved human clinical trials at three US sites are nearly complete for evaluating an antiaging hydrating daily serum, an antiaging serum for damaged skin, and a restorative serum to be applied following cosmetic procedures, all containing the extract. The product furthest along is a “super gel” that contains properties of the urodele collagen extract.

In a proof-of-concept study using a third-degree burn model in two pigs, Waibel and colleagues at the University of Miami, found that 3 days after the injury was induced, application of the gel led to 92% reepithelialization of the pig’s skin, compared with only 54% in untreated skin.

Shortly after this study was conducted, a burn patient was referred to Waibel — 4 years after he was struck by lightning while fishing on a boat in Mississippi, an accident that resulted in the loss of his right arm and both legs. During a telemedicine consultation, Waibel noticed open ulcers on his chest. “What are those from?” she asked. “They’re from my accident 4 years ago,” he replied. 

After the man flew to Miami for an in-person evaluation, Waibel treated his ulcers with a fractional laser to debride the wound, then applied the gel as part of a proof-of-concept approach, testing its potential in a real-world patient setting. Within 3 weeks, the long-standing ulcerated area had healed completely, marking the first time a human was treated with the super gel.

Looking ahead, the million-dollar question, Waibel noted, is how much healing can be achieved in humans with formulations of axolotl-derived technology. “For example, can we help a spinal cord injury patient? That sounds like a science fiction movie, but there are proteins in genes in this animal that we have turned off that potentially can be turned on in a human,” she said. “It’s very exciting.”

 

Arisa E. Ortiz, MD, director of Laser and Cosmetic Dermatology at the University of California, San Diego, and current president of the American Society for Laser Medicine and Surgery, who was asked to comment on this work, said that the use of urodele collagen extract derived from axolotl tissue “is an exciting innovation, especially given its unique properties like scarless healing and antimicrobial activity.” 

While the results from preclinical and proof-of-concept studies are promising, “a key limitation lies in understanding the extent to which these findings will translate to human applications,” Ortiz said. “Overall, this research contributes significantly to the fields of regenerative medicine and dermatology, offering hope for more effective treatments in the future.” 

 

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was also asked to provide her insights on the topic, said that, if researchers could replicate the axolotl salamander’s ability to regenerate its own limbs and organs, “medicine would be transformed. Rather than transplant another person’s organ with lifelong immunosuppression, a regenerative treatment could program a patient’s own body to create a needed organ. 

“On a simpler level,” she continued, “regenerating skin and its underlying structures could hasten wound healing and potentially even treat hair loss. This is not a pipe dream, as Waibel has successfully treated severe ulcers using a super gel containing urodele collagen extract. Urodele collagen is type XII collagen, important in the salamander’s capacity to heal and regenerate.”

Waibel disclosed that she is a scientific adviser to RegenX and is a member of the company’s board of directors. Ortiz and Ko reported having no relevant disclosures.

A version of this article first appeared on Medscape.com.

For over 200 years, researchers have been captivated by axolotl salamanders (Ambystoma mexicanum) and their remarkable regenerative abilities, seeking to uncover secrets that could revolutionize regenerative medicine, including the scarless healing of wounds.

“The axolotl salamander is the most studied animal ever in science for its neotenic ability to regenerate,” Jill S. Waibel, MD, dermatologist and researcher in Miami, Florida, said in an interview. Neotenic tissue retains a juvenile or immature state throughout an organism’s life. In the case of the axolotl, “it can regenerate limbs, part of its heart, even its brain.”

 

A 2019 review of several studies on the regenerative abilities of axolotls highlights the importance of gene activity in controlling its skin regeneration. Specifically, growth factors such as fibroblast growth factors, transforming growth factor beta, and Wnt play a key role in guiding how the creature’s skin cells behave during healing and regrowth. The immune response , particularly the actions of macrophages and neutrophils, is also crucial in the early stages of regeneration, as these cells clear away dead tissue and kickstart the healing process.

After studying the axolotl for the past 8 years, including mapping its genetic makeup, Waibel and researchers at RegenX Science are developing a line of cosmeceutical and over-the-counter products containing urodele collagen extract derived from the creature’s neotenic tissue, without harming the animal. In axolotls, Waibel explained, damaged neotenic tissue “still thinks it’s in fetal mode, so if it injures its muscle, bone, nerves, collagen, or skin, everything will redevelop. After a few months in utero, that process stops in humans, but it never stops in the axolotl. The axolotl has scarless healing and immunity because of antimicrobial properties found in the neotenic tissue.”

RegenX scientists have developed a proprietary decellularization process that renders the urodele collagen extract safe and effective for use in humans. “We then harnessed a reservoir of bioactive peptides, which are small proteins that come from the axolotl, but they don’t contain any RNA or DNA that could confer the risk of any diseases or cancer,” she added.

According to Waibel, who is also subsection chief of dermatology at Baptist Hospital and past medical director of the Miami Cancer Institute’s Multidisciplinary Skin Cancer Clinic, genetic analysis of the axolotl revealed genes that have not been seen in humans. The urodele collagen extract also has anti-inflammatory and analgesic properties. “It decreases TNF [tumor necrosis factor] and IL [interleukin]–23 and stimulates regenerative pathways like FETUB (Fetuin-B), which is a gene involved in tissue regeneration,” she said. “We’re exploring these for some products.”

Institutional Review Board–approved human clinical trials at three US sites are nearly complete for evaluating an antiaging hydrating daily serum, an antiaging serum for damaged skin, and a restorative serum to be applied following cosmetic procedures, all containing the extract. The product furthest along is a “super gel” that contains properties of the urodele collagen extract.

In a proof-of-concept study using a third-degree burn model in two pigs, Waibel and colleagues at the University of Miami, found that 3 days after the injury was induced, application of the gel led to 92% reepithelialization of the pig’s skin, compared with only 54% in untreated skin.

Shortly after this study was conducted, a burn patient was referred to Waibel — 4 years after he was struck by lightning while fishing on a boat in Mississippi, an accident that resulted in the loss of his right arm and both legs. During a telemedicine consultation, Waibel noticed open ulcers on his chest. “What are those from?” she asked. “They’re from my accident 4 years ago,” he replied. 

After the man flew to Miami for an in-person evaluation, Waibel treated his ulcers with a fractional laser to debride the wound, then applied the gel as part of a proof-of-concept approach, testing its potential in a real-world patient setting. Within 3 weeks, the long-standing ulcerated area had healed completely, marking the first time a human was treated with the super gel.

Looking ahead, the million-dollar question, Waibel noted, is how much healing can be achieved in humans with formulations of axolotl-derived technology. “For example, can we help a spinal cord injury patient? That sounds like a science fiction movie, but there are proteins in genes in this animal that we have turned off that potentially can be turned on in a human,” she said. “It’s very exciting.”

 

Arisa E. Ortiz, MD, director of Laser and Cosmetic Dermatology at the University of California, San Diego, and current president of the American Society for Laser Medicine and Surgery, who was asked to comment on this work, said that the use of urodele collagen extract derived from axolotl tissue “is an exciting innovation, especially given its unique properties like scarless healing and antimicrobial activity.” 

While the results from preclinical and proof-of-concept studies are promising, “a key limitation lies in understanding the extent to which these findings will translate to human applications,” Ortiz said. “Overall, this research contributes significantly to the fields of regenerative medicine and dermatology, offering hope for more effective treatments in the future.” 

 

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was also asked to provide her insights on the topic, said that, if researchers could replicate the axolotl salamander’s ability to regenerate its own limbs and organs, “medicine would be transformed. Rather than transplant another person’s organ with lifelong immunosuppression, a regenerative treatment could program a patient’s own body to create a needed organ. 

“On a simpler level,” she continued, “regenerating skin and its underlying structures could hasten wound healing and potentially even treat hair loss. This is not a pipe dream, as Waibel has successfully treated severe ulcers using a super gel containing urodele collagen extract. Urodele collagen is type XII collagen, important in the salamander’s capacity to heal and regenerate.”

Waibel disclosed that she is a scientific adviser to RegenX and is a member of the company’s board of directors. Ortiz and Ko reported having no relevant disclosures.

A version of this article first appeared on Medscape.com.

For over 200 years, researchers have been captivated by axolotl salamanders (Ambystoma mexicanum) and their remarkable regenerative abilities, seeking to uncover secrets that could revolutionize regenerative medicine, including the scarless healing of wounds.

“The axolotl salamander is the most studied animal ever in science for its neotenic ability to regenerate,” Jill S. Waibel, MD, dermatologist and researcher in Miami, Florida, said in an interview. Neotenic tissue retains a juvenile or immature state throughout an organism’s life. In the case of the axolotl, “it can regenerate limbs, part of its heart, even its brain.”

 

A 2019 review of several studies on the regenerative abilities of axolotls highlights the importance of gene activity in controlling its skin regeneration. Specifically, growth factors such as fibroblast growth factors, transforming growth factor beta, and Wnt play a key role in guiding how the creature’s skin cells behave during healing and regrowth. The immune response , particularly the actions of macrophages and neutrophils, is also crucial in the early stages of regeneration, as these cells clear away dead tissue and kickstart the healing process.

After studying the axolotl for the past 8 years, including mapping its genetic makeup, Waibel and researchers at RegenX Science are developing a line of cosmeceutical and over-the-counter products containing urodele collagen extract derived from the creature’s neotenic tissue, without harming the animal. In axolotls, Waibel explained, damaged neotenic tissue “still thinks it’s in fetal mode, so if it injures its muscle, bone, nerves, collagen, or skin, everything will redevelop. After a few months in utero, that process stops in humans, but it never stops in the axolotl. The axolotl has scarless healing and immunity because of antimicrobial properties found in the neotenic tissue.”

RegenX scientists have developed a proprietary decellularization process that renders the urodele collagen extract safe and effective for use in humans. “We then harnessed a reservoir of bioactive peptides, which are small proteins that come from the axolotl, but they don’t contain any RNA or DNA that could confer the risk of any diseases or cancer,” she added.

According to Waibel, who is also subsection chief of dermatology at Baptist Hospital and past medical director of the Miami Cancer Institute’s Multidisciplinary Skin Cancer Clinic, genetic analysis of the axolotl revealed genes that have not been seen in humans. The urodele collagen extract also has anti-inflammatory and analgesic properties. “It decreases TNF [tumor necrosis factor] and IL [interleukin]–23 and stimulates regenerative pathways like FETUB (Fetuin-B), which is a gene involved in tissue regeneration,” she said. “We’re exploring these for some products.”

Institutional Review Board–approved human clinical trials at three US sites are nearly complete for evaluating an antiaging hydrating daily serum, an antiaging serum for damaged skin, and a restorative serum to be applied following cosmetic procedures, all containing the extract. The product furthest along is a “super gel” that contains properties of the urodele collagen extract.

In a proof-of-concept study using a third-degree burn model in two pigs, Waibel and colleagues at the University of Miami, found that 3 days after the injury was induced, application of the gel led to 92% reepithelialization of the pig’s skin, compared with only 54% in untreated skin.

Shortly after this study was conducted, a burn patient was referred to Waibel — 4 years after he was struck by lightning while fishing on a boat in Mississippi, an accident that resulted in the loss of his right arm and both legs. During a telemedicine consultation, Waibel noticed open ulcers on his chest. “What are those from?” she asked. “They’re from my accident 4 years ago,” he replied. 

After the man flew to Miami for an in-person evaluation, Waibel treated his ulcers with a fractional laser to debride the wound, then applied the gel as part of a proof-of-concept approach, testing its potential in a real-world patient setting. Within 3 weeks, the long-standing ulcerated area had healed completely, marking the first time a human was treated with the super gel.

Looking ahead, the million-dollar question, Waibel noted, is how much healing can be achieved in humans with formulations of axolotl-derived technology. “For example, can we help a spinal cord injury patient? That sounds like a science fiction movie, but there are proteins in genes in this animal that we have turned off that potentially can be turned on in a human,” she said. “It’s very exciting.”

 

Arisa E. Ortiz, MD, director of Laser and Cosmetic Dermatology at the University of California, San Diego, and current president of the American Society for Laser Medicine and Surgery, who was asked to comment on this work, said that the use of urodele collagen extract derived from axolotl tissue “is an exciting innovation, especially given its unique properties like scarless healing and antimicrobial activity.” 

While the results from preclinical and proof-of-concept studies are promising, “a key limitation lies in understanding the extent to which these findings will translate to human applications,” Ortiz said. “Overall, this research contributes significantly to the fields of regenerative medicine and dermatology, offering hope for more effective treatments in the future.” 

 

Christine Ko, MD, professor of dermatology and pathology at Yale University, New Haven, Connecticut, who was also asked to provide her insights on the topic, said that, if researchers could replicate the axolotl salamander’s ability to regenerate its own limbs and organs, “medicine would be transformed. Rather than transplant another person’s organ with lifelong immunosuppression, a regenerative treatment could program a patient’s own body to create a needed organ. 

“On a simpler level,” she continued, “regenerating skin and its underlying structures could hasten wound healing and potentially even treat hair loss. This is not a pipe dream, as Waibel has successfully treated severe ulcers using a super gel containing urodele collagen extract. Urodele collagen is type XII collagen, important in the salamander’s capacity to heal and regenerate.”

Waibel disclosed that she is a scientific adviser to RegenX and is a member of the company’s board of directors. Ortiz and Ko reported having no relevant disclosures.

A version of this article first appeared on Medscape.com.

What current events are keeping Americans up at night? The economy, gun violence, and hate crimes top the list, results from a newly released American Psychiatric Association (APA) survey showed.

Anxiety about international conflicts — namely, the Russia-Ukraine and Israel-Hamas wars — also remains high.

“While we like to stay informed, the news can also impact our mental health, and being mindful of that impact is important. If current events seem overwhelming it may be time to limit your news consumption,” APA CEO and Medical Director Marketa M. Wills, MD, MBD, said in a statement.

Survey results also revealed the election and the holidays were common sources of stress.

“Election stress is common, and it’s important to recognize that, as we’re spending more time with family around the holidays, we might need to have a strategy to manage our own mental health during these times,” Howard Liu, MD, MBA, chair of the Department of Psychiatry, University of Nebraska Medical Center, Omaha, told this news organization.

“As with any difficult topic, we all have different levels of avoidance or desire to engage, and it’s okay to set boundaries based on past conversations with family. I think sometimes we get drawn into arguments that we don’t want to have or may not be productive for either side,” said Liu, who chairs the APA Council on Communications.

In line with trends throughout 2024, adults polled by the APA in November were most anxious about the economy (75%), gun violence (64%), and hate crimes (60%). The survey included 2200 US adults as part of the APA’s Healthy Minds monthly series.

Anxiety about international conflicts remained high in November at 57% — but was down from 65% in August.

Election anxiety remained high in mid-November but not as high as before the election. In August, 72% of Americans said they were anxious about the 2024 election. In November, just after the election, 50% reported anxiety over the election outcome.

“I think the anticipation of change can sometimes be worse than the change itself. So I think a lot of people are now taking the attitude of — let’s wait and see what actually happens,” said Liu.

Half the adults (50%) anticipate the same amount of stress as the 2023 holiday season, while almost one third expect more stress (28%), and one fourth anticipate less stress (23%).

When asked how the holidays generally affect their mental health, 38% said it has positive effects, and 21% said the opposite was true.

 

Anxiety About the Future

After a divisive election, most Americans were ready to avoid politics at holiday gatherings, results of a separate poll conducted by the American Psychological Association in late November showed.

That poll, which included 2000 US adults, showed that more than 7 in 10 (72%) said they wanted to avoid talking about politics with family and friends over the holidays.

In addition, nearly two in five adults (39%) reported they were stressed by the thought of politics being raised at holiday gatherings and would try to avoid family members they disagree with. Younger adults were significantly more likely than were their older counterparts to report they planned to avoid family over the holidays.

The future of the nation also weighs on the minds of many Americans.

Another poll conducted by the American Psychological Association in August prior to the 2024 US presidential election showed that 77% of respondents said the future of the nation was a significant source of stress for them.

In the postelection poll, more than one third of adults (35%) said they are more stressed about the future of the nation now than they were leading up to the election, and another third reported they are now less stressed (32%). A quarter of adults (24%) said their stress about the future of the nation was unchanged, and 9% said they were not stressed about the future of the nation then or now.

“There’s still clearly a lot of uncertainty, and there’s a lot of activity right now for the president-elect,” which can contribute to anxiety, C. Vaile Wright, PhD, psychologist, researcher and spokesperson for the American Psychological Association, told this news organization.

These data also show that many Americans have little or no trust in the government, with some wanting to leave the United States.

“It’s a reflection of the lack of strong leadership across the board in this country. We have a governmental system in place that does not seem to serve the people, but to serve corporations and maintenance of power. I think people are disillusioned with it and that creates a lack of trust and hopelessness,” Wright noted.

Liu and Wright reported no relevant disclosures.

A version of this article appeared on Medscape.com.

What current events are keeping Americans up at night? The economy, gun violence, and hate crimes top the list, results from a newly released American Psychiatric Association (APA) survey showed.

Anxiety about international conflicts — namely, the Russia-Ukraine and Israel-Hamas wars — also remains high.

“While we like to stay informed, the news can also impact our mental health, and being mindful of that impact is important. If current events seem overwhelming it may be time to limit your news consumption,” APA CEO and Medical Director Marketa M. Wills, MD, MBD, said in a statement.

Survey results also revealed the election and the holidays were common sources of stress.

“Election stress is common, and it’s important to recognize that, as we’re spending more time with family around the holidays, we might need to have a strategy to manage our own mental health during these times,” Howard Liu, MD, MBA, chair of the Department of Psychiatry, University of Nebraska Medical Center, Omaha, told this news organization.

“As with any difficult topic, we all have different levels of avoidance or desire to engage, and it’s okay to set boundaries based on past conversations with family. I think sometimes we get drawn into arguments that we don’t want to have or may not be productive for either side,” said Liu, who chairs the APA Council on Communications.

In line with trends throughout 2024, adults polled by the APA in November were most anxious about the economy (75%), gun violence (64%), and hate crimes (60%). The survey included 2200 US adults as part of the APA’s Healthy Minds monthly series.

Anxiety about international conflicts remained high in November at 57% — but was down from 65% in August.

Election anxiety remained high in mid-November but not as high as before the election. In August, 72% of Americans said they were anxious about the 2024 election. In November, just after the election, 50% reported anxiety over the election outcome.

“I think the anticipation of change can sometimes be worse than the change itself. So I think a lot of people are now taking the attitude of — let’s wait and see what actually happens,” said Liu.

Half the adults (50%) anticipate the same amount of stress as the 2023 holiday season, while almost one third expect more stress (28%), and one fourth anticipate less stress (23%).

When asked how the holidays generally affect their mental health, 38% said it has positive effects, and 21% said the opposite was true.

 

Anxiety About the Future

After a divisive election, most Americans were ready to avoid politics at holiday gatherings, results of a separate poll conducted by the American Psychological Association in late November showed.

That poll, which included 2000 US adults, showed that more than 7 in 10 (72%) said they wanted to avoid talking about politics with family and friends over the holidays.

In addition, nearly two in five adults (39%) reported they were stressed by the thought of politics being raised at holiday gatherings and would try to avoid family members they disagree with. Younger adults were significantly more likely than were their older counterparts to report they planned to avoid family over the holidays.

The future of the nation also weighs on the minds of many Americans.

Another poll conducted by the American Psychological Association in August prior to the 2024 US presidential election showed that 77% of respondents said the future of the nation was a significant source of stress for them.

In the postelection poll, more than one third of adults (35%) said they are more stressed about the future of the nation now than they were leading up to the election, and another third reported they are now less stressed (32%). A quarter of adults (24%) said their stress about the future of the nation was unchanged, and 9% said they were not stressed about the future of the nation then or now.

“There’s still clearly a lot of uncertainty, and there’s a lot of activity right now for the president-elect,” which can contribute to anxiety, C. Vaile Wright, PhD, psychologist, researcher and spokesperson for the American Psychological Association, told this news organization.

These data also show that many Americans have little or no trust in the government, with some wanting to leave the United States.

“It’s a reflection of the lack of strong leadership across the board in this country. We have a governmental system in place that does not seem to serve the people, but to serve corporations and maintenance of power. I think people are disillusioned with it and that creates a lack of trust and hopelessness,” Wright noted.

Liu and Wright reported no relevant disclosures.

A version of this article appeared on Medscape.com.

What current events are keeping Americans up at night? The economy, gun violence, and hate crimes top the list, results from a newly released American Psychiatric Association (APA) survey showed.

Anxiety about international conflicts — namely, the Russia-Ukraine and Israel-Hamas wars — also remains high.

“While we like to stay informed, the news can also impact our mental health, and being mindful of that impact is important. If current events seem overwhelming it may be time to limit your news consumption,” APA CEO and Medical Director Marketa M. Wills, MD, MBD, said in a statement.

Survey results also revealed the election and the holidays were common sources of stress.

“Election stress is common, and it’s important to recognize that, as we’re spending more time with family around the holidays, we might need to have a strategy to manage our own mental health during these times,” Howard Liu, MD, MBA, chair of the Department of Psychiatry, University of Nebraska Medical Center, Omaha, told this news organization.

“As with any difficult topic, we all have different levels of avoidance or desire to engage, and it’s okay to set boundaries based on past conversations with family. I think sometimes we get drawn into arguments that we don’t want to have or may not be productive for either side,” said Liu, who chairs the APA Council on Communications.

In line with trends throughout 2024, adults polled by the APA in November were most anxious about the economy (75%), gun violence (64%), and hate crimes (60%). The survey included 2200 US adults as part of the APA’s Healthy Minds monthly series.

Anxiety about international conflicts remained high in November at 57% — but was down from 65% in August.

Election anxiety remained high in mid-November but not as high as before the election. In August, 72% of Americans said they were anxious about the 2024 election. In November, just after the election, 50% reported anxiety over the election outcome.

“I think the anticipation of change can sometimes be worse than the change itself. So I think a lot of people are now taking the attitude of — let’s wait and see what actually happens,” said Liu.

Half the adults (50%) anticipate the same amount of stress as the 2023 holiday season, while almost one third expect more stress (28%), and one fourth anticipate less stress (23%).

When asked how the holidays generally affect their mental health, 38% said it has positive effects, and 21% said the opposite was true.

 

Anxiety About the Future

After a divisive election, most Americans were ready to avoid politics at holiday gatherings, results of a separate poll conducted by the American Psychological Association in late November showed.

That poll, which included 2000 US adults, showed that more than 7 in 10 (72%) said they wanted to avoid talking about politics with family and friends over the holidays.

In addition, nearly two in five adults (39%) reported they were stressed by the thought of politics being raised at holiday gatherings and would try to avoid family members they disagree with. Younger adults were significantly more likely than were their older counterparts to report they planned to avoid family over the holidays.

The future of the nation also weighs on the minds of many Americans.

Another poll conducted by the American Psychological Association in August prior to the 2024 US presidential election showed that 77% of respondents said the future of the nation was a significant source of stress for them.

In the postelection poll, more than one third of adults (35%) said they are more stressed about the future of the nation now than they were leading up to the election, and another third reported they are now less stressed (32%). A quarter of adults (24%) said their stress about the future of the nation was unchanged, and 9% said they were not stressed about the future of the nation then or now.

“There’s still clearly a lot of uncertainty, and there’s a lot of activity right now for the president-elect,” which can contribute to anxiety, C. Vaile Wright, PhD, psychologist, researcher and spokesperson for the American Psychological Association, told this news organization.

These data also show that many Americans have little or no trust in the government, with some wanting to leave the United States.

“It’s a reflection of the lack of strong leadership across the board in this country. We have a governmental system in place that does not seem to serve the people, but to serve corporations and maintenance of power. I think people are disillusioned with it and that creates a lack of trust and hopelessness,” Wright noted.

Liu and Wright reported no relevant disclosures.

A version of this article appeared on Medscape.com.