Feature

In seconds, Ravi Parikh, MD, an oncologist at the Emory University School of Medicine in Atlanta, had a summary of his patient’s entire medical history. Normally, Parikh skimmed the cumbersome files before seeing a patient. However, the artificial intelligence (AI) tool his institution was testing could list the highlights he needed in a fraction of the time.

“On the whole, I like it ... it saves me time,” Parikh said of the tool. “But I’d be lying if I told you it was perfect all the time. It’s interpreting the [patient] history in some ways that may be inaccurate,” he said.

Within the first week of testing the tool, Parikh started to notice that the large language model (LLM) made a particular mistake in his patients with prostate cancer. If their prostate-specific antigen test results came back slightly elevated — which is part of normal variation — the LLM recorded it as disease progression. Because Parikh reviews all his notes — with or without using an AI tool — after a visit, he easily caught the mistake before it was added to the chart. “The problem, I think, is if these mistakes go under the hood,” he said.

In the data science world, these mistakes are called hallucinations. And a growing body of research suggests they’re happening more frequently than is safe for healthcare. The industry promised LLMs would alleviate administrative burden and reduce physician burnout. But so far, studies show these AI-tool mistakes often create more work for doctors, not less. To truly help physicians and be safe for patients, some experts say healthcare needs to build its own LLMs from the ground up. And all agree that the field desperately needs a way to vet these algorithms more thoroughly.
 

Prone to Error

Right now, “I think the industry is focused on taking existing LLMs and forcing them into usage for healthcare,” said Nigam H. Shah, MBBS, PhD, chief data scientist for Stanford Health. However, the value of deploying general LLMs in the healthcare space is questionable. “People are starting to wonder if we’re using these tools wrong,” he told this news organization.

In 2023, Shah and his colleagues evaluated seven LLMs on their ability to answer electronic health record–based questions. For realistic tasks, the error rate in the best cases was about 35%, he said. “To me, that rate seems a bit high ... to adopt for routine use.”

A study earlier this year by the UC San Diego School of Medicine showed that using LLMs to respond to patient messages increased the time doctors spent on messages. And this summer, a study by the clinical AI firm Mendel found that when GPT-4o or Llama-3 were used to summarize patient medical records, almost every summary contained at least one type of hallucination.

“We’ve seen cases where a patient does have drug allergies, but the system says ‘no known drug allergies’ ” in the medical history summary, said Wael Salloum, PhD, cofounder and chief science officer at Mendel. “That’s a serious hallucination.” And if physicians have to constantly verify what the system is telling them, that “defeats the purpose [of summarization],” he said.
 

A Higher Quality Diet

Part of the trouble with LLMs is that there’s just not enough high-quality information to feed them. The algorithms are insatiable, requiring vast swaths of data for training. GPT-3.5, for instance, was trained on 570 GB of data from the internet, more than 300 billion words. And to train GPT-4o, OpenAI reportedly transcribed more than 1 million hours of YouTube content.

However, the strategies that built these general LLMs don’t always translate well to healthcare. The internet is full of low-quality or misleading health information from wellness sites and supplement advertisements. And even data that are trustworthy, like the millions of clinical studies and the US Food and Drug Administration (FDA) statements, can be outdated, Salloum said. And “an LLM in training can’t distinguish good from bad,” he added.

The good news is that clinicians don’t rely on controversial information in the real world. Medical knowledge is standardized. “Healthcare is a domain rich with explicit knowledge,” Salloum said. So there’s potential to build a more reliable LLM that is guided by robust medical standards and guidelines.

It’s possible that healthcare could use small language models, which are LLM’s pocket-sized cousins, and perform tasks needing only bite-sized datasets requiring fewer resources and easier fine-tuning, according to Microsoft’s website. Shah said training these smaller models on real medical data might be an option, like an LLM meant to respond to patient messages that could be trained with real messages sent by physicians.

Several groups are already working on databases of standardized human medical knowledge or real physician responses. “Perhaps that will work better than using LLMs trained on the general internet. Those studies need to be done,” Shah said.

Jon Tamir, assistant professor of electrical and computer engineering and co-lead of the AI Health Lab at The University of Texas at Austin, said, “The community has recognized that we are entering a new era of AI where the dataset itself is the most important aspect. We need training sets that are highly curated and highly specialized.

“If the dataset is highly specialized, it will definitely help reduce hallucinations,” he said.
 

Cutting Overconfidence

A major problem with LLM mistakes is that they are often hard to detect. Hallucinations can be highly convincing even if they’re highly inaccurate, according to Tamir.

When Shah, for instance, was recently testing an LLM on de-identified patient data, he asked the LLM which blood test the patient last had. The model responded with “complete blood count [CBC].” But when he asked for the results, the model gave him white blood count and other values. “Turns out that record did not have a CBC done at all! The result was entirely made up,” he said.

Making healthcare LLMs safer and more reliable will mean training AI to acknowledge potential mistakes and uncertainty. Existing LLMs are trained to project confidence and produce a lot of answers, even when there isn’t one, Salloum said. They rarely respond with “I don’t know” even when their prediction has low confidence, he added.

Healthcare stands to benefit from a system that highlights uncertainty and potential errors. For instance, if a patient’s history shows they have smoked, stopped smoking, vaped, and started smoking again. The LLM might call them a smoker but flag the comment as uncertain because the chronology is complicated, Salloum said.

Tamir added that this strategy could improve LLM and doctor collaboration by honing in on where human expertise is needed most.
 

Too Little Evaluation

For any improvement strategy to work, LLMs — and all AI-assisted healthcare tools — first need a better evaluation framework. So far, LLMs have “been used in really exciting ways but not really well-vetted ways,” Tamir said.

While some AI-assisted tools, particularly in medical imaging, have undergone rigorous FDA evaluations and earned approval, most haven’t. And because the FDA only regulates algorithms that are considered medical devices, Parikh said that most LLMs used for administrative tasks and efficiency don’t fall under the regulatory agency’s purview.

But these algorithms still have access to patient information and can directly influence patient and doctor decisions. Third-party regulatory agencies are expected to emerge, but it’s still unclear who those will be. Before developers can build a safer and more efficient LLM for healthcare, they’ll need better guidelines and guardrails. “Unless we figure out evaluation, how would we know whether the healthcare-appropriate large language models are better or worse?” Shah asked.
 

A version of this article appeared on Medscape.com.

In seconds, Ravi Parikh, MD, an oncologist at the Emory University School of Medicine in Atlanta, had a summary of his patient’s entire medical history. Normally, Parikh skimmed the cumbersome files before seeing a patient. However, the artificial intelligence (AI) tool his institution was testing could list the highlights he needed in a fraction of the time.

“On the whole, I like it ... it saves me time,” Parikh said of the tool. “But I’d be lying if I told you it was perfect all the time. It’s interpreting the [patient] history in some ways that may be inaccurate,” he said.

Within the first week of testing the tool, Parikh started to notice that the large language model (LLM) made a particular mistake in his patients with prostate cancer. If their prostate-specific antigen test results came back slightly elevated — which is part of normal variation — the LLM recorded it as disease progression. Because Parikh reviews all his notes — with or without using an AI tool — after a visit, he easily caught the mistake before it was added to the chart. “The problem, I think, is if these mistakes go under the hood,” he said.

In the data science world, these mistakes are called hallucinations. And a growing body of research suggests they’re happening more frequently than is safe for healthcare. The industry promised LLMs would alleviate administrative burden and reduce physician burnout. But so far, studies show these AI-tool mistakes often create more work for doctors, not less. To truly help physicians and be safe for patients, some experts say healthcare needs to build its own LLMs from the ground up. And all agree that the field desperately needs a way to vet these algorithms more thoroughly.
 

Prone to Error

Right now, “I think the industry is focused on taking existing LLMs and forcing them into usage for healthcare,” said Nigam H. Shah, MBBS, PhD, chief data scientist for Stanford Health. However, the value of deploying general LLMs in the healthcare space is questionable. “People are starting to wonder if we’re using these tools wrong,” he told this news organization.

In 2023, Shah and his colleagues evaluated seven LLMs on their ability to answer electronic health record–based questions. For realistic tasks, the error rate in the best cases was about 35%, he said. “To me, that rate seems a bit high ... to adopt for routine use.”

A study earlier this year by the UC San Diego School of Medicine showed that using LLMs to respond to patient messages increased the time doctors spent on messages. And this summer, a study by the clinical AI firm Mendel found that when GPT-4o or Llama-3 were used to summarize patient medical records, almost every summary contained at least one type of hallucination.

“We’ve seen cases where a patient does have drug allergies, but the system says ‘no known drug allergies’ ” in the medical history summary, said Wael Salloum, PhD, cofounder and chief science officer at Mendel. “That’s a serious hallucination.” And if physicians have to constantly verify what the system is telling them, that “defeats the purpose [of summarization],” he said.
 

A Higher Quality Diet

Part of the trouble with LLMs is that there’s just not enough high-quality information to feed them. The algorithms are insatiable, requiring vast swaths of data for training. GPT-3.5, for instance, was trained on 570 GB of data from the internet, more than 300 billion words. And to train GPT-4o, OpenAI reportedly transcribed more than 1 million hours of YouTube content.

However, the strategies that built these general LLMs don’t always translate well to healthcare. The internet is full of low-quality or misleading health information from wellness sites and supplement advertisements. And even data that are trustworthy, like the millions of clinical studies and the US Food and Drug Administration (FDA) statements, can be outdated, Salloum said. And “an LLM in training can’t distinguish good from bad,” he added.

The good news is that clinicians don’t rely on controversial information in the real world. Medical knowledge is standardized. “Healthcare is a domain rich with explicit knowledge,” Salloum said. So there’s potential to build a more reliable LLM that is guided by robust medical standards and guidelines.

It’s possible that healthcare could use small language models, which are LLM’s pocket-sized cousins, and perform tasks needing only bite-sized datasets requiring fewer resources and easier fine-tuning, according to Microsoft’s website. Shah said training these smaller models on real medical data might be an option, like an LLM meant to respond to patient messages that could be trained with real messages sent by physicians.

Several groups are already working on databases of standardized human medical knowledge or real physician responses. “Perhaps that will work better than using LLMs trained on the general internet. Those studies need to be done,” Shah said.

Jon Tamir, assistant professor of electrical and computer engineering and co-lead of the AI Health Lab at The University of Texas at Austin, said, “The community has recognized that we are entering a new era of AI where the dataset itself is the most important aspect. We need training sets that are highly curated and highly specialized.

“If the dataset is highly specialized, it will definitely help reduce hallucinations,” he said.
 

Cutting Overconfidence

A major problem with LLM mistakes is that they are often hard to detect. Hallucinations can be highly convincing even if they’re highly inaccurate, according to Tamir.

When Shah, for instance, was recently testing an LLM on de-identified patient data, he asked the LLM which blood test the patient last had. The model responded with “complete blood count [CBC].” But when he asked for the results, the model gave him white blood count and other values. “Turns out that record did not have a CBC done at all! The result was entirely made up,” he said.

Making healthcare LLMs safer and more reliable will mean training AI to acknowledge potential mistakes and uncertainty. Existing LLMs are trained to project confidence and produce a lot of answers, even when there isn’t one, Salloum said. They rarely respond with “I don’t know” even when their prediction has low confidence, he added.

Healthcare stands to benefit from a system that highlights uncertainty and potential errors. For instance, if a patient’s history shows they have smoked, stopped smoking, vaped, and started smoking again. The LLM might call them a smoker but flag the comment as uncertain because the chronology is complicated, Salloum said.

Tamir added that this strategy could improve LLM and doctor collaboration by honing in on where human expertise is needed most.
 

Too Little Evaluation

For any improvement strategy to work, LLMs — and all AI-assisted healthcare tools — first need a better evaluation framework. So far, LLMs have “been used in really exciting ways but not really well-vetted ways,” Tamir said.

While some AI-assisted tools, particularly in medical imaging, have undergone rigorous FDA evaluations and earned approval, most haven’t. And because the FDA only regulates algorithms that are considered medical devices, Parikh said that most LLMs used for administrative tasks and efficiency don’t fall under the regulatory agency’s purview.

But these algorithms still have access to patient information and can directly influence patient and doctor decisions. Third-party regulatory agencies are expected to emerge, but it’s still unclear who those will be. Before developers can build a safer and more efficient LLM for healthcare, they’ll need better guidelines and guardrails. “Unless we figure out evaluation, how would we know whether the healthcare-appropriate large language models are better or worse?” Shah asked.
 

A version of this article appeared on Medscape.com.

In seconds, Ravi Parikh, MD, an oncologist at the Emory University School of Medicine in Atlanta, had a summary of his patient’s entire medical history. Normally, Parikh skimmed the cumbersome files before seeing a patient. However, the artificial intelligence (AI) tool his institution was testing could list the highlights he needed in a fraction of the time.

“On the whole, I like it ... it saves me time,” Parikh said of the tool. “But I’d be lying if I told you it was perfect all the time. It’s interpreting the [patient] history in some ways that may be inaccurate,” he said.

Within the first week of testing the tool, Parikh started to notice that the large language model (LLM) made a particular mistake in his patients with prostate cancer. If their prostate-specific antigen test results came back slightly elevated — which is part of normal variation — the LLM recorded it as disease progression. Because Parikh reviews all his notes — with or without using an AI tool — after a visit, he easily caught the mistake before it was added to the chart. “The problem, I think, is if these mistakes go under the hood,” he said.

In the data science world, these mistakes are called hallucinations. And a growing body of research suggests they’re happening more frequently than is safe for healthcare. The industry promised LLMs would alleviate administrative burden and reduce physician burnout. But so far, studies show these AI-tool mistakes often create more work for doctors, not less. To truly help physicians and be safe for patients, some experts say healthcare needs to build its own LLMs from the ground up. And all agree that the field desperately needs a way to vet these algorithms more thoroughly.
 

Prone to Error

Right now, “I think the industry is focused on taking existing LLMs and forcing them into usage for healthcare,” said Nigam H. Shah, MBBS, PhD, chief data scientist for Stanford Health. However, the value of deploying general LLMs in the healthcare space is questionable. “People are starting to wonder if we’re using these tools wrong,” he told this news organization.

In 2023, Shah and his colleagues evaluated seven LLMs on their ability to answer electronic health record–based questions. For realistic tasks, the error rate in the best cases was about 35%, he said. “To me, that rate seems a bit high ... to adopt for routine use.”

A study earlier this year by the UC San Diego School of Medicine showed that using LLMs to respond to patient messages increased the time doctors spent on messages. And this summer, a study by the clinical AI firm Mendel found that when GPT-4o or Llama-3 were used to summarize patient medical records, almost every summary contained at least one type of hallucination.

“We’ve seen cases where a patient does have drug allergies, but the system says ‘no known drug allergies’ ” in the medical history summary, said Wael Salloum, PhD, cofounder and chief science officer at Mendel. “That’s a serious hallucination.” And if physicians have to constantly verify what the system is telling them, that “defeats the purpose [of summarization],” he said.
 

A Higher Quality Diet

Part of the trouble with LLMs is that there’s just not enough high-quality information to feed them. The algorithms are insatiable, requiring vast swaths of data for training. GPT-3.5, for instance, was trained on 570 GB of data from the internet, more than 300 billion words. And to train GPT-4o, OpenAI reportedly transcribed more than 1 million hours of YouTube content.

However, the strategies that built these general LLMs don’t always translate well to healthcare. The internet is full of low-quality or misleading health information from wellness sites and supplement advertisements. And even data that are trustworthy, like the millions of clinical studies and the US Food and Drug Administration (FDA) statements, can be outdated, Salloum said. And “an LLM in training can’t distinguish good from bad,” he added.

The good news is that clinicians don’t rely on controversial information in the real world. Medical knowledge is standardized. “Healthcare is a domain rich with explicit knowledge,” Salloum said. So there’s potential to build a more reliable LLM that is guided by robust medical standards and guidelines.

It’s possible that healthcare could use small language models, which are LLM’s pocket-sized cousins, and perform tasks needing only bite-sized datasets requiring fewer resources and easier fine-tuning, according to Microsoft’s website. Shah said training these smaller models on real medical data might be an option, like an LLM meant to respond to patient messages that could be trained with real messages sent by physicians.

Several groups are already working on databases of standardized human medical knowledge or real physician responses. “Perhaps that will work better than using LLMs trained on the general internet. Those studies need to be done,” Shah said.

Jon Tamir, assistant professor of electrical and computer engineering and co-lead of the AI Health Lab at The University of Texas at Austin, said, “The community has recognized that we are entering a new era of AI where the dataset itself is the most important aspect. We need training sets that are highly curated and highly specialized.

“If the dataset is highly specialized, it will definitely help reduce hallucinations,” he said.
 

Cutting Overconfidence

A major problem with LLM mistakes is that they are often hard to detect. Hallucinations can be highly convincing even if they’re highly inaccurate, according to Tamir.

When Shah, for instance, was recently testing an LLM on de-identified patient data, he asked the LLM which blood test the patient last had. The model responded with “complete blood count [CBC].” But when he asked for the results, the model gave him white blood count and other values. “Turns out that record did not have a CBC done at all! The result was entirely made up,” he said.

Making healthcare LLMs safer and more reliable will mean training AI to acknowledge potential mistakes and uncertainty. Existing LLMs are trained to project confidence and produce a lot of answers, even when there isn’t one, Salloum said. They rarely respond with “I don’t know” even when their prediction has low confidence, he added.

Healthcare stands to benefit from a system that highlights uncertainty and potential errors. For instance, if a patient’s history shows they have smoked, stopped smoking, vaped, and started smoking again. The LLM might call them a smoker but flag the comment as uncertain because the chronology is complicated, Salloum said.

Tamir added that this strategy could improve LLM and doctor collaboration by honing in on where human expertise is needed most.
 

Too Little Evaluation

For any improvement strategy to work, LLMs — and all AI-assisted healthcare tools — first need a better evaluation framework. So far, LLMs have “been used in really exciting ways but not really well-vetted ways,” Tamir said.

While some AI-assisted tools, particularly in medical imaging, have undergone rigorous FDA evaluations and earned approval, most haven’t. And because the FDA only regulates algorithms that are considered medical devices, Parikh said that most LLMs used for administrative tasks and efficiency don’t fall under the regulatory agency’s purview.

But these algorithms still have access to patient information and can directly influence patient and doctor decisions. Third-party regulatory agencies are expected to emerge, but it’s still unclear who those will be. Before developers can build a safer and more efficient LLM for healthcare, they’ll need better guidelines and guardrails. “Unless we figure out evaluation, how would we know whether the healthcare-appropriate large language models are better or worse?” Shah asked.
 

A version of this article appeared on Medscape.com.

Labor and delivery centers run by family medicine (FM) healthcare providers have a lower cesarean delivery rate and better safety culture than centers led by obstetricians (OBs), based on observational data from Iowa hospitals.

These findings show how FM providers backed up by general surgeons can deliver a high standard of obstetric care, suggesting that this team-based model could address growing maternity care deserts across the United States, lead author Emily White VanGompel, MD, of the University of Illinois College of Medicine in Chicago, and colleagues reported.

“Despite decades of research documenting the high quality of care provided by FM physicians, controversy continues regarding whether family physicians trained in existing FM residency programs should provide intrapartum obstetric care,” the investigators wrote in Annals of Family Medicine.

This controversy, though long-standing, has gained more attention in the past decade with worsening severe maternal morbidity and maternal health disparities in rural areas, along with state-based perinatal quality initiatives to improve care and reduce severe maternal morbidity. These efforts have largely involved obstetric, nursing, and midwifery organizations, with minimal input from FM professionals.

The role of FM in these initiatives therefore remains unexplored.

This is a clear blind spot, according to White VanGompel and colleagues, who noted that 40% of counties in the United States do not have an OB or a midwife, while only 6.5% of counties lack an FM physician. In other words, FM providers may be the most rational — and widely available — specialty to close gaps in obstetric care.
 

Study Reveals Fewer C-Sections, Better Safety Culture Among FM-Led Centers

To explore the viability of an FM-led model, the investigators used a cross-sectional survey to assess the relationship between staffing models and perinatal outcomes. A total of 849 clinicians, including physicians, nurses, and midwives from 39 hospitals, were surveyed as part of a statewide quality improvement initiative designed to reduce cesarean delivery rates. The hospitals were categorized on the basis of the type of physician providing intrapartum care: Some hospitals were staffed exclusively by FM physicians (13), some by OBs only (11), and others by both types of providers (15).

The primary outcome measured was the low-risk cesarean delivery rate, specifically the nulliparous, term, singleton, vertex cesarean delivery rate.

The study found that FM-only hospitals, all of which were located in rural areas with fewer than 1000 annual births, had significantly lower cesarean delivery rates than hospitals with mixed or OB-only staffing. After adjusting for factors such as hospital birth volume, geographic location, patient body mass index, maternal age, and insurance status, FM-only hospitals had an adjusted 34.3% lower rate of cesarean sections than hospitals with both FM and OB physicians (adjusted incidence rate ratio, 0.66; 95% CI, 0.52-0.98).

In addition to lower cesarean delivery rates, the study revealed that hospitals staffed exclusively by FM physicians reported a stronger safety culture, as measured by nurse perceptions of unit norms supporting vaginal birth. Nurses at FM-only hospitals were more likely to endorse safety practices that favored vaginal delivery, a finding that was statistically significant. The study also found that nurses at FM-only hospitals rated overall unit safety culture higher than those at hospitals staffed solely by OBs or a combination of FM physicians and OBs.

“I’m not surprised [by these findings],” said Joedrecka S. Brown Speights, MD, professor and chair of the Department of Family Medicine and Rural Health at Florida State University College of Medicine, Tallahassee.

She noted that the data echo previous reports demonstrating the broader benefits of FM involvement.

“When people get primary care, life is better,” Brown Speights said, citing improved outcomes, greater health equity, and lower overall healthcare costs associated with high-quality primary care.

“That’s what we need for women and for pregnant persons, especially in rural areas,” she said.
 

The Model Itself Could Be the Biggest Finding

According to White VanGompel, the biggest finding from the study is the existence of the team-based model itself — where FM providers lead obstetric care with support from general surgeons.

“Quite honestly, many people around the country, including family physicians like myself, did not know [this model] existed and was thriving in these rural areas that are on the verge of becoming maternity care deserts,” White VanGompel said in an interview. “That makes a huge difference clinically because those are patients that otherwise wouldn’t have access to comprehensive pregnancy care.”

This FM-led model has the added advantage of improving continuity of care, she added, noting that issues like maternal mental health — a major contributor to postpartum morbidity and mortality — are a primary care issue.

“If we are not involved in that patient’s pregnancy care, and we don’t know that they’ve had this postpartum course or they’ve had antepartum depression, it’s very hard for us to then jump in and accurately treat that person,” White VanGompel said. “If we’re involved in the entire course of care, we can make that contribution.”

Emilio A. Russo, MD, Marie Lahasky Professor of Family Medicine and chair of the Department of Family Medicine at Louisiana State University (LSU) Health Sciences Center New Orleans, and program director of the LSU Rural Family Medicine Program, Bogalusa, Louisiana, agreed that FM providers’ more continuous care, along with experience treating both mothers and babies, make them invaluable in the maternity care setting.

“We are missing the opportunity to incorporate family physicians and nurse midwives into the continuum of care for women, especially in these remote areas,” Russo said in an interview. “Family physicians and nurse midwives are the only two [groups] in the health system trained and licensed to care for both mother and baby, and I have to believe that there’s something profoundly important about that.”
 

Barriers May Block FM Providers From Obstetric Practice

In a recent Birth editorial, Simone Hampton, MD, of Carle Health Family Medicine, Urbana, Illinois, explored a key question: Why aren’t we using FM to help confront the maternal mortality crisis in the United States?

Hampton described how obstetric care is often siloed between specialties and barriers, including insufficient training, organizational constraints, and malpractice coverage, deter FM physicians from practicing obstetrics.

In an additional written comment, Hampton suggested that family doctors also face misconceptions about their ability to provide obstetric care, even with rigorous training and a comprehensive skill set.

“We are interested in caring for families,” Hampton said, emphasizing how FM providers are uniquely trained to care for the maternal dyad in a way that OBs are not and often view birth as a more natural process that typically does not require intervention.

Unfortunately, hospital administrators often maintain a different view, Brown Speights said, describing how some centers limit obstetric care privileges exclusively to OBs or require case volume minimums that can be tough to reach in a rural setting.

“If you have low-volume places, you can have a challenge meeting the numbers to keep up the requirements to get credentialed to practice obstetrics at the hospital,” she said, which only exacerbates gaps in maternity care access.

“This type of skill set in a rural place often, by default, represents a lower volume,” Russo said. “So how do the interests of competency and access intersect in this space?”

Generating more data to support the quality of FM-led obstetric models could be the clearest path forward, according to White VanGompel. She suggested that team-based approaches like the one described in the present study deserve further investigation in other hospital systems.

Until then, this gap in maternity care remains an ongoing, and often personal, concern.

“The more I do this quality work, the more I’m in these rooms where I’m the only family physician and I’m surrounded by all of these amazing labor and delivery nurses and obstetricians and maternal-fetal medicine doctors and midwives and doulas,” White VanGompel said. “I’m just constantly asking myself, Why am I the only family doctor in the room?”

This study was supported by the Agency for Healthcare Research and Quality and the North Shore Auxiliary. The Iowa Maternal Quality Care Collaborative is supported by a State Maternal Health Innovation award from the Health Resources and Services Administration. The investigators, Hampton and Brown Speights, disclosed no conflicts of interest.

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

Labor and delivery centers run by family medicine (FM) healthcare providers have a lower cesarean delivery rate and better safety culture than centers led by obstetricians (OBs), based on observational data from Iowa hospitals.

These findings show how FM providers backed up by general surgeons can deliver a high standard of obstetric care, suggesting that this team-based model could address growing maternity care deserts across the United States, lead author Emily White VanGompel, MD, of the University of Illinois College of Medicine in Chicago, and colleagues reported.

“Despite decades of research documenting the high quality of care provided by FM physicians, controversy continues regarding whether family physicians trained in existing FM residency programs should provide intrapartum obstetric care,” the investigators wrote in Annals of Family Medicine.

This controversy, though long-standing, has gained more attention in the past decade with worsening severe maternal morbidity and maternal health disparities in rural areas, along with state-based perinatal quality initiatives to improve care and reduce severe maternal morbidity. These efforts have largely involved obstetric, nursing, and midwifery organizations, with minimal input from FM professionals.

The role of FM in these initiatives therefore remains unexplored.

This is a clear blind spot, according to White VanGompel and colleagues, who noted that 40% of counties in the United States do not have an OB or a midwife, while only 6.5% of counties lack an FM physician. In other words, FM providers may be the most rational — and widely available — specialty to close gaps in obstetric care.
 

Study Reveals Fewer C-Sections, Better Safety Culture Among FM-Led Centers

To explore the viability of an FM-led model, the investigators used a cross-sectional survey to assess the relationship between staffing models and perinatal outcomes. A total of 849 clinicians, including physicians, nurses, and midwives from 39 hospitals, were surveyed as part of a statewide quality improvement initiative designed to reduce cesarean delivery rates. The hospitals were categorized on the basis of the type of physician providing intrapartum care: Some hospitals were staffed exclusively by FM physicians (13), some by OBs only (11), and others by both types of providers (15).

The primary outcome measured was the low-risk cesarean delivery rate, specifically the nulliparous, term, singleton, vertex cesarean delivery rate.

The study found that FM-only hospitals, all of which were located in rural areas with fewer than 1000 annual births, had significantly lower cesarean delivery rates than hospitals with mixed or OB-only staffing. After adjusting for factors such as hospital birth volume, geographic location, patient body mass index, maternal age, and insurance status, FM-only hospitals had an adjusted 34.3% lower rate of cesarean sections than hospitals with both FM and OB physicians (adjusted incidence rate ratio, 0.66; 95% CI, 0.52-0.98).

In addition to lower cesarean delivery rates, the study revealed that hospitals staffed exclusively by FM physicians reported a stronger safety culture, as measured by nurse perceptions of unit norms supporting vaginal birth. Nurses at FM-only hospitals were more likely to endorse safety practices that favored vaginal delivery, a finding that was statistically significant. The study also found that nurses at FM-only hospitals rated overall unit safety culture higher than those at hospitals staffed solely by OBs or a combination of FM physicians and OBs.

“I’m not surprised [by these findings],” said Joedrecka S. Brown Speights, MD, professor and chair of the Department of Family Medicine and Rural Health at Florida State University College of Medicine, Tallahassee.

She noted that the data echo previous reports demonstrating the broader benefits of FM involvement.

“When people get primary care, life is better,” Brown Speights said, citing improved outcomes, greater health equity, and lower overall healthcare costs associated with high-quality primary care.

“That’s what we need for women and for pregnant persons, especially in rural areas,” she said.
 

The Model Itself Could Be the Biggest Finding

According to White VanGompel, the biggest finding from the study is the existence of the team-based model itself — where FM providers lead obstetric care with support from general surgeons.

“Quite honestly, many people around the country, including family physicians like myself, did not know [this model] existed and was thriving in these rural areas that are on the verge of becoming maternity care deserts,” White VanGompel said in an interview. “That makes a huge difference clinically because those are patients that otherwise wouldn’t have access to comprehensive pregnancy care.”

This FM-led model has the added advantage of improving continuity of care, she added, noting that issues like maternal mental health — a major contributor to postpartum morbidity and mortality — are a primary care issue.

“If we are not involved in that patient’s pregnancy care, and we don’t know that they’ve had this postpartum course or they’ve had antepartum depression, it’s very hard for us to then jump in and accurately treat that person,” White VanGompel said. “If we’re involved in the entire course of care, we can make that contribution.”

Emilio A. Russo, MD, Marie Lahasky Professor of Family Medicine and chair of the Department of Family Medicine at Louisiana State University (LSU) Health Sciences Center New Orleans, and program director of the LSU Rural Family Medicine Program, Bogalusa, Louisiana, agreed that FM providers’ more continuous care, along with experience treating both mothers and babies, make them invaluable in the maternity care setting.

“We are missing the opportunity to incorporate family physicians and nurse midwives into the continuum of care for women, especially in these remote areas,” Russo said in an interview. “Family physicians and nurse midwives are the only two [groups] in the health system trained and licensed to care for both mother and baby, and I have to believe that there’s something profoundly important about that.”
 

Barriers May Block FM Providers From Obstetric Practice

In a recent Birth editorial, Simone Hampton, MD, of Carle Health Family Medicine, Urbana, Illinois, explored a key question: Why aren’t we using FM to help confront the maternal mortality crisis in the United States?

Hampton described how obstetric care is often siloed between specialties and barriers, including insufficient training, organizational constraints, and malpractice coverage, deter FM physicians from practicing obstetrics.

In an additional written comment, Hampton suggested that family doctors also face misconceptions about their ability to provide obstetric care, even with rigorous training and a comprehensive skill set.

“We are interested in caring for families,” Hampton said, emphasizing how FM providers are uniquely trained to care for the maternal dyad in a way that OBs are not and often view birth as a more natural process that typically does not require intervention.

Unfortunately, hospital administrators often maintain a different view, Brown Speights said, describing how some centers limit obstetric care privileges exclusively to OBs or require case volume minimums that can be tough to reach in a rural setting.

“If you have low-volume places, you can have a challenge meeting the numbers to keep up the requirements to get credentialed to practice obstetrics at the hospital,” she said, which only exacerbates gaps in maternity care access.

“This type of skill set in a rural place often, by default, represents a lower volume,” Russo said. “So how do the interests of competency and access intersect in this space?”

Generating more data to support the quality of FM-led obstetric models could be the clearest path forward, according to White VanGompel. She suggested that team-based approaches like the one described in the present study deserve further investigation in other hospital systems.

Until then, this gap in maternity care remains an ongoing, and often personal, concern.

“The more I do this quality work, the more I’m in these rooms where I’m the only family physician and I’m surrounded by all of these amazing labor and delivery nurses and obstetricians and maternal-fetal medicine doctors and midwives and doulas,” White VanGompel said. “I’m just constantly asking myself, Why am I the only family doctor in the room?”

This study was supported by the Agency for Healthcare Research and Quality and the North Shore Auxiliary. The Iowa Maternal Quality Care Collaborative is supported by a State Maternal Health Innovation award from the Health Resources and Services Administration. The investigators, Hampton and Brown Speights, disclosed no conflicts of interest.

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

Labor and delivery centers run by family medicine (FM) healthcare providers have a lower cesarean delivery rate and better safety culture than centers led by obstetricians (OBs), based on observational data from Iowa hospitals.

These findings show how FM providers backed up by general surgeons can deliver a high standard of obstetric care, suggesting that this team-based model could address growing maternity care deserts across the United States, lead author Emily White VanGompel, MD, of the University of Illinois College of Medicine in Chicago, and colleagues reported.

“Despite decades of research documenting the high quality of care provided by FM physicians, controversy continues regarding whether family physicians trained in existing FM residency programs should provide intrapartum obstetric care,” the investigators wrote in Annals of Family Medicine.

This controversy, though long-standing, has gained more attention in the past decade with worsening severe maternal morbidity and maternal health disparities in rural areas, along with state-based perinatal quality initiatives to improve care and reduce severe maternal morbidity. These efforts have largely involved obstetric, nursing, and midwifery organizations, with minimal input from FM professionals.

The role of FM in these initiatives therefore remains unexplored.

This is a clear blind spot, according to White VanGompel and colleagues, who noted that 40% of counties in the United States do not have an OB or a midwife, while only 6.5% of counties lack an FM physician. In other words, FM providers may be the most rational — and widely available — specialty to close gaps in obstetric care.
 

Study Reveals Fewer C-Sections, Better Safety Culture Among FM-Led Centers

To explore the viability of an FM-led model, the investigators used a cross-sectional survey to assess the relationship between staffing models and perinatal outcomes. A total of 849 clinicians, including physicians, nurses, and midwives from 39 hospitals, were surveyed as part of a statewide quality improvement initiative designed to reduce cesarean delivery rates. The hospitals were categorized on the basis of the type of physician providing intrapartum care: Some hospitals were staffed exclusively by FM physicians (13), some by OBs only (11), and others by both types of providers (15).

The primary outcome measured was the low-risk cesarean delivery rate, specifically the nulliparous, term, singleton, vertex cesarean delivery rate.

The study found that FM-only hospitals, all of which were located in rural areas with fewer than 1000 annual births, had significantly lower cesarean delivery rates than hospitals with mixed or OB-only staffing. After adjusting for factors such as hospital birth volume, geographic location, patient body mass index, maternal age, and insurance status, FM-only hospitals had an adjusted 34.3% lower rate of cesarean sections than hospitals with both FM and OB physicians (adjusted incidence rate ratio, 0.66; 95% CI, 0.52-0.98).

In addition to lower cesarean delivery rates, the study revealed that hospitals staffed exclusively by FM physicians reported a stronger safety culture, as measured by nurse perceptions of unit norms supporting vaginal birth. Nurses at FM-only hospitals were more likely to endorse safety practices that favored vaginal delivery, a finding that was statistically significant. The study also found that nurses at FM-only hospitals rated overall unit safety culture higher than those at hospitals staffed solely by OBs or a combination of FM physicians and OBs.

“I’m not surprised [by these findings],” said Joedrecka S. Brown Speights, MD, professor and chair of the Department of Family Medicine and Rural Health at Florida State University College of Medicine, Tallahassee.

She noted that the data echo previous reports demonstrating the broader benefits of FM involvement.

“When people get primary care, life is better,” Brown Speights said, citing improved outcomes, greater health equity, and lower overall healthcare costs associated with high-quality primary care.

“That’s what we need for women and for pregnant persons, especially in rural areas,” she said.
 

The Model Itself Could Be the Biggest Finding

According to White VanGompel, the biggest finding from the study is the existence of the team-based model itself — where FM providers lead obstetric care with support from general surgeons.

“Quite honestly, many people around the country, including family physicians like myself, did not know [this model] existed and was thriving in these rural areas that are on the verge of becoming maternity care deserts,” White VanGompel said in an interview. “That makes a huge difference clinically because those are patients that otherwise wouldn’t have access to comprehensive pregnancy care.”

This FM-led model has the added advantage of improving continuity of care, she added, noting that issues like maternal mental health — a major contributor to postpartum morbidity and mortality — are a primary care issue.

“If we are not involved in that patient’s pregnancy care, and we don’t know that they’ve had this postpartum course or they’ve had antepartum depression, it’s very hard for us to then jump in and accurately treat that person,” White VanGompel said. “If we’re involved in the entire course of care, we can make that contribution.”

Emilio A. Russo, MD, Marie Lahasky Professor of Family Medicine and chair of the Department of Family Medicine at Louisiana State University (LSU) Health Sciences Center New Orleans, and program director of the LSU Rural Family Medicine Program, Bogalusa, Louisiana, agreed that FM providers’ more continuous care, along with experience treating both mothers and babies, make them invaluable in the maternity care setting.

“We are missing the opportunity to incorporate family physicians and nurse midwives into the continuum of care for women, especially in these remote areas,” Russo said in an interview. “Family physicians and nurse midwives are the only two [groups] in the health system trained and licensed to care for both mother and baby, and I have to believe that there’s something profoundly important about that.”
 

Barriers May Block FM Providers From Obstetric Practice

In a recent Birth editorial, Simone Hampton, MD, of Carle Health Family Medicine, Urbana, Illinois, explored a key question: Why aren’t we using FM to help confront the maternal mortality crisis in the United States?

Hampton described how obstetric care is often siloed between specialties and barriers, including insufficient training, organizational constraints, and malpractice coverage, deter FM physicians from practicing obstetrics.

In an additional written comment, Hampton suggested that family doctors also face misconceptions about their ability to provide obstetric care, even with rigorous training and a comprehensive skill set.

“We are interested in caring for families,” Hampton said, emphasizing how FM providers are uniquely trained to care for the maternal dyad in a way that OBs are not and often view birth as a more natural process that typically does not require intervention.

Unfortunately, hospital administrators often maintain a different view, Brown Speights said, describing how some centers limit obstetric care privileges exclusively to OBs or require case volume minimums that can be tough to reach in a rural setting.

“If you have low-volume places, you can have a challenge meeting the numbers to keep up the requirements to get credentialed to practice obstetrics at the hospital,” she said, which only exacerbates gaps in maternity care access.

“This type of skill set in a rural place often, by default, represents a lower volume,” Russo said. “So how do the interests of competency and access intersect in this space?”

Generating more data to support the quality of FM-led obstetric models could be the clearest path forward, according to White VanGompel. She suggested that team-based approaches like the one described in the present study deserve further investigation in other hospital systems.

Until then, this gap in maternity care remains an ongoing, and often personal, concern.

“The more I do this quality work, the more I’m in these rooms where I’m the only family physician and I’m surrounded by all of these amazing labor and delivery nurses and obstetricians and maternal-fetal medicine doctors and midwives and doulas,” White VanGompel said. “I’m just constantly asking myself, Why am I the only family doctor in the room?”

This study was supported by the Agency for Healthcare Research and Quality and the North Shore Auxiliary. The Iowa Maternal Quality Care Collaborative is supported by a State Maternal Health Innovation award from the Health Resources and Services Administration. The investigators, Hampton and Brown Speights, disclosed no conflicts of interest.

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

Trying to reduce your carbohydrate intake means going against nearly a million years of evolution.

Humans are among a few species with multiple copies of certain genes that help us break down starch — carbs like potatoes, beans, corn, and grains — so that we can turn it into energy our bodies can use.

However, it’s been difficult for researchers to pinpoint when in human history we acquired multiple copies of these genes because they’re in a region of the genome that’s hard to sequence.

A recent study published in Science suggests that humans may have developed multiple copies of the gene for amylase — an enzyme that’s the first step in starch digestion — over 800,000 years ago, long before the agricultural revolution. This genetic change could have helped us adapt to eating starchy foods.

The study shows how “what your ancestors ate thousands of years ago could be affecting our genetics today,” said Kelsey Jorgensen, PhD, a biological anthropologist at The University of Kansas, Lawrence, who was not involved in the study.

The double-edged sword has sharpened over all those centuries. On one hand, the human body needs and craves carbs to function. On the other hand, our modern-day consumption of carbs, especially calorie-dense/nutritionally-barren processed carbs, has long since passed “healthy.”
 

How Researchers Found Our Carb-Lover Gene

The enzyme amylase turns complex carbs into maltose, a sweet-tasting sugar that is made of two glucose molecules linked together. We make two kinds of amylases: Salivary amylase that breaks down carbs in our mouths and pancreatic amylase that is secreted into our small intestines.

Modern humans have multiple copies of both amylases. Past research showed that human populations with diets high in starch can have up to nine copies of the gene for salivary amylase, called AMY1.

To pinpoint when in human history we acquired multiple copies of AMY1, the new study utilized novel techniques, called optical genome mapping and long-read sequencing, to sequence and analyze the genes. They sequenced 98 modern-day samples and 68 ancient DNA samples, including one from a Siberian person who lived 45,000 years ago.

The ancient DNA data in the study allowed the researchers to track how the number of amylase genes changed over time, said George Perry, PhD, an anthropological geneticist at The Pennsylvania State University-University Park (he was not involved in the study).

Based on the sequencing, the team analyzed changes in the genes in their samples to gauge evolutionary timelines. Perry noted that this was a “very clever approach to estimating the amylase copy number mutation rate, which in turn can really help in testing evolutionary hypotheses.”

The researchers found that even before farming, hunter-gatherers had between four and eight AMY1 genes in their cells. This suggests that people across Eurasia already had a number of these genes long before they started growing crops. (Recent research indicates that Neanderthals also ate starchy foods.)

“Even archaic hominins had these [genetic] variations and that indicates that they were consuming starch,” said Feyza Yilmaz, PhD, an associate computational scientist at The Jackson Laboratory in Bar Harbor, Maine, and a lead author of the study.

However, 4000 years ago, after the agricultural revolution, the research indicates that there were even more AMY1 copies acquired. Yilmaz noted, “with the advance of agriculture, we see an increase in high amylase copy number haplotypes. So genetic variation goes hand in hand with adaptation to the environment.” 

A previous study showed that species that share an environment with humans, such as dogs and pigs, also have copy number variation of amylase genes, said Yilmaz, indicating a link between genome changes and an increase in starch consumption.
 

Potential Health Impacts on Modern Humans

The duplications in the AMY1 gene could have allowed humans to better digest starches. And it’s conceivable that having more copies of the gene means being able to break down starches even more efficiently, and those with more copies “may be more prone to having high blood sugar, prediabetes, that sort of thing,” Jorgensen said.

Whether those with more AMY1 genes have more health risks is an active area of research. “Researchers tested whether there’s a correlation between AMY1 gene copies and diabetes or BMI [body mass index]. And so far, some studies show that there is indeed correlation, but other studies show that there is no correlation at all,” said Yilmaz.

Yilmaz pointed out that only 5 or 10% of carb digestion happens in our mouths, the rest occurs in our small intestine, plus there are many other factors involved in eating and metabolism.

“I am really looking forward to seeing studies which truly figure out the connection between AMY1 copy number and metabolic health and also what type of factors play a role in metabolic health,” said Yilmaz.

It’s also possible that having more AMY1 copies could lead to more carb cravings as the enzyme creates a type of sugar in our mouths. “Previous studies show that there’s a correlation between AMY1 copy number and also the amylase enzyme levels, so the faster we process the starch, the taste [of starches] will be sweeter,” said Yilmaz.

However, the link between cravings and copy numbers isn’t clear. And we don’t exactly know what came first — did the starch in humans’ diet lead to more copies of amylase genes, or did the copies of the amylase genes drive cravings that lead us to cultivate more carbs? We’ll need more research to find out.
 

How Will Today’s Processed Carbs Affect Our Genes Tomorrow?

As our diet changes to increasingly include processed carbs, what will happen to our AMY1 genes is fuzzy. “I don’t know what this could do to our genomes in the next 1000 years or more than 1000 years,” Yilmaz noted, but she said from the evidence it seems as though we may have peaked in AMY1 copies.

Jorgensen noted that this research is focused on a European population. She wonders whether the pattern of AMY1 duplication will be repeated in other populations “because the rise of starch happened first in the Middle East and then Europe and then later in the Americas,” she said.

“There’s individual variation and then there’s population-wide variation,” Jorgensen pointed out. She speculates that the historical diet of different cultures could explain population-based variations in AMY1 genes — it’s something future research could investigate. Other populations may also experience genetic changes as much of the world shifts to a more carb-heavy Western diet.

Overall, this research adds to the growing evidence that humans have a long history of loving carbs — for better and, at least over our most recent history and immediate future, for worse.
 

A version of this article appeared on Medscape.com.

Trying to reduce your carbohydrate intake means going against nearly a million years of evolution.

Humans are among a few species with multiple copies of certain genes that help us break down starch — carbs like potatoes, beans, corn, and grains — so that we can turn it into energy our bodies can use.

However, it’s been difficult for researchers to pinpoint when in human history we acquired multiple copies of these genes because they’re in a region of the genome that’s hard to sequence.

A recent study published in Science suggests that humans may have developed multiple copies of the gene for amylase — an enzyme that’s the first step in starch digestion — over 800,000 years ago, long before the agricultural revolution. This genetic change could have helped us adapt to eating starchy foods.

The study shows how “what your ancestors ate thousands of years ago could be affecting our genetics today,” said Kelsey Jorgensen, PhD, a biological anthropologist at The University of Kansas, Lawrence, who was not involved in the study.

The double-edged sword has sharpened over all those centuries. On one hand, the human body needs and craves carbs to function. On the other hand, our modern-day consumption of carbs, especially calorie-dense/nutritionally-barren processed carbs, has long since passed “healthy.”
 

How Researchers Found Our Carb-Lover Gene

The enzyme amylase turns complex carbs into maltose, a sweet-tasting sugar that is made of two glucose molecules linked together. We make two kinds of amylases: Salivary amylase that breaks down carbs in our mouths and pancreatic amylase that is secreted into our small intestines.

Modern humans have multiple copies of both amylases. Past research showed that human populations with diets high in starch can have up to nine copies of the gene for salivary amylase, called AMY1.

To pinpoint when in human history we acquired multiple copies of AMY1, the new study utilized novel techniques, called optical genome mapping and long-read sequencing, to sequence and analyze the genes. They sequenced 98 modern-day samples and 68 ancient DNA samples, including one from a Siberian person who lived 45,000 years ago.

The ancient DNA data in the study allowed the researchers to track how the number of amylase genes changed over time, said George Perry, PhD, an anthropological geneticist at The Pennsylvania State University-University Park (he was not involved in the study).

Based on the sequencing, the team analyzed changes in the genes in their samples to gauge evolutionary timelines. Perry noted that this was a “very clever approach to estimating the amylase copy number mutation rate, which in turn can really help in testing evolutionary hypotheses.”

The researchers found that even before farming, hunter-gatherers had between four and eight AMY1 genes in their cells. This suggests that people across Eurasia already had a number of these genes long before they started growing crops. (Recent research indicates that Neanderthals also ate starchy foods.)

“Even archaic hominins had these [genetic] variations and that indicates that they were consuming starch,” said Feyza Yilmaz, PhD, an associate computational scientist at The Jackson Laboratory in Bar Harbor, Maine, and a lead author of the study.

However, 4000 years ago, after the agricultural revolution, the research indicates that there were even more AMY1 copies acquired. Yilmaz noted, “with the advance of agriculture, we see an increase in high amylase copy number haplotypes. So genetic variation goes hand in hand with adaptation to the environment.” 

A previous study showed that species that share an environment with humans, such as dogs and pigs, also have copy number variation of amylase genes, said Yilmaz, indicating a link between genome changes and an increase in starch consumption.
 

Potential Health Impacts on Modern Humans

The duplications in the AMY1 gene could have allowed humans to better digest starches. And it’s conceivable that having more copies of the gene means being able to break down starches even more efficiently, and those with more copies “may be more prone to having high blood sugar, prediabetes, that sort of thing,” Jorgensen said.

Whether those with more AMY1 genes have more health risks is an active area of research. “Researchers tested whether there’s a correlation between AMY1 gene copies and diabetes or BMI [body mass index]. And so far, some studies show that there is indeed correlation, but other studies show that there is no correlation at all,” said Yilmaz.

Yilmaz pointed out that only 5 or 10% of carb digestion happens in our mouths, the rest occurs in our small intestine, plus there are many other factors involved in eating and metabolism.

“I am really looking forward to seeing studies which truly figure out the connection between AMY1 copy number and metabolic health and also what type of factors play a role in metabolic health,” said Yilmaz.

It’s also possible that having more AMY1 copies could lead to more carb cravings as the enzyme creates a type of sugar in our mouths. “Previous studies show that there’s a correlation between AMY1 copy number and also the amylase enzyme levels, so the faster we process the starch, the taste [of starches] will be sweeter,” said Yilmaz.

However, the link between cravings and copy numbers isn’t clear. And we don’t exactly know what came first — did the starch in humans’ diet lead to more copies of amylase genes, or did the copies of the amylase genes drive cravings that lead us to cultivate more carbs? We’ll need more research to find out.
 

How Will Today’s Processed Carbs Affect Our Genes Tomorrow?

As our diet changes to increasingly include processed carbs, what will happen to our AMY1 genes is fuzzy. “I don’t know what this could do to our genomes in the next 1000 years or more than 1000 years,” Yilmaz noted, but she said from the evidence it seems as though we may have peaked in AMY1 copies.

Jorgensen noted that this research is focused on a European population. She wonders whether the pattern of AMY1 duplication will be repeated in other populations “because the rise of starch happened first in the Middle East and then Europe and then later in the Americas,” she said.

“There’s individual variation and then there’s population-wide variation,” Jorgensen pointed out. She speculates that the historical diet of different cultures could explain population-based variations in AMY1 genes — it’s something future research could investigate. Other populations may also experience genetic changes as much of the world shifts to a more carb-heavy Western diet.

Overall, this research adds to the growing evidence that humans have a long history of loving carbs — for better and, at least over our most recent history and immediate future, for worse.
 

A version of this article appeared on Medscape.com.

Trying to reduce your carbohydrate intake means going against nearly a million years of evolution.

Humans are among a few species with multiple copies of certain genes that help us break down starch — carbs like potatoes, beans, corn, and grains — so that we can turn it into energy our bodies can use.

However, it’s been difficult for researchers to pinpoint when in human history we acquired multiple copies of these genes because they’re in a region of the genome that’s hard to sequence.

A recent study published in Science suggests that humans may have developed multiple copies of the gene for amylase — an enzyme that’s the first step in starch digestion — over 800,000 years ago, long before the agricultural revolution. This genetic change could have helped us adapt to eating starchy foods.

The study shows how “what your ancestors ate thousands of years ago could be affecting our genetics today,” said Kelsey Jorgensen, PhD, a biological anthropologist at The University of Kansas, Lawrence, who was not involved in the study.

The double-edged sword has sharpened over all those centuries. On one hand, the human body needs and craves carbs to function. On the other hand, our modern-day consumption of carbs, especially calorie-dense/nutritionally-barren processed carbs, has long since passed “healthy.”
 

How Researchers Found Our Carb-Lover Gene

The enzyme amylase turns complex carbs into maltose, a sweet-tasting sugar that is made of two glucose molecules linked together. We make two kinds of amylases: Salivary amylase that breaks down carbs in our mouths and pancreatic amylase that is secreted into our small intestines.

Modern humans have multiple copies of both amylases. Past research showed that human populations with diets high in starch can have up to nine copies of the gene for salivary amylase, called AMY1.

To pinpoint when in human history we acquired multiple copies of AMY1, the new study utilized novel techniques, called optical genome mapping and long-read sequencing, to sequence and analyze the genes. They sequenced 98 modern-day samples and 68 ancient DNA samples, including one from a Siberian person who lived 45,000 years ago.

The ancient DNA data in the study allowed the researchers to track how the number of amylase genes changed over time, said George Perry, PhD, an anthropological geneticist at The Pennsylvania State University-University Park (he was not involved in the study).

Based on the sequencing, the team analyzed changes in the genes in their samples to gauge evolutionary timelines. Perry noted that this was a “very clever approach to estimating the amylase copy number mutation rate, which in turn can really help in testing evolutionary hypotheses.”

The researchers found that even before farming, hunter-gatherers had between four and eight AMY1 genes in their cells. This suggests that people across Eurasia already had a number of these genes long before they started growing crops. (Recent research indicates that Neanderthals also ate starchy foods.)

“Even archaic hominins had these [genetic] variations and that indicates that they were consuming starch,” said Feyza Yilmaz, PhD, an associate computational scientist at The Jackson Laboratory in Bar Harbor, Maine, and a lead author of the study.

However, 4000 years ago, after the agricultural revolution, the research indicates that there were even more AMY1 copies acquired. Yilmaz noted, “with the advance of agriculture, we see an increase in high amylase copy number haplotypes. So genetic variation goes hand in hand with adaptation to the environment.” 

A previous study showed that species that share an environment with humans, such as dogs and pigs, also have copy number variation of amylase genes, said Yilmaz, indicating a link between genome changes and an increase in starch consumption.
 

Potential Health Impacts on Modern Humans

The duplications in the AMY1 gene could have allowed humans to better digest starches. And it’s conceivable that having more copies of the gene means being able to break down starches even more efficiently, and those with more copies “may be more prone to having high blood sugar, prediabetes, that sort of thing,” Jorgensen said.

Whether those with more AMY1 genes have more health risks is an active area of research. “Researchers tested whether there’s a correlation between AMY1 gene copies and diabetes or BMI [body mass index]. And so far, some studies show that there is indeed correlation, but other studies show that there is no correlation at all,” said Yilmaz.

Yilmaz pointed out that only 5 or 10% of carb digestion happens in our mouths, the rest occurs in our small intestine, plus there are many other factors involved in eating and metabolism.

“I am really looking forward to seeing studies which truly figure out the connection between AMY1 copy number and metabolic health and also what type of factors play a role in metabolic health,” said Yilmaz.

It’s also possible that having more AMY1 copies could lead to more carb cravings as the enzyme creates a type of sugar in our mouths. “Previous studies show that there’s a correlation between AMY1 copy number and also the amylase enzyme levels, so the faster we process the starch, the taste [of starches] will be sweeter,” said Yilmaz.

However, the link between cravings and copy numbers isn’t clear. And we don’t exactly know what came first — did the starch in humans’ diet lead to more copies of amylase genes, or did the copies of the amylase genes drive cravings that lead us to cultivate more carbs? We’ll need more research to find out.
 

How Will Today’s Processed Carbs Affect Our Genes Tomorrow?

As our diet changes to increasingly include processed carbs, what will happen to our AMY1 genes is fuzzy. “I don’t know what this could do to our genomes in the next 1000 years or more than 1000 years,” Yilmaz noted, but she said from the evidence it seems as though we may have peaked in AMY1 copies.

Jorgensen noted that this research is focused on a European population. She wonders whether the pattern of AMY1 duplication will be repeated in other populations “because the rise of starch happened first in the Middle East and then Europe and then later in the Americas,” she said.

“There’s individual variation and then there’s population-wide variation,” Jorgensen pointed out. She speculates that the historical diet of different cultures could explain population-based variations in AMY1 genes — it’s something future research could investigate. Other populations may also experience genetic changes as much of the world shifts to a more carb-heavy Western diet.

Overall, this research adds to the growing evidence that humans have a long history of loving carbs — for better and, at least over our most recent history and immediate future, for worse.
 

A version of this article appeared on Medscape.com.

As a physician, you might be contacted by the media to provide your professional opinion and advice. Or you might be looking for media interview opportunities to market your practice or side project. And if you do research, media interviews can be an effective way to spread the word. It’s important to prepare for a media interview so that you achieve the outcome you are looking for. Here are six tips I learned from writing health articles, interviewing experts, and being interviewed myself. 

Keep your message simple. When you are a subject expert, you might think that the basics are obvious or even boring, and that the nuances are more important. However, most of the audience is looking for big-picture information that they can apply to their lives. Consider a few key takeaways, keeping in mind that your interview is likely to be edited to short sound bites or a few quotes. It may help to jot down notes so that you cover the fundamentals clearly. You could even write and rehearse a script beforehand. If there is something complicated or subtle that you want to convey, you can preface it by saying, “This is confusing but very important …” to let the audience know to give extra consideration to what you are about to say.

Avoid extremes and hyperbole. Sometimes, exaggerated statements make their way into medical discussions. Statements such as “it doesn’t matter how many calories you consume — it’s all about the quality” are common oversimplifications. But you might be upset to see your name next to a comment like this because it is not actually correct. Check the phrasing of your key takeaways to avoid being stuck defending or explaining an inaccurate statement when your patients ask you about it later. 

Ask the interviewers what they are looking for. Many medical topics have some controversial element, so it is good to know what you’re getting into. Find out the purpose of the article or interview before you decide whether it is right for you. It could be about another doctor in town who is being sued; if you don’t want to be associated with that story, it might be best to decline the interview. 

Explain your goals. You might accept or pursue an interview to raise awareness about an underrecognized condition. You might want the public to identify and get help for early symptoms, or you might want to create empathy for people coping with a disease you treat. Consider why you are participating in an interview, and communicate that to the interviewer to ensure that your objective can be part of the final product. 

Know whom you’re dealing with. It is good to learn about the publication/media channel before you agree to participate. It may have a political bias, or perhaps the interview is intended to promote a specific product. If you agree with and support their purposes, then you may be happy to lend your opinion. But learning about the “voice” of the publication in advance allows you to make an informed decision about whether you want to be identified with a particular political ideology or product endorsement.

Ask to see your quotes before publication. It’s good to have the opportunity to make corrections in case you are accidentally misquoted or misunderstood. It is best to ask to see quotes before you agree to the interview. Some reporters may agree to (or even prefer) a written question-and-answer format so that they can directly quote your responses without rephrasing your words. You could suggest this, especially if you are too busy for a call or live meeting.

As a physician, your insights and advice can be highly beneficial to others. You can also use media interviews to propel your career forward. Doing your homework can ensure that you will be pleased with the final product and how your words were used. 
 

Dr. Moawad, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

As a physician, you might be contacted by the media to provide your professional opinion and advice. Or you might be looking for media interview opportunities to market your practice or side project. And if you do research, media interviews can be an effective way to spread the word. It’s important to prepare for a media interview so that you achieve the outcome you are looking for. Here are six tips I learned from writing health articles, interviewing experts, and being interviewed myself. 

Keep your message simple. When you are a subject expert, you might think that the basics are obvious or even boring, and that the nuances are more important. However, most of the audience is looking for big-picture information that they can apply to their lives. Consider a few key takeaways, keeping in mind that your interview is likely to be edited to short sound bites or a few quotes. It may help to jot down notes so that you cover the fundamentals clearly. You could even write and rehearse a script beforehand. If there is something complicated or subtle that you want to convey, you can preface it by saying, “This is confusing but very important …” to let the audience know to give extra consideration to what you are about to say.

Avoid extremes and hyperbole. Sometimes, exaggerated statements make their way into medical discussions. Statements such as “it doesn’t matter how many calories you consume — it’s all about the quality” are common oversimplifications. But you might be upset to see your name next to a comment like this because it is not actually correct. Check the phrasing of your key takeaways to avoid being stuck defending or explaining an inaccurate statement when your patients ask you about it later. 

Ask the interviewers what they are looking for. Many medical topics have some controversial element, so it is good to know what you’re getting into. Find out the purpose of the article or interview before you decide whether it is right for you. It could be about another doctor in town who is being sued; if you don’t want to be associated with that story, it might be best to decline the interview. 

Explain your goals. You might accept or pursue an interview to raise awareness about an underrecognized condition. You might want the public to identify and get help for early symptoms, or you might want to create empathy for people coping with a disease you treat. Consider why you are participating in an interview, and communicate that to the interviewer to ensure that your objective can be part of the final product. 

Know whom you’re dealing with. It is good to learn about the publication/media channel before you agree to participate. It may have a political bias, or perhaps the interview is intended to promote a specific product. If you agree with and support their purposes, then you may be happy to lend your opinion. But learning about the “voice” of the publication in advance allows you to make an informed decision about whether you want to be identified with a particular political ideology or product endorsement.

Ask to see your quotes before publication. It’s good to have the opportunity to make corrections in case you are accidentally misquoted or misunderstood. It is best to ask to see quotes before you agree to the interview. Some reporters may agree to (or even prefer) a written question-and-answer format so that they can directly quote your responses without rephrasing your words. You could suggest this, especially if you are too busy for a call or live meeting.

As a physician, your insights and advice can be highly beneficial to others. You can also use media interviews to propel your career forward. Doing your homework can ensure that you will be pleased with the final product and how your words were used. 
 

Dr. Moawad, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

As a physician, you might be contacted by the media to provide your professional opinion and advice. Or you might be looking for media interview opportunities to market your practice or side project. And if you do research, media interviews can be an effective way to spread the word. It’s important to prepare for a media interview so that you achieve the outcome you are looking for. Here are six tips I learned from writing health articles, interviewing experts, and being interviewed myself. 

Keep your message simple. When you are a subject expert, you might think that the basics are obvious or even boring, and that the nuances are more important. However, most of the audience is looking for big-picture information that they can apply to their lives. Consider a few key takeaways, keeping in mind that your interview is likely to be edited to short sound bites or a few quotes. It may help to jot down notes so that you cover the fundamentals clearly. You could even write and rehearse a script beforehand. If there is something complicated or subtle that you want to convey, you can preface it by saying, “This is confusing but very important …” to let the audience know to give extra consideration to what you are about to say.

Avoid extremes and hyperbole. Sometimes, exaggerated statements make their way into medical discussions. Statements such as “it doesn’t matter how many calories you consume — it’s all about the quality” are common oversimplifications. But you might be upset to see your name next to a comment like this because it is not actually correct. Check the phrasing of your key takeaways to avoid being stuck defending or explaining an inaccurate statement when your patients ask you about it later. 

Ask the interviewers what they are looking for. Many medical topics have some controversial element, so it is good to know what you’re getting into. Find out the purpose of the article or interview before you decide whether it is right for you. It could be about another doctor in town who is being sued; if you don’t want to be associated with that story, it might be best to decline the interview. 

Explain your goals. You might accept or pursue an interview to raise awareness about an underrecognized condition. You might want the public to identify and get help for early symptoms, or you might want to create empathy for people coping with a disease you treat. Consider why you are participating in an interview, and communicate that to the interviewer to ensure that your objective can be part of the final product. 

Know whom you’re dealing with. It is good to learn about the publication/media channel before you agree to participate. It may have a political bias, or perhaps the interview is intended to promote a specific product. If you agree with and support their purposes, then you may be happy to lend your opinion. But learning about the “voice” of the publication in advance allows you to make an informed decision about whether you want to be identified with a particular political ideology or product endorsement.

Ask to see your quotes before publication. It’s good to have the opportunity to make corrections in case you are accidentally misquoted or misunderstood. It is best to ask to see quotes before you agree to the interview. Some reporters may agree to (or even prefer) a written question-and-answer format so that they can directly quote your responses without rephrasing your words. You could suggest this, especially if you are too busy for a call or live meeting.

As a physician, your insights and advice can be highly beneficial to others. You can also use media interviews to propel your career forward. Doing your homework can ensure that you will be pleased with the final product and how your words were used. 
 

Dr. Moawad, Clinical Assistant Professor, Department of Medical Education, Case Western Reserve University School of Medicine, Cleveland, Ohio, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

SAN FRANCISCO — While the physical toll of cancer is well documented, the financial toll can also be severe and lasting.

Overall, patients with cancer tend to face higher rates of debt collection, medical collections, and bankruptcies, as well as lower credit scores, according to two new studies presented at the American College of Surgeons Clinical Congress 2024.

“These are the first studies to provide numerical evidence of financial toxicity among cancer survivors,” Benjamin C. James, MD, with Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, Massachusetts, who worked on both studies, said in a statement. “Previous data on this topic largely relies on subjective survey reviews.”

In one study, researchers used the Massachusetts Cancer Registry to identify 99,175 patients diagnosed with cancer between 2010 and 2019 and matched them with 188,875 control individuals without cancer. Researchers then assessed financial toxicity using Experian credit bureau data for participants.

Overall, patients with cancer faced a range of financial challenges that often lasted years following their diagnosis.

Patients were nearly five times more likely to experience bankruptcy and had average credit scores nearly 80 points lower than control individuals without cancer. The drop in credit scores was more pronounced for survivors of bladder, liver, lung, and colorectal cancer (CRC) and persisted for up to 9.5 years.

For certain cancer types, in particular, “we are looking years after a diagnosis, and we see that the credit score goes down and it never comes back up,” James said.

The other study, which used a sample of 7227 patients with CRC from Massachusetts, identified several factors that correlated with lower credit scores.

Compared with patients who only had surgery, peers who underwent radiation only experienced a 62-point drop in their credit score after their diagnosis, while those who had chemotherapy alone had just over a 14-point drop in their credit score. Among patients who had combination treatments, those who underwent both surgery and radiation experienced a nearly 16-point drop in their credit score and those who had surgery and chemoradiation actually experienced a 2.59 bump, compared with those who had surgery alone.

Financial toxicity was worse for patients younger than 62 years, those identifying as Black or Hispanic individuals, unmarried individuals, those with an annual income below $52,000, and those living in deprived areas.

The studies add to findings from the 2015 North American Thyroid Cancer Survivorship Study, which reported that 50% of thyroid cancer survivors encountered financial toxicity because of their diagnosis.

James said the persistent financial strain of cancer care, even in a state like Massachusetts, which mandates universal healthcare, underscores the need for “broader policy changes and reforms, including reconsidering debt collection practices.”

“Financial security should be a priority in cancer care,” he added.

The studies had no specific funding. The authors have disclosed no relevant conflict of interest.

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

SAN FRANCISCO — While the physical toll of cancer is well documented, the financial toll can also be severe and lasting.

Overall, patients with cancer tend to face higher rates of debt collection, medical collections, and bankruptcies, as well as lower credit scores, according to two new studies presented at the American College of Surgeons Clinical Congress 2024.

“These are the first studies to provide numerical evidence of financial toxicity among cancer survivors,” Benjamin C. James, MD, with Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, Massachusetts, who worked on both studies, said in a statement. “Previous data on this topic largely relies on subjective survey reviews.”

In one study, researchers used the Massachusetts Cancer Registry to identify 99,175 patients diagnosed with cancer between 2010 and 2019 and matched them with 188,875 control individuals without cancer. Researchers then assessed financial toxicity using Experian credit bureau data for participants.

Overall, patients with cancer faced a range of financial challenges that often lasted years following their diagnosis.

Patients were nearly five times more likely to experience bankruptcy and had average credit scores nearly 80 points lower than control individuals without cancer. The drop in credit scores was more pronounced for survivors of bladder, liver, lung, and colorectal cancer (CRC) and persisted for up to 9.5 years.

For certain cancer types, in particular, “we are looking years after a diagnosis, and we see that the credit score goes down and it never comes back up,” James said.

The other study, which used a sample of 7227 patients with CRC from Massachusetts, identified several factors that correlated with lower credit scores.

Compared with patients who only had surgery, peers who underwent radiation only experienced a 62-point drop in their credit score after their diagnosis, while those who had chemotherapy alone had just over a 14-point drop in their credit score. Among patients who had combination treatments, those who underwent both surgery and radiation experienced a nearly 16-point drop in their credit score and those who had surgery and chemoradiation actually experienced a 2.59 bump, compared with those who had surgery alone.

Financial toxicity was worse for patients younger than 62 years, those identifying as Black or Hispanic individuals, unmarried individuals, those with an annual income below $52,000, and those living in deprived areas.

The studies add to findings from the 2015 North American Thyroid Cancer Survivorship Study, which reported that 50% of thyroid cancer survivors encountered financial toxicity because of their diagnosis.

James said the persistent financial strain of cancer care, even in a state like Massachusetts, which mandates universal healthcare, underscores the need for “broader policy changes and reforms, including reconsidering debt collection practices.”

“Financial security should be a priority in cancer care,” he added.

The studies had no specific funding. The authors have disclosed no relevant conflict of interest.

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

SAN FRANCISCO — While the physical toll of cancer is well documented, the financial toll can also be severe and lasting.

Overall, patients with cancer tend to face higher rates of debt collection, medical collections, and bankruptcies, as well as lower credit scores, according to two new studies presented at the American College of Surgeons Clinical Congress 2024.

“These are the first studies to provide numerical evidence of financial toxicity among cancer survivors,” Benjamin C. James, MD, with Beth Israel Deaconess Medical Center and Harvard Medical School, both in Boston, Massachusetts, who worked on both studies, said in a statement. “Previous data on this topic largely relies on subjective survey reviews.”

In one study, researchers used the Massachusetts Cancer Registry to identify 99,175 patients diagnosed with cancer between 2010 and 2019 and matched them with 188,875 control individuals without cancer. Researchers then assessed financial toxicity using Experian credit bureau data for participants.

Overall, patients with cancer faced a range of financial challenges that often lasted years following their diagnosis.

Patients were nearly five times more likely to experience bankruptcy and had average credit scores nearly 80 points lower than control individuals without cancer. The drop in credit scores was more pronounced for survivors of bladder, liver, lung, and colorectal cancer (CRC) and persisted for up to 9.5 years.

For certain cancer types, in particular, “we are looking years after a diagnosis, and we see that the credit score goes down and it never comes back up,” James said.

The other study, which used a sample of 7227 patients with CRC from Massachusetts, identified several factors that correlated with lower credit scores.

Compared with patients who only had surgery, peers who underwent radiation only experienced a 62-point drop in their credit score after their diagnosis, while those who had chemotherapy alone had just over a 14-point drop in their credit score. Among patients who had combination treatments, those who underwent both surgery and radiation experienced a nearly 16-point drop in their credit score and those who had surgery and chemoradiation actually experienced a 2.59 bump, compared with those who had surgery alone.

Financial toxicity was worse for patients younger than 62 years, those identifying as Black or Hispanic individuals, unmarried individuals, those with an annual income below $52,000, and those living in deprived areas.

The studies add to findings from the 2015 North American Thyroid Cancer Survivorship Study, which reported that 50% of thyroid cancer survivors encountered financial toxicity because of their diagnosis.

James said the persistent financial strain of cancer care, even in a state like Massachusetts, which mandates universal healthcare, underscores the need for “broader policy changes and reforms, including reconsidering debt collection practices.”

“Financial security should be a priority in cancer care,” he added.

The studies had no specific funding. The authors have disclosed no relevant conflict of interest.

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

For more than three decades, the federal government sought to make amends to countless Americans who developed cancer after being exposed to radiation from nuclear testing in the Southwest or while working in the uranium mining industry.

As of 2022, more than 40,000 patients with cancer successfully applied for $2.6 billion in compensation. Recipients included “downwinders” who were eligible for $50,000 each if they lived in certain areas of Nevada, Utah, and Arizona during specified nuclear testing periods and developed a covered form of cancer.

In June 2024, however, the Radiation Exposure Compensation Program expired amid infighting among Republicans in Congress over whether to expand it. For now, no one can make a claim, even though many downwinders are still alive and continue to be diagnosed with covered cancers decades after they were exposed in the 1940s, 1950s, and 1960s.

There’s a glimmer of good news. The federal government continues to support free medical screenings for eligible people, including certain downwinders and uranium workers. Meanwhile, there are still important roles for clinicians across the country to play as politicians figure out what — if anything — to do next regarding those exposed to radiation.

“We are still here. We can still screen people,” Zachary Davis, program director for the Radiation Exposure Screening and Education Program, The University of New Mexico, in Albuquerque, New Mexico, said in an interview.
 

Still-Unfolding Legacy of Radiation Exposure

No one knew just how far radiation would spread when the first nuclear bomb was tested in New Mexico in July 1945. Would it cover the state? The entire Southwest? The whole nation?

It also wasn’t clear how radiation would affect people’s health. “There was an awareness that some cancers were caused by radiation, but there wasn’t a cohesive understanding of what the problem was,” Joseph Shonka, PhD, a health physicist who studies radiation exposure and has worked for decades in nuclear engineering, said in an interview.

Now, nearly eight decades later, scientists are still figuring out the full extent of radioactive fallout from nuclear testing. Just last year, a study suggested that radiation from 94 nuclear weapon tests in the Southwest from 1945 to 1962 reached 46 states along with Canada and Mexico.

Activists believe the tests triggered untold number of cancer cases in residents who were exposed in downwind areas:

“My brother died of stomach cancer; my mom died of bone cancer. One of my sisters is surviving brain tumors, and the other one is surviving thyroid cancer,” one New Mexico man recently told ABC-TV’s “Nightline.”

In Idaho, a downwinder advocate told Idaho Capital Sun that everyone who attended a reception for her newly married parents in 1952 — just weeks after a nuclear test — developed cancer or “weird medical complications.” That included her parents, who both had cancer. Her two older brothers, born in 1953 and 1955, also developed cancer, and she’s tracked many other cases in the small town of Emmett.

In Utah, another downwinder advocate told Utah News Dispatch that cancer was common in Salt Lake City neighborhood, where she grew up, which was exposed to fallout. She developed thyroid cancer, her younger sister developed stomach cancer, and an older sister died of lupus, which is connected to radiation exposure. But Salt Lake City isn’t in one of the regions of Utah covered by the federal compensation program, so the advocate can’t get a $50,000 payment.

Downwinders who lived in New Mexico, Idaho, and the Salt Lake City area of Utah are not covered by the federal compensation program. That means none of these people or their descendants are eligible for payments — yet.
 

Decades After Nuclear Testing, the Government Responds

In 1990, Congress passed the Radiation Exposure Compensation Act, which allowed compensation to people with cancer at several levels. It was later expanded. Downwinders — including those who’ve moved elsewhere over the years — were eligible for $50,000. Onsite participants in nuclear testing could get $75,000. Uranium miners, millers, and ore transporters in 11 states west of the Mississippi River could get $100,000.

Among downwinders, eligible cancers included blood cancers (leukemias with the exception of chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin’s lymphomas) and a long list of solid organ cancers such as thyroid, breast, stomach, brain, lung, colon, and liver cancers.

“When it comes to blood-related cancers, we do see leukemias, lymphomas, and multiple myeloma, but these cancers were more likely to occur sooner after fallout exposure,” said Laura Shaw, MD, principal investigator who oversees the radiation exposure screening program at the University of Nevada, Las Vegas. “At this point, we see more pancreatic, thyroid, lung, stomach, bladder, and breast cancer.”

The compensation program had major limitations, critics said. “It left out a lot of communities that were exposed,” said Lilly Adams, senior outreach coordinator with the Union of Concerned Scientists (UCS), which supports expanding the program. A national nonprofit organization, UCS was founded more than 50 years ago by scientists and students at the Massachusetts Institute of Technology.

“You have this pretty small amount of one-time compensation, and that’s it,” Adams said in an interview. “You can’t get reimbursed for medical costs or lost wages.” Still, “as flawed as the program is, it’s really valuable for the people who are eligible,” she noted.
 

Now Congress Is Divided on Next Steps

Some lawmakers have recognized the need to do more for those who developed cancer that’s potentially linked to radiation exposure. As the June 2024 expiration of the Radiation Exposure Compensation Act loomed, Democrats and Republicans in Congress worked together to extend and expand the program.

They introduced a bill for higher compensation — $100,000 per person — and the widening of covered downwinder areas to all of Arizona, Nevada, and Utah (which had only been partially covered), along with all of Colorado, Idaho, New Mexico, Montana, and Guam. Under the legislation, the program also would expand to cover some uranium workers who were on the job after 1971 and residents exposed to nuclear waste in Kentucky, Missouri, and Tennessee.

In March, the new legislation easily passed the US Senate by a vote of 69-30, with support from both political parties — but the Republican-led House hasn’t taken it up. As a result, the Radiation Exposure Compensation Act expired in June, and no one can submit new applications for compensation.

A spokesman for House Speaker Mike Johnson told Missouri Independent “unfortunately, the current Senate bill is estimated to cost $50-$60 billion in new mandatory spending with no offsets and was supported by only 20 of 49 Republicans in the Senate.”

Adams rejected these arguments. “The government spends literally trillions of dollars on our nuclear weapons. Whether or not you support that spending, the human cost of building those weapons should be factored in,” she said. She added that she hopes the House will act by the end of the year to pass the bill, but that’s uncertain.
 

As Compensation Is On Hold, Medical Screening Continues

A major benefit is still available for downwinders and uranium workers: Free medical screening and referrals for medical treatment. The Radiation Exposure Screening and Education Program’s funding has not been affected by the congressional impasse, so screenings are continuing for eligible people exposed to radiation.

Radiation exposure clinics offer screening in Arizona, Colorado, Nevada, New Mexico, and Utah, and health providers can get funding to offer screening in other affected states.

In Nevada, “we hold screening clinics throughout the state: Caliente, Ely, and Winnemucca. Also, in Reno and Las Vegas, which are not in designated downwind areas, but many downwinders have migrated there,” said Shaw in an interview. Among downwinders, “our youngest patients are in their 60s and range up to a few in their 90s,” she said.

Patients fill out questionnaires that ask about their medical problems, family history, and medications. “Ely patients in particular seem to have extensive family histories of cancer, and this may be due to their location directly downwind of the Nevada Test Site,” Shaw said. (Ely is a remote town in central eastern Nevada near the Utah border.)

The screenings cover both cancer and noncancer conditions. Shaw said clinicians often diagnose problems other than the covered cancers — new cases of atrial fibrillation, diabetes, and hypertension. “We see a ton of prostate and skin cancer” but don’t make patients eligible for the compensation program because they’re not covered, she said.

Even as compensation is on hold, doctors can get the word out that screenings are still available, Shaw said. “We continue to get contacted by individuals who in these communities who have never heard of this program, even though we’ve been holding clinics since 2005,” Shaw said. “Despite outreach activities and advertising through newspapers and radio, we find the most successful method of reaching these patients is through word of mouth — either from other patients or their doctors. That is why we feel it is so important to reach other physicians as well.”
 

Affected Patients Don’t Just Live in the West

On the outreach front, clinicians in states outside of the western US region can be helpful, too. Shaw urged oncologists nationwide to ask older patients where they lived in the 1950s and 1960s. “Did they live in Nevada, Arizona, Utah, and other Western states that are downwind? They may qualify for needed services and future compensation.”

With regard to compensation, she noted that applicants need to prove that they lived in affected areas many decades ago. And, of course, they must prove that they’ve had cancer. Locating residency records “has often been an enormous challenge.” Old utility bills, pay stubs, and high school annuals can be helpful, “but these records tend to disappear. People and their families throw stuff away.”

Even proving a cancer diagnosis can be a challenge because records can be missing. In Nevada, the law says clinicians only need to keep medical records for 5 years, Shaw said. “Imaging and pathology reports are destroyed. Patients that have been diagnosed with cancer can’t prove it.”

Shaw said she hopes oncologists will offer these messages to patients: “Be an advocate for your own health and keep copies of your own records. Discuss your diagnosis with your family and contact a cancer registry if you are diagnosed with cancer.”
 

A version of this article appeared on Medscape.com.

For more than three decades, the federal government sought to make amends to countless Americans who developed cancer after being exposed to radiation from nuclear testing in the Southwest or while working in the uranium mining industry.

As of 2022, more than 40,000 patients with cancer successfully applied for $2.6 billion in compensation. Recipients included “downwinders” who were eligible for $50,000 each if they lived in certain areas of Nevada, Utah, and Arizona during specified nuclear testing periods and developed a covered form of cancer.

In June 2024, however, the Radiation Exposure Compensation Program expired amid infighting among Republicans in Congress over whether to expand it. For now, no one can make a claim, even though many downwinders are still alive and continue to be diagnosed with covered cancers decades after they were exposed in the 1940s, 1950s, and 1960s.

There’s a glimmer of good news. The federal government continues to support free medical screenings for eligible people, including certain downwinders and uranium workers. Meanwhile, there are still important roles for clinicians across the country to play as politicians figure out what — if anything — to do next regarding those exposed to radiation.

“We are still here. We can still screen people,” Zachary Davis, program director for the Radiation Exposure Screening and Education Program, The University of New Mexico, in Albuquerque, New Mexico, said in an interview.
 

Still-Unfolding Legacy of Radiation Exposure

No one knew just how far radiation would spread when the first nuclear bomb was tested in New Mexico in July 1945. Would it cover the state? The entire Southwest? The whole nation?

It also wasn’t clear how radiation would affect people’s health. “There was an awareness that some cancers were caused by radiation, but there wasn’t a cohesive understanding of what the problem was,” Joseph Shonka, PhD, a health physicist who studies radiation exposure and has worked for decades in nuclear engineering, said in an interview.

Now, nearly eight decades later, scientists are still figuring out the full extent of radioactive fallout from nuclear testing. Just last year, a study suggested that radiation from 94 nuclear weapon tests in the Southwest from 1945 to 1962 reached 46 states along with Canada and Mexico.

Activists believe the tests triggered untold number of cancer cases in residents who were exposed in downwind areas:

“My brother died of stomach cancer; my mom died of bone cancer. One of my sisters is surviving brain tumors, and the other one is surviving thyroid cancer,” one New Mexico man recently told ABC-TV’s “Nightline.”

In Idaho, a downwinder advocate told Idaho Capital Sun that everyone who attended a reception for her newly married parents in 1952 — just weeks after a nuclear test — developed cancer or “weird medical complications.” That included her parents, who both had cancer. Her two older brothers, born in 1953 and 1955, also developed cancer, and she’s tracked many other cases in the small town of Emmett.

In Utah, another downwinder advocate told Utah News Dispatch that cancer was common in Salt Lake City neighborhood, where she grew up, which was exposed to fallout. She developed thyroid cancer, her younger sister developed stomach cancer, and an older sister died of lupus, which is connected to radiation exposure. But Salt Lake City isn’t in one of the regions of Utah covered by the federal compensation program, so the advocate can’t get a $50,000 payment.

Downwinders who lived in New Mexico, Idaho, and the Salt Lake City area of Utah are not covered by the federal compensation program. That means none of these people or their descendants are eligible for payments — yet.
 

Decades After Nuclear Testing, the Government Responds

In 1990, Congress passed the Radiation Exposure Compensation Act, which allowed compensation to people with cancer at several levels. It was later expanded. Downwinders — including those who’ve moved elsewhere over the years — were eligible for $50,000. Onsite participants in nuclear testing could get $75,000. Uranium miners, millers, and ore transporters in 11 states west of the Mississippi River could get $100,000.

Among downwinders, eligible cancers included blood cancers (leukemias with the exception of chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin’s lymphomas) and a long list of solid organ cancers such as thyroid, breast, stomach, brain, lung, colon, and liver cancers.

“When it comes to blood-related cancers, we do see leukemias, lymphomas, and multiple myeloma, but these cancers were more likely to occur sooner after fallout exposure,” said Laura Shaw, MD, principal investigator who oversees the radiation exposure screening program at the University of Nevada, Las Vegas. “At this point, we see more pancreatic, thyroid, lung, stomach, bladder, and breast cancer.”

The compensation program had major limitations, critics said. “It left out a lot of communities that were exposed,” said Lilly Adams, senior outreach coordinator with the Union of Concerned Scientists (UCS), which supports expanding the program. A national nonprofit organization, UCS was founded more than 50 years ago by scientists and students at the Massachusetts Institute of Technology.

“You have this pretty small amount of one-time compensation, and that’s it,” Adams said in an interview. “You can’t get reimbursed for medical costs or lost wages.” Still, “as flawed as the program is, it’s really valuable for the people who are eligible,” she noted.
 

Now Congress Is Divided on Next Steps

Some lawmakers have recognized the need to do more for those who developed cancer that’s potentially linked to radiation exposure. As the June 2024 expiration of the Radiation Exposure Compensation Act loomed, Democrats and Republicans in Congress worked together to extend and expand the program.

They introduced a bill for higher compensation — $100,000 per person — and the widening of covered downwinder areas to all of Arizona, Nevada, and Utah (which had only been partially covered), along with all of Colorado, Idaho, New Mexico, Montana, and Guam. Under the legislation, the program also would expand to cover some uranium workers who were on the job after 1971 and residents exposed to nuclear waste in Kentucky, Missouri, and Tennessee.

In March, the new legislation easily passed the US Senate by a vote of 69-30, with support from both political parties — but the Republican-led House hasn’t taken it up. As a result, the Radiation Exposure Compensation Act expired in June, and no one can submit new applications for compensation.

A spokesman for House Speaker Mike Johnson told Missouri Independent “unfortunately, the current Senate bill is estimated to cost $50-$60 billion in new mandatory spending with no offsets and was supported by only 20 of 49 Republicans in the Senate.”

Adams rejected these arguments. “The government spends literally trillions of dollars on our nuclear weapons. Whether or not you support that spending, the human cost of building those weapons should be factored in,” she said. She added that she hopes the House will act by the end of the year to pass the bill, but that’s uncertain.
 

As Compensation Is On Hold, Medical Screening Continues

A major benefit is still available for downwinders and uranium workers: Free medical screening and referrals for medical treatment. The Radiation Exposure Screening and Education Program’s funding has not been affected by the congressional impasse, so screenings are continuing for eligible people exposed to radiation.

Radiation exposure clinics offer screening in Arizona, Colorado, Nevada, New Mexico, and Utah, and health providers can get funding to offer screening in other affected states.

In Nevada, “we hold screening clinics throughout the state: Caliente, Ely, and Winnemucca. Also, in Reno and Las Vegas, which are not in designated downwind areas, but many downwinders have migrated there,” said Shaw in an interview. Among downwinders, “our youngest patients are in their 60s and range up to a few in their 90s,” she said.

Patients fill out questionnaires that ask about their medical problems, family history, and medications. “Ely patients in particular seem to have extensive family histories of cancer, and this may be due to their location directly downwind of the Nevada Test Site,” Shaw said. (Ely is a remote town in central eastern Nevada near the Utah border.)

The screenings cover both cancer and noncancer conditions. Shaw said clinicians often diagnose problems other than the covered cancers — new cases of atrial fibrillation, diabetes, and hypertension. “We see a ton of prostate and skin cancer” but don’t make patients eligible for the compensation program because they’re not covered, she said.

Even as compensation is on hold, doctors can get the word out that screenings are still available, Shaw said. “We continue to get contacted by individuals who in these communities who have never heard of this program, even though we’ve been holding clinics since 2005,” Shaw said. “Despite outreach activities and advertising through newspapers and radio, we find the most successful method of reaching these patients is through word of mouth — either from other patients or their doctors. That is why we feel it is so important to reach other physicians as well.”
 

Affected Patients Don’t Just Live in the West

On the outreach front, clinicians in states outside of the western US region can be helpful, too. Shaw urged oncologists nationwide to ask older patients where they lived in the 1950s and 1960s. “Did they live in Nevada, Arizona, Utah, and other Western states that are downwind? They may qualify for needed services and future compensation.”

With regard to compensation, she noted that applicants need to prove that they lived in affected areas many decades ago. And, of course, they must prove that they’ve had cancer. Locating residency records “has often been an enormous challenge.” Old utility bills, pay stubs, and high school annuals can be helpful, “but these records tend to disappear. People and their families throw stuff away.”

Even proving a cancer diagnosis can be a challenge because records can be missing. In Nevada, the law says clinicians only need to keep medical records for 5 years, Shaw said. “Imaging and pathology reports are destroyed. Patients that have been diagnosed with cancer can’t prove it.”

Shaw said she hopes oncologists will offer these messages to patients: “Be an advocate for your own health and keep copies of your own records. Discuss your diagnosis with your family and contact a cancer registry if you are diagnosed with cancer.”
 

A version of this article appeared on Medscape.com.

For more than three decades, the federal government sought to make amends to countless Americans who developed cancer after being exposed to radiation from nuclear testing in the Southwest or while working in the uranium mining industry.

As of 2022, more than 40,000 patients with cancer successfully applied for $2.6 billion in compensation. Recipients included “downwinders” who were eligible for $50,000 each if they lived in certain areas of Nevada, Utah, and Arizona during specified nuclear testing periods and developed a covered form of cancer.

In June 2024, however, the Radiation Exposure Compensation Program expired amid infighting among Republicans in Congress over whether to expand it. For now, no one can make a claim, even though many downwinders are still alive and continue to be diagnosed with covered cancers decades after they were exposed in the 1940s, 1950s, and 1960s.

There’s a glimmer of good news. The federal government continues to support free medical screenings for eligible people, including certain downwinders and uranium workers. Meanwhile, there are still important roles for clinicians across the country to play as politicians figure out what — if anything — to do next regarding those exposed to radiation.

“We are still here. We can still screen people,” Zachary Davis, program director for the Radiation Exposure Screening and Education Program, The University of New Mexico, in Albuquerque, New Mexico, said in an interview.
 

Still-Unfolding Legacy of Radiation Exposure

No one knew just how far radiation would spread when the first nuclear bomb was tested in New Mexico in July 1945. Would it cover the state? The entire Southwest? The whole nation?

It also wasn’t clear how radiation would affect people’s health. “There was an awareness that some cancers were caused by radiation, but there wasn’t a cohesive understanding of what the problem was,” Joseph Shonka, PhD, a health physicist who studies radiation exposure and has worked for decades in nuclear engineering, said in an interview.

Now, nearly eight decades later, scientists are still figuring out the full extent of radioactive fallout from nuclear testing. Just last year, a study suggested that radiation from 94 nuclear weapon tests in the Southwest from 1945 to 1962 reached 46 states along with Canada and Mexico.

Activists believe the tests triggered untold number of cancer cases in residents who were exposed in downwind areas:

“My brother died of stomach cancer; my mom died of bone cancer. One of my sisters is surviving brain tumors, and the other one is surviving thyroid cancer,” one New Mexico man recently told ABC-TV’s “Nightline.”

In Idaho, a downwinder advocate told Idaho Capital Sun that everyone who attended a reception for her newly married parents in 1952 — just weeks after a nuclear test — developed cancer or “weird medical complications.” That included her parents, who both had cancer. Her two older brothers, born in 1953 and 1955, also developed cancer, and she’s tracked many other cases in the small town of Emmett.

In Utah, another downwinder advocate told Utah News Dispatch that cancer was common in Salt Lake City neighborhood, where she grew up, which was exposed to fallout. She developed thyroid cancer, her younger sister developed stomach cancer, and an older sister died of lupus, which is connected to radiation exposure. But Salt Lake City isn’t in one of the regions of Utah covered by the federal compensation program, so the advocate can’t get a $50,000 payment.

Downwinders who lived in New Mexico, Idaho, and the Salt Lake City area of Utah are not covered by the federal compensation program. That means none of these people or their descendants are eligible for payments — yet.
 

Decades After Nuclear Testing, the Government Responds

In 1990, Congress passed the Radiation Exposure Compensation Act, which allowed compensation to people with cancer at several levels. It was later expanded. Downwinders — including those who’ve moved elsewhere over the years — were eligible for $50,000. Onsite participants in nuclear testing could get $75,000. Uranium miners, millers, and ore transporters in 11 states west of the Mississippi River could get $100,000.

Among downwinders, eligible cancers included blood cancers (leukemias with the exception of chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin’s lymphomas) and a long list of solid organ cancers such as thyroid, breast, stomach, brain, lung, colon, and liver cancers.

“When it comes to blood-related cancers, we do see leukemias, lymphomas, and multiple myeloma, but these cancers were more likely to occur sooner after fallout exposure,” said Laura Shaw, MD, principal investigator who oversees the radiation exposure screening program at the University of Nevada, Las Vegas. “At this point, we see more pancreatic, thyroid, lung, stomach, bladder, and breast cancer.”

The compensation program had major limitations, critics said. “It left out a lot of communities that were exposed,” said Lilly Adams, senior outreach coordinator with the Union of Concerned Scientists (UCS), which supports expanding the program. A national nonprofit organization, UCS was founded more than 50 years ago by scientists and students at the Massachusetts Institute of Technology.

“You have this pretty small amount of one-time compensation, and that’s it,” Adams said in an interview. “You can’t get reimbursed for medical costs or lost wages.” Still, “as flawed as the program is, it’s really valuable for the people who are eligible,” she noted.
 

Now Congress Is Divided on Next Steps

Some lawmakers have recognized the need to do more for those who developed cancer that’s potentially linked to radiation exposure. As the June 2024 expiration of the Radiation Exposure Compensation Act loomed, Democrats and Republicans in Congress worked together to extend and expand the program.

They introduced a bill for higher compensation — $100,000 per person — and the widening of covered downwinder areas to all of Arizona, Nevada, and Utah (which had only been partially covered), along with all of Colorado, Idaho, New Mexico, Montana, and Guam. Under the legislation, the program also would expand to cover some uranium workers who were on the job after 1971 and residents exposed to nuclear waste in Kentucky, Missouri, and Tennessee.

In March, the new legislation easily passed the US Senate by a vote of 69-30, with support from both political parties — but the Republican-led House hasn’t taken it up. As a result, the Radiation Exposure Compensation Act expired in June, and no one can submit new applications for compensation.

A spokesman for House Speaker Mike Johnson told Missouri Independent “unfortunately, the current Senate bill is estimated to cost $50-$60 billion in new mandatory spending with no offsets and was supported by only 20 of 49 Republicans in the Senate.”

Adams rejected these arguments. “The government spends literally trillions of dollars on our nuclear weapons. Whether or not you support that spending, the human cost of building those weapons should be factored in,” she said. She added that she hopes the House will act by the end of the year to pass the bill, but that’s uncertain.
 

As Compensation Is On Hold, Medical Screening Continues

A major benefit is still available for downwinders and uranium workers: Free medical screening and referrals for medical treatment. The Radiation Exposure Screening and Education Program’s funding has not been affected by the congressional impasse, so screenings are continuing for eligible people exposed to radiation.

Radiation exposure clinics offer screening in Arizona, Colorado, Nevada, New Mexico, and Utah, and health providers can get funding to offer screening in other affected states.

In Nevada, “we hold screening clinics throughout the state: Caliente, Ely, and Winnemucca. Also, in Reno and Las Vegas, which are not in designated downwind areas, but many downwinders have migrated there,” said Shaw in an interview. Among downwinders, “our youngest patients are in their 60s and range up to a few in their 90s,” she said.

Patients fill out questionnaires that ask about their medical problems, family history, and medications. “Ely patients in particular seem to have extensive family histories of cancer, and this may be due to their location directly downwind of the Nevada Test Site,” Shaw said. (Ely is a remote town in central eastern Nevada near the Utah border.)

The screenings cover both cancer and noncancer conditions. Shaw said clinicians often diagnose problems other than the covered cancers — new cases of atrial fibrillation, diabetes, and hypertension. “We see a ton of prostate and skin cancer” but don’t make patients eligible for the compensation program because they’re not covered, she said.

Even as compensation is on hold, doctors can get the word out that screenings are still available, Shaw said. “We continue to get contacted by individuals who in these communities who have never heard of this program, even though we’ve been holding clinics since 2005,” Shaw said. “Despite outreach activities and advertising through newspapers and radio, we find the most successful method of reaching these patients is through word of mouth — either from other patients or their doctors. That is why we feel it is so important to reach other physicians as well.”
 

Affected Patients Don’t Just Live in the West

On the outreach front, clinicians in states outside of the western US region can be helpful, too. Shaw urged oncologists nationwide to ask older patients where they lived in the 1950s and 1960s. “Did they live in Nevada, Arizona, Utah, and other Western states that are downwind? They may qualify for needed services and future compensation.”

With regard to compensation, she noted that applicants need to prove that they lived in affected areas many decades ago. And, of course, they must prove that they’ve had cancer. Locating residency records “has often been an enormous challenge.” Old utility bills, pay stubs, and high school annuals can be helpful, “but these records tend to disappear. People and their families throw stuff away.”

Even proving a cancer diagnosis can be a challenge because records can be missing. In Nevada, the law says clinicians only need to keep medical records for 5 years, Shaw said. “Imaging and pathology reports are destroyed. Patients that have been diagnosed with cancer can’t prove it.”

Shaw said she hopes oncologists will offer these messages to patients: “Be an advocate for your own health and keep copies of your own records. Discuss your diagnosis with your family and contact a cancer registry if you are diagnosed with cancer.”
 

A version of this article appeared on Medscape.com.

As the number of drug-resistant and other troublesome tinea infections grows, perhaps the only certainty is that these are not the tinea subtypes that most providers studied in medical school. As dermatologists, public health officials, and infectious disease specialists scramble to raise awareness about prevention and treatment, challenges ranging from a dearth of testing facilities and data to payer pushback over longer therapeutic courses remain.

Dermatophyte Discourse Changing

“Trichophyton indotineae is changing the way we talk about dermatophyte infections,” Avrom S. Caplan, MD, assistant professor in the Department of Dermatology at New York University, New York City, said in an interview. Called T mentagrophytes VIII (TMVIII) before a 2020 report in the journal Mycopathologia proposed the name T indotineae, this species requires clinicians to expand their conception of how tinea looks, acts, and responds to treatment.

Dr. Lu Yin, New York University

University of Alabama, Birmingham

Tracking Cases

Because T indotineae does not require reporting to public health agencies, said Jeremy Gold, MD, MS, a medical officer with the US Centers for Disease Control and Prevention (CDC) Mycotic Diseases Branch in Atlanta, “there is no official public health surveillance keeping track of exactly how many cases have occurred.”

Dr. Gold

The same is true for TMVII and terbinafine-resistant T rubrum, which are also on the rise. Regarding T indotineae, authors from the University of Texas Health Science Center at San Antonio retrospectively reported 21 terbinafine-resistant isolates from North America in the July 2023 Journal of Clinical Microbiology .

Dr. Vignesh Ramachandran, New York University

Caplan has seen approximately 12 T indotineae cases to date, including the first two confirmed US cases, which he and co-authors, including Gold, reported in the CDC’s Morbidity and Mortality Weekly Report in May 2023. T indotineae is likely underreported, he said, because it eludes standard culture-based techniques, and identifying it requires molecular testing, which is available at only a handful of labs nationally.

To help educate providers, in July, the American Academy of Dermatology (AAD) and the International League of Dermatological Societies unveiled an Emerging Diseases Resource Center, which includes resources for providers and a registry for reporting confirmed and suspected resistant dermatophytes.

Dr. Lu Yin, New York University

Dr. Lu Yin, New York University

The new registry resides within the AAD’s existing COVID-19, Mpox, and Emerging Infections Registry. “Our registry efforts have already captured 2500 COVID-19 and mpox cases from 72 different countries,” Freeman said. For all these infections, she added, “we hope that real-time data analysis of cases worldwide will provide information that helps physicians recognize and treat cases.”

Consistent with the registry’s approach, said Caplan and Gold, there is no silver bullet for battling dermatophyte resistance. What is needed, said Gold, is a coordinated approach involving public health officials, dermatologists, primary care providers, infectious disease specialists, pharmacists, and patients. “It’s going to be a team effort to address the challenge of emerging complex dermatophytosis,” he said.
 

Resistant T rubrum

“The biggest difference with T rubrum resistance is you may not see that widespread infection that we see with T indotineae,” said Caplan. T rubrum is probably the most common dermatophyte that dermatologists see, added Elewski, who encounters a resistant case at least monthly. One such patient, featured in a January 2021 British Journal of Dermatology research letter, cleared on itraconazole and ciclopirox cream but subsequently returned with itraconazole-resistant T rubrum because he had been doctor-shopping for the drug intermittently for years, she said. He cleared on posaconazole 300 mg daily, then was lost to follow-up.

TMVII

A 2023 Emerging Infectious Diseases report highlighted the potential for this dermatophyte to spread among men who have sex with men (MSM), presenting as an itchy, scaly rash affecting the pubic, genital, and buttocks skin. “People don’t generally think of a fungal infection as something that could behave like a sexually transmitted infection (STI),” said Gold.

Caplan and coauthors recently reported the first confirmed US TMVII case in JAMA Dermatology. Many experts suspect that unreported US cases existed previously, he said. “When it circulates in Europe and there’s so much travel, it’s probably here too.”

The fact that T indotineae was formerly called TMVIII has created confusion, added Caplan. “I’ve had patients say, ‘I’m worried I have that resistant ringworm that’s spreading among MSM.’ Whenever we talk about STIs and introduce the word ‘resistant,’ that comes with the potential for stigma, anxiety, and concern.” Fortunately, he said, TMVII has shown no resistance to first-line antifungals.

NYU Langone

Why the Rise

Gold said, “We don’t know for sure why we’re seeing these different drug-resistant species popping up.” One possibility, he said, is the common misuse and overuse of topical antifungals — especially those available overseas in combination with high-potency steroids, such as clobetasol. Consumers use these products for a few weeks until symptoms resolve, then reapply them off and on over years, fueling resistance, said Gold.

“We are worried that with warming temperatures, there’s potential to see expansion of the geographic range of epidemic fungi,” he added. “That could be part of what has fueled recent increases in resistant dermatophytes. But it’s hard to prove.”

Climate change may be behind the emergence of Candida auris, according to a 2022 article in The Lancet Regional Health – Americas. This potentially fatal multidrug-resistant infection spreads easily among sick patients in healthcare facilities, according to a CDC information page on C auris.
 

Confirming Dermatophyte Infection

“A biopsy will only confirm the presence of fungus,” said Elewski. “Here you will need a lab that knows how to do a fungal culture.” Most state laboratories can do this, she said, as can some hospitals and special labs such as CMM in Cleveland.

It takes a Clinical Laboratory Improvement Amendments–certified lab to perform KOH prep in-house, added Caplan, plus up-to-date gear and knowledge of where and how to scrape and what to look for microscopically. Moreover, identifying T indotineae requires molecular testing available at only a handful of laboratories — listed on the AAD Emerging Dermatophytes webpage — nationwide.

Nevertheless, said Caplan, nailing down a diagnosis can guide treatment, often supplanting empirically prescribed antifungal steroid creams. “Those are probably not going to help. And people may be using those on areas of the body they shouldn’t. Both the clinical clues and the steps to make the diagnosis need to come together. But that’s often easier said than done, especially in a busy practice.”

Identifying resistance requires antifungal sensitivity testing, he added, which few labs perform. “Practically speaking,” said Elewski, “if the patient failed terbinafine, I would try itraconazole. You don’t necessarily need proof” of resistance. But if a patient does not respond to itraconazole and terbinafine clinically, she said that she might consider fungal susceptibility testing.
 

Treatment Tips

To address any resistant dermatophyte, Elewski recommended getting comfortable with itraconazole. For decades, she said, dermatologists have avoided itraconazole because terbinafine typically costs patients $10 for 3 months. “Itraconazole could be $200 per month,” said Elewski. Because of potential drug-drug interactions and absorption issues — and a boxed warning regarding congestive heart failure — physicians historically reserved itraconazole for severe fungal infections.

Itraconazole labeled dosing for onychomycosis is 200 mg daily for 12 weeks. Elewski favors a two-pronged attack, often combining an -azole antifungal with topical ciclopirox.

Another element that emerging tinea pathogens share is slower response to treatment. For T indotineae, reports appearing in the Journal of the American Academy of Dermatology in 2022 and 2024 suggest duration from 6-8 weeks up to 20 weeks.

To avoid recurrences of resistant T rubrum, Elewski treats for a year. However, she has problems getting itraconazole approved, when often it is the only agent that works. “I’ve written more letters than I like to insurance companies” to document terbinafine failure, she said.

Rarely, said Gold, dermatophyte infections resist both terbinafine and itraconazole. Next-line agents such as voriconazole, which some dermatologists have used for resistant T indotineae, can be much harder to tolerate, with more drug interactions, he said.

And because itraconazole, voriconazole, and posaconazole are all triazoles, added Elewski, the latter two might not work better than the former. But because these drugs might outperform itraconazole in selected cases, she said, “that’s when you want to do fungal susceptibility testing.”

TMVII is so new, said Caplan, that optimal therapy duration remains unclear. “One of the challenges with TMVII is when it gets into the genital skin, it’s a hair-bearing area. And based on various grooming practices, there’s an opportunity for the tinea to get deeper into the hair follicle and dermis. That may also be true of T indotineae.”
 

Anemic Arsenal

Unfortunately, said Gold, the arsenal of antifungals available in the United States remains limited. “Depending on how you count, there are only three to four classes of antifungal drugs designed to treat severe or invasive infections. So whenever we hear about a new fungal pathogen that’s causing resistant infections, it causes public health concern.”

Promising drugs in development include olorofim (F2G) and fosmanogepix (Basilea), according to Gold. However, he said, the development of these drugs to date has targeted invasive fungal infections such as aspergillosis. In June 2023, the Food and Drug Administration rejected the new drug application for olorofim, requesting additional data and analyses. Regarding fosmanogepix, a double-blinded noninferiority phase 3 trial in invasive yeast infections was recently launched, according to a September 24 press release.

Gold, Caplan, and Elewski reported no relevant financial disclosures. Freeman is a COVID-19 co-author for UpToDate and chair of the AAD Emerging Diseases Task Force.
 

A version of this article appeared on Medscape.com.

As the number of drug-resistant and other troublesome tinea infections grows, perhaps the only certainty is that these are not the tinea subtypes that most providers studied in medical school. As dermatologists, public health officials, and infectious disease specialists scramble to raise awareness about prevention and treatment, challenges ranging from a dearth of testing facilities and data to payer pushback over longer therapeutic courses remain.

Dermatophyte Discourse Changing

“Trichophyton indotineae is changing the way we talk about dermatophyte infections,” Avrom S. Caplan, MD, assistant professor in the Department of Dermatology at New York University, New York City, said in an interview. Called T mentagrophytes VIII (TMVIII) before a 2020 report in the journal Mycopathologia proposed the name T indotineae, this species requires clinicians to expand their conception of how tinea looks, acts, and responds to treatment.

Dr. Lu Yin, New York University

University of Alabama, Birmingham

Tracking Cases

Because T indotineae does not require reporting to public health agencies, said Jeremy Gold, MD, MS, a medical officer with the US Centers for Disease Control and Prevention (CDC) Mycotic Diseases Branch in Atlanta, “there is no official public health surveillance keeping track of exactly how many cases have occurred.”

Dr. Gold

The same is true for TMVII and terbinafine-resistant T rubrum, which are also on the rise. Regarding T indotineae, authors from the University of Texas Health Science Center at San Antonio retrospectively reported 21 terbinafine-resistant isolates from North America in the July 2023 Journal of Clinical Microbiology .

Dr. Vignesh Ramachandran, New York University

Caplan has seen approximately 12 T indotineae cases to date, including the first two confirmed US cases, which he and co-authors, including Gold, reported in the CDC’s Morbidity and Mortality Weekly Report in May 2023. T indotineae is likely underreported, he said, because it eludes standard culture-based techniques, and identifying it requires molecular testing, which is available at only a handful of labs nationally.

To help educate providers, in July, the American Academy of Dermatology (AAD) and the International League of Dermatological Societies unveiled an Emerging Diseases Resource Center, which includes resources for providers and a registry for reporting confirmed and suspected resistant dermatophytes.

Dr. Lu Yin, New York University

Dr. Lu Yin, New York University

The new registry resides within the AAD’s existing COVID-19, Mpox, and Emerging Infections Registry. “Our registry efforts have already captured 2500 COVID-19 and mpox cases from 72 different countries,” Freeman said. For all these infections, she added, “we hope that real-time data analysis of cases worldwide will provide information that helps physicians recognize and treat cases.”

Consistent with the registry’s approach, said Caplan and Gold, there is no silver bullet for battling dermatophyte resistance. What is needed, said Gold, is a coordinated approach involving public health officials, dermatologists, primary care providers, infectious disease specialists, pharmacists, and patients. “It’s going to be a team effort to address the challenge of emerging complex dermatophytosis,” he said.
 

Resistant T rubrum

“The biggest difference with T rubrum resistance is you may not see that widespread infection that we see with T indotineae,” said Caplan. T rubrum is probably the most common dermatophyte that dermatologists see, added Elewski, who encounters a resistant case at least monthly. One such patient, featured in a January 2021 British Journal of Dermatology research letter, cleared on itraconazole and ciclopirox cream but subsequently returned with itraconazole-resistant T rubrum because he had been doctor-shopping for the drug intermittently for years, she said. He cleared on posaconazole 300 mg daily, then was lost to follow-up.

TMVII

A 2023 Emerging Infectious Diseases report highlighted the potential for this dermatophyte to spread among men who have sex with men (MSM), presenting as an itchy, scaly rash affecting the pubic, genital, and buttocks skin. “People don’t generally think of a fungal infection as something that could behave like a sexually transmitted infection (STI),” said Gold.

Caplan and coauthors recently reported the first confirmed US TMVII case in JAMA Dermatology. Many experts suspect that unreported US cases existed previously, he said. “When it circulates in Europe and there’s so much travel, it’s probably here too.”

The fact that T indotineae was formerly called TMVIII has created confusion, added Caplan. “I’ve had patients say, ‘I’m worried I have that resistant ringworm that’s spreading among MSM.’ Whenever we talk about STIs and introduce the word ‘resistant,’ that comes with the potential for stigma, anxiety, and concern.” Fortunately, he said, TMVII has shown no resistance to first-line antifungals.

NYU Langone

Why the Rise

Gold said, “We don’t know for sure why we’re seeing these different drug-resistant species popping up.” One possibility, he said, is the common misuse and overuse of topical antifungals — especially those available overseas in combination with high-potency steroids, such as clobetasol. Consumers use these products for a few weeks until symptoms resolve, then reapply them off and on over years, fueling resistance, said Gold.

“We are worried that with warming temperatures, there’s potential to see expansion of the geographic range of epidemic fungi,” he added. “That could be part of what has fueled recent increases in resistant dermatophytes. But it’s hard to prove.”

Climate change may be behind the emergence of Candida auris, according to a 2022 article in The Lancet Regional Health – Americas. This potentially fatal multidrug-resistant infection spreads easily among sick patients in healthcare facilities, according to a CDC information page on C auris.
 

Confirming Dermatophyte Infection

“A biopsy will only confirm the presence of fungus,” said Elewski. “Here you will need a lab that knows how to do a fungal culture.” Most state laboratories can do this, she said, as can some hospitals and special labs such as CMM in Cleveland.

It takes a Clinical Laboratory Improvement Amendments–certified lab to perform KOH prep in-house, added Caplan, plus up-to-date gear and knowledge of where and how to scrape and what to look for microscopically. Moreover, identifying T indotineae requires molecular testing available at only a handful of laboratories — listed on the AAD Emerging Dermatophytes webpage — nationwide.

Nevertheless, said Caplan, nailing down a diagnosis can guide treatment, often supplanting empirically prescribed antifungal steroid creams. “Those are probably not going to help. And people may be using those on areas of the body they shouldn’t. Both the clinical clues and the steps to make the diagnosis need to come together. But that’s often easier said than done, especially in a busy practice.”

Identifying resistance requires antifungal sensitivity testing, he added, which few labs perform. “Practically speaking,” said Elewski, “if the patient failed terbinafine, I would try itraconazole. You don’t necessarily need proof” of resistance. But if a patient does not respond to itraconazole and terbinafine clinically, she said that she might consider fungal susceptibility testing.
 

Treatment Tips

To address any resistant dermatophyte, Elewski recommended getting comfortable with itraconazole. For decades, she said, dermatologists have avoided itraconazole because terbinafine typically costs patients $10 for 3 months. “Itraconazole could be $200 per month,” said Elewski. Because of potential drug-drug interactions and absorption issues — and a boxed warning regarding congestive heart failure — physicians historically reserved itraconazole for severe fungal infections.

Itraconazole labeled dosing for onychomycosis is 200 mg daily for 12 weeks. Elewski favors a two-pronged attack, often combining an -azole antifungal with topical ciclopirox.

Another element that emerging tinea pathogens share is slower response to treatment. For T indotineae, reports appearing in the Journal of the American Academy of Dermatology in 2022 and 2024 suggest duration from 6-8 weeks up to 20 weeks.

To avoid recurrences of resistant T rubrum, Elewski treats for a year. However, she has problems getting itraconazole approved, when often it is the only agent that works. “I’ve written more letters than I like to insurance companies” to document terbinafine failure, she said.

Rarely, said Gold, dermatophyte infections resist both terbinafine and itraconazole. Next-line agents such as voriconazole, which some dermatologists have used for resistant T indotineae, can be much harder to tolerate, with more drug interactions, he said.

And because itraconazole, voriconazole, and posaconazole are all triazoles, added Elewski, the latter two might not work better than the former. But because these drugs might outperform itraconazole in selected cases, she said, “that’s when you want to do fungal susceptibility testing.”

TMVII is so new, said Caplan, that optimal therapy duration remains unclear. “One of the challenges with TMVII is when it gets into the genital skin, it’s a hair-bearing area. And based on various grooming practices, there’s an opportunity for the tinea to get deeper into the hair follicle and dermis. That may also be true of T indotineae.”
 

Anemic Arsenal

Unfortunately, said Gold, the arsenal of antifungals available in the United States remains limited. “Depending on how you count, there are only three to four classes of antifungal drugs designed to treat severe or invasive infections. So whenever we hear about a new fungal pathogen that’s causing resistant infections, it causes public health concern.”

Promising drugs in development include olorofim (F2G) and fosmanogepix (Basilea), according to Gold. However, he said, the development of these drugs to date has targeted invasive fungal infections such as aspergillosis. In June 2023, the Food and Drug Administration rejected the new drug application for olorofim, requesting additional data and analyses. Regarding fosmanogepix, a double-blinded noninferiority phase 3 trial in invasive yeast infections was recently launched, according to a September 24 press release.

Gold, Caplan, and Elewski reported no relevant financial disclosures. Freeman is a COVID-19 co-author for UpToDate and chair of the AAD Emerging Diseases Task Force.
 

A version of this article appeared on Medscape.com.

As the number of drug-resistant and other troublesome tinea infections grows, perhaps the only certainty is that these are not the tinea subtypes that most providers studied in medical school. As dermatologists, public health officials, and infectious disease specialists scramble to raise awareness about prevention and treatment, challenges ranging from a dearth of testing facilities and data to payer pushback over longer therapeutic courses remain.

Dermatophyte Discourse Changing

“Trichophyton indotineae is changing the way we talk about dermatophyte infections,” Avrom S. Caplan, MD, assistant professor in the Department of Dermatology at New York University, New York City, said in an interview. Called T mentagrophytes VIII (TMVIII) before a 2020 report in the journal Mycopathologia proposed the name T indotineae, this species requires clinicians to expand their conception of how tinea looks, acts, and responds to treatment.

Dr. Lu Yin, New York University

University of Alabama, Birmingham

Tracking Cases

Because T indotineae does not require reporting to public health agencies, said Jeremy Gold, MD, MS, a medical officer with the US Centers for Disease Control and Prevention (CDC) Mycotic Diseases Branch in Atlanta, “there is no official public health surveillance keeping track of exactly how many cases have occurred.”

Dr. Gold

The same is true for TMVII and terbinafine-resistant T rubrum, which are also on the rise. Regarding T indotineae, authors from the University of Texas Health Science Center at San Antonio retrospectively reported 21 terbinafine-resistant isolates from North America in the July 2023 Journal of Clinical Microbiology .

Dr. Vignesh Ramachandran, New York University

Caplan has seen approximately 12 T indotineae cases to date, including the first two confirmed US cases, which he and co-authors, including Gold, reported in the CDC’s Morbidity and Mortality Weekly Report in May 2023. T indotineae is likely underreported, he said, because it eludes standard culture-based techniques, and identifying it requires molecular testing, which is available at only a handful of labs nationally.

To help educate providers, in July, the American Academy of Dermatology (AAD) and the International League of Dermatological Societies unveiled an Emerging Diseases Resource Center, which includes resources for providers and a registry for reporting confirmed and suspected resistant dermatophytes.

Dr. Lu Yin, New York University

Dr. Lu Yin, New York University

The new registry resides within the AAD’s existing COVID-19, Mpox, and Emerging Infections Registry. “Our registry efforts have already captured 2500 COVID-19 and mpox cases from 72 different countries,” Freeman said. For all these infections, she added, “we hope that real-time data analysis of cases worldwide will provide information that helps physicians recognize and treat cases.”

Consistent with the registry’s approach, said Caplan and Gold, there is no silver bullet for battling dermatophyte resistance. What is needed, said Gold, is a coordinated approach involving public health officials, dermatologists, primary care providers, infectious disease specialists, pharmacists, and patients. “It’s going to be a team effort to address the challenge of emerging complex dermatophytosis,” he said.
 

Resistant T rubrum

“The biggest difference with T rubrum resistance is you may not see that widespread infection that we see with T indotineae,” said Caplan. T rubrum is probably the most common dermatophyte that dermatologists see, added Elewski, who encounters a resistant case at least monthly. One such patient, featured in a January 2021 British Journal of Dermatology research letter, cleared on itraconazole and ciclopirox cream but subsequently returned with itraconazole-resistant T rubrum because he had been doctor-shopping for the drug intermittently for years, she said. He cleared on posaconazole 300 mg daily, then was lost to follow-up.

TMVII

A 2023 Emerging Infectious Diseases report highlighted the potential for this dermatophyte to spread among men who have sex with men (MSM), presenting as an itchy, scaly rash affecting the pubic, genital, and buttocks skin. “People don’t generally think of a fungal infection as something that could behave like a sexually transmitted infection (STI),” said Gold.

Caplan and coauthors recently reported the first confirmed US TMVII case in JAMA Dermatology. Many experts suspect that unreported US cases existed previously, he said. “When it circulates in Europe and there’s so much travel, it’s probably here too.”

The fact that T indotineae was formerly called TMVIII has created confusion, added Caplan. “I’ve had patients say, ‘I’m worried I have that resistant ringworm that’s spreading among MSM.’ Whenever we talk about STIs and introduce the word ‘resistant,’ that comes with the potential for stigma, anxiety, and concern.” Fortunately, he said, TMVII has shown no resistance to first-line antifungals.

NYU Langone

Why the Rise

Gold said, “We don’t know for sure why we’re seeing these different drug-resistant species popping up.” One possibility, he said, is the common misuse and overuse of topical antifungals — especially those available overseas in combination with high-potency steroids, such as clobetasol. Consumers use these products for a few weeks until symptoms resolve, then reapply them off and on over years, fueling resistance, said Gold.

“We are worried that with warming temperatures, there’s potential to see expansion of the geographic range of epidemic fungi,” he added. “That could be part of what has fueled recent increases in resistant dermatophytes. But it’s hard to prove.”

Climate change may be behind the emergence of Candida auris, according to a 2022 article in The Lancet Regional Health – Americas. This potentially fatal multidrug-resistant infection spreads easily among sick patients in healthcare facilities, according to a CDC information page on C auris.
 

Confirming Dermatophyte Infection

“A biopsy will only confirm the presence of fungus,” said Elewski. “Here you will need a lab that knows how to do a fungal culture.” Most state laboratories can do this, she said, as can some hospitals and special labs such as CMM in Cleveland.

It takes a Clinical Laboratory Improvement Amendments–certified lab to perform KOH prep in-house, added Caplan, plus up-to-date gear and knowledge of where and how to scrape and what to look for microscopically. Moreover, identifying T indotineae requires molecular testing available at only a handful of laboratories — listed on the AAD Emerging Dermatophytes webpage — nationwide.

Nevertheless, said Caplan, nailing down a diagnosis can guide treatment, often supplanting empirically prescribed antifungal steroid creams. “Those are probably not going to help. And people may be using those on areas of the body they shouldn’t. Both the clinical clues and the steps to make the diagnosis need to come together. But that’s often easier said than done, especially in a busy practice.”

Identifying resistance requires antifungal sensitivity testing, he added, which few labs perform. “Practically speaking,” said Elewski, “if the patient failed terbinafine, I would try itraconazole. You don’t necessarily need proof” of resistance. But if a patient does not respond to itraconazole and terbinafine clinically, she said that she might consider fungal susceptibility testing.
 

Treatment Tips

To address any resistant dermatophyte, Elewski recommended getting comfortable with itraconazole. For decades, she said, dermatologists have avoided itraconazole because terbinafine typically costs patients $10 for 3 months. “Itraconazole could be $200 per month,” said Elewski. Because of potential drug-drug interactions and absorption issues — and a boxed warning regarding congestive heart failure — physicians historically reserved itraconazole for severe fungal infections.

Itraconazole labeled dosing for onychomycosis is 200 mg daily for 12 weeks. Elewski favors a two-pronged attack, often combining an -azole antifungal with topical ciclopirox.

Another element that emerging tinea pathogens share is slower response to treatment. For T indotineae, reports appearing in the Journal of the American Academy of Dermatology in 2022 and 2024 suggest duration from 6-8 weeks up to 20 weeks.

To avoid recurrences of resistant T rubrum, Elewski treats for a year. However, she has problems getting itraconazole approved, when often it is the only agent that works. “I’ve written more letters than I like to insurance companies” to document terbinafine failure, she said.

Rarely, said Gold, dermatophyte infections resist both terbinafine and itraconazole. Next-line agents such as voriconazole, which some dermatologists have used for resistant T indotineae, can be much harder to tolerate, with more drug interactions, he said.

And because itraconazole, voriconazole, and posaconazole are all triazoles, added Elewski, the latter two might not work better than the former. But because these drugs might outperform itraconazole in selected cases, she said, “that’s when you want to do fungal susceptibility testing.”

TMVII is so new, said Caplan, that optimal therapy duration remains unclear. “One of the challenges with TMVII is when it gets into the genital skin, it’s a hair-bearing area. And based on various grooming practices, there’s an opportunity for the tinea to get deeper into the hair follicle and dermis. That may also be true of T indotineae.”
 

Anemic Arsenal

Unfortunately, said Gold, the arsenal of antifungals available in the United States remains limited. “Depending on how you count, there are only three to four classes of antifungal drugs designed to treat severe or invasive infections. So whenever we hear about a new fungal pathogen that’s causing resistant infections, it causes public health concern.”

Promising drugs in development include olorofim (F2G) and fosmanogepix (Basilea), according to Gold. However, he said, the development of these drugs to date has targeted invasive fungal infections such as aspergillosis. In June 2023, the Food and Drug Administration rejected the new drug application for olorofim, requesting additional data and analyses. Regarding fosmanogepix, a double-blinded noninferiority phase 3 trial in invasive yeast infections was recently launched, according to a September 24 press release.

Gold, Caplan, and Elewski reported no relevant financial disclosures. Freeman is a COVID-19 co-author for UpToDate and chair of the AAD Emerging Diseases Task Force.
 

A version of this article appeared on Medscape.com.

Adding a second checkpoint inhibitor to chemotherapy improves outcomes among patients with non–small cell lung cancer (NSCLC) who have STK11 and/or KEAP1 mutations, according to the authors of a new paper.

These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.

“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.

Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
 

What Were the Original Findings of POSEIDON?

The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.

Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.

These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
 

What Did Post Hoc Analysis Highlight About POSEIDON?

The present analysis aimed to validate two actionable biomarkers.

“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.

From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.

As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.

This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.

Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
 

How Do Findings Relate to Previous NSCLC Subgroup Research?

Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.

“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.

Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.

“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”

Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.
 

What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?

To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.

“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.

Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.

Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.

Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.

“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
 

Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?

“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”

This view, however, remains contested by some oncologists.

Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.

“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”

The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.

“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”

On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”

Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.

“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”

Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.

“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”

Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.

“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”

The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
 

A version of this article appeared on Medscape.com.

Adding a second checkpoint inhibitor to chemotherapy improves outcomes among patients with non–small cell lung cancer (NSCLC) who have STK11 and/or KEAP1 mutations, according to the authors of a new paper.

These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.

“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.

Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
 

What Were the Original Findings of POSEIDON?

The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.

Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.

These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
 

What Did Post Hoc Analysis Highlight About POSEIDON?

The present analysis aimed to validate two actionable biomarkers.

“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.

From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.

As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.

This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.

Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
 

How Do Findings Relate to Previous NSCLC Subgroup Research?

Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.

“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.

Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.

“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”

Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.
 

What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?

To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.

“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.

Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.

Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.

Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.

“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
 

Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?

“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”

This view, however, remains contested by some oncologists.

Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.

“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”

The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.

“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”

On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”

Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.

“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”

Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.

“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”

Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.

“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”

The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
 

A version of this article appeared on Medscape.com.

Adding a second checkpoint inhibitor to chemotherapy improves outcomes among patients with non–small cell lung cancer (NSCLC) who have STK11 and/or KEAP1 mutations, according to the authors of a new paper.

These findings, drawn from a post hoc analysis of phase 3 data, are backed up by cell line and mouse data revealing clear mechanisms of efficacy, making the collective evidence compelling enough to reshape clinical practice, reported lead author Ferdinandos Skoulidis, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston.

“Although STK11 and KEAP1 mutations are associated with limited benefit from PD-1 or PD-L1 [PD-(L)1] inhibition, the association between these mutations and benefit from combinations of PD-(L)1 inhibitors with chemotherapy is not yet as well established,” the investigators wrote in Nature.

Skoulidis and colleagues conducted the subgroup analysis of POSEIDON trial data and characterized underlying biologic mechanisms using mouse models to address this knowledge gap.
 

What Were the Original Findings of POSEIDON?

The POSEIDON trial involved 1013 patients with metastatic NSCLC. Treatment arms included standard chemotherapy alone, chemotherapy plus programmed death ligand 1 (PD-L1) inhibitor durvalumab, and chemotherapy plus durvalumab and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor tremelimumab.

Adding durvalumab to chemotherapy significantly improved median progression-free survival (PFS) but not median overall survival (OS), while dual checkpoint blockade boosted both PFS and OS.

These findings provided support for the dual approach in the first-line setting, but not preferentially so. Experts called for more long-term data, questioned the survival benefit in terms of the increased toxicity, and noted the lack of biomarkers for patient selection.
 

What Did Post Hoc Analysis Highlight About POSEIDON?

The present analysis aimed to validate two actionable biomarkers.

“We and others have previously observed that alterations in STK11 and KEAP1 can promote an immunosuppressive tumor microenvironment and together might be responsible for half or more of the primary resistance to PD-(L)1 inhibition among patients with nsNSCLC when given as monotherapy,” Skoulidis and colleagues wrote.

From the original 1013 patients, 612 had non-squamous NSCLC and were evaluable for mutations. Among them, 87 had STK11 mutations and 37 had KEAP1 mutations.

As anticipated, patients in the STK11/KEAP1 subgroup saw little to no benefit from adding durvalumab to chemotherapy, but adding tremelimumab on top yielded notable improvement.

This was first observed in the objective response rate, which was 42.9% with dual checkpoint blockade plus chemotherapy vs 30.2% with single checkpoint blockade plus chemotherapy and 28% for chemotherapy alone. Durations of response improved in kind.

Survival outcomes also trended toward improvement in the dual checkpoint arm, which had a median OS of 15.8 months vs 7.3 months for durvalumab plus chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.40-1.04) and 10.5 months for chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.87). PFS showed similar trends.
 

How Do Findings Relate to Previous NSCLC Subgroup Research?

Skoulidis and colleagues noted that their findings align with those of the CheckMate 9LA trial, which showed that patients with STK11 and/or KEAP1 mutations had better outcomes with dual checkpoint blockade plus chemotherapy than with chemotherapy alone.

“These data support the hypothesis that CTLA-4 inhibition can mitigate the resistance to chemotherapy plus PD-(L)1 inhibition observed in patients who have STK11 and/or KEAP1 mutations and suggest that this group of patients derives greater benefit from CTLA-4 inhibition than do patients who lack either alteration,” Skoulidis and colleagues wrote.

Grace Dy, MD, professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center, Buffalo, New York, noted that in the present analysis, PD-L1 expression status did not predict outcomes; however, patients with STK11 and/or KEAP1 mutations typically have low or negative PD-L1 expression, which has been linked with better responses to CTLA-4 inhibition in multiple trials.

“In the CheckMate 227 and CheckMate 9LA studies, we have seen that patients with PD-L1–negative tumors appear to derive greater and more durable long-term overall survival benefit from dual immune checkpoint blockade compared to patients receiving anti-PD1-based therapy alone,” Dy said in a written comment. “While we take the necessary caveats on cross-trial comparisons, the same survival trend favoring CTLA-4-based immune checkpoint blockade is seen compared to the tail of the survival curves observed in PD-L1–negative patients enrolled in the KEYNOTE studies (KEYNOTE-189, KEYNOTE-407).”

Detecting improvements in survival within PD-L1 patients “may not be readily apparent until later when looking at the tail of the survival curves,” she added.
 

What Mechanisms of Action Explain Relative Benefits of Dual Checkpoint Blockade?

To elucidate underlying mechanisms of action, Skoulidis and colleagues conducted a series of experiments involving cell lines and mouse models of Stk11- and Keap1-deficient NSCLC.

“For us, it was critical to provide mechanistic support for the observed clinical benefit in POSEIDON, especially since this is based on a retrospective subgroup analysis,” Skoulidis said in an interview.

Their efforts revealed a strong link between the mutations and resistance to PD-(L)1 inhibition.

Inactivation of Stk11 and Keap1 promoted an immunosuppressive tumor microenvironment, marked by increased infiltration of suppressive myeloid cells and a reduction in CD8+ effector T cells. This immune imbalance contributed to evasion of immune destruction and limited the efficacy of programmed cell death protein 1 (PD-1) blockade.

Dual checkpoint blockade reprogrammed the immune microenvironment, leading to increased activation of CD4+ T helper (Th) cells, specifically the Th1 subtype, while inducing tumoricidal changes in myeloid cells. Consequently, antitumor responses improved, resulting in tumor regression and prolonged survival, compared with PD-1 monotherapy.

“Addition of CTLA-4 [inhibition] turns the two cardinal components of the suppressive microenvironment of these tumors on its head, and that’s why we believe we are observing this clinical benefit,” Skoulidis said. “This is not a mere association…but also based on very solid mechanistic data across a multitude of different models.”
 

Are Data Sufficient to Shift to First-Line Dual Checkpoint Blockade?

“Our work strengthens the available evidence that this regimen — and chemoimmunotherapy more broadly, with dual immune checkpoint blockade — constitutes a preferred approach for these patients,” Skoulidis said. “I personally, and I think physicians within MD Anderson, as well as a lot of physicians that I talk to, are already using — based on these data — the POSEIDON regimen, as well as, more broadly, chemoimmunotherapy with dual immune checkpoint for patients with these alterations.”

This view, however, remains contested by some oncologists.

Lei Deng, MD, assistant professor in the Division of Hematology and Oncology at the University of Washington, Fred Hutchinson Cancer Center, Seattle, called the new data “intriguing” and “hypothesis-generating,” but stopped short of supporting preferential first-line use.

“This study is a post hoc analysis, so you don’t have a lot of patients,” Deng said. “It is still not strong enough or definitive enough to make it standard of care to use dual checkpoint blockade for [patients with STK11 and/or KEAP1 mutations].”

The cell line and mouse data help explain biologic mechanisms of efficacy, he said, but these findings do not obviate toxicity concerns.

“You are adding one more agent, and this agent is more toxic than single checkpoint blockade,” Deng said. “So, if you weigh the risk, it is known, [but] the benefit is suggestive. I am not sure if the risk-benefit ratio would argue for routine implementation of this regimen yet.”

On the other hand, he noted, the combination is the US Food and Drug Administration–approved in this setting, so “it is not wrong to use it.”

Jyoti Malhotra, MD, director of thoracic medical oncology at City of Hope Orange County in Irvine, California, had a similar take.

“The clinical data presented so far is exploratory and limited by the small sample size,” Malhotra said in a written comment. “Data from an ongoing phase 3 trial (TRITON) is awaited before dual checkpoint blockade becomes the standard of care in this setting.”

Hossein Borghaei, DO, chief of the Division of Thoracic Medical Oncology at Fox Chase Cancer Center, Philadelphia, was also unequivocal when asked if dual checkpoint blockade with chemotherapy should be considered the preferred first-line treatment option in patients with STK11 and/or KEAP1 mutations.

“No,” he said in a written comment. “The data and the hypothesis are very strong, but it is all based on retrospective clinical data, cell line data, and mouse models. We need a randomized study to test the hypothesis.”

Incidentally, Borghaei is on the steering committee for the TRITON trial. He shared this potential conflict of interest before praising Skoulidis and colleagues for their efforts, noting that the present findings underscore the broader importance of widespread tumor profiling and access to resultant data.

“This is a beautiful story that has developed over the last few years based on the research by the group from MD Anderson who has reported the current Nature article,” he said. “This highlights the possible utility of collecting sequencing data on [all] patients’ tumors. These sorts of understandings and new ideas could arise only if there is access to this information.”

The study was supported by AstraZeneca, the National Cancer Institute, the Gunnigar Fund, and others. The investigators disclosed additional relationships with Novartis, Merck, Amgen, and others. Deng disclosed relationships with Merck, BridgeBio, MJH Life Sciences, and others. Dy disclosed relationships with Eli Lilly and Company, Janssen Pharmaceuticals, Meru, and others. Malhotra has previously served as a consultant for AstraZeneca. Borghaei has served as a consultant for AstraZeneca and is on the steering committee for the TRITON trial.
 

A version of this article appeared on Medscape.com.

Therapeutic drug monitoring (TDM) — the practice of using laboratory testing to measure blood levels of drugs — has garnered growing interest among rheumatologists in managing patients on disease-modifying antirheumatic drugs (DMARDs), but that hasn’t exactly translated to widespread practice.

While TDM has made some inroads with patients taking monoclonal antibodies, specifically infliximab, its uptake has encountered a number of headwinds, not the least of which is a lack of evidence and clinical guidelines, uneven access and standards of assays, and even an uncertainty about how to interpret laboratory results.

“In some fields, such as neurology, TDM is accepted for antiepileptics,” Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center, Baltimore, told Medscape Medical News. “In rheumatology, though, TDM is underutilized and not adequately championed by the American College of Rheumatology.”

Johns Hopkins University

Duke University

Reactive vs Proactive TDM

Among the few trials that examined TDM in rheumatology patients are the NOR-DRUM A and B trials in Norway. Marthe Brun, MD, PhD, a rheumatologist at the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and a coauthor of the NOR-DRUM trials, told Medscape Medical News that the trials found an overall benefit to TDM during infliximab maintenance therapy. The trials included not only patients with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) but also patients with inflammatory bowel disease and psoriasis, Brun said.

Nicolas Tourrenc

Brun explained that two types of TDM exist: Reactive and proactive. “Reactive TDM is when you use it to find the reason for a patient having a flare or disease worsening,” she told Medscape Medical News. “Proactive TDM would be regular testing to keep a patient within a therapeutic range to avoid flare because of low drug concentrations.”

Gastroenterologists are more inclined than rheumatologists and dermatologists to use reactive TDM, she said. “There have been no recommendations regarding proactive TDM because of the lack of data.”

In Europe, Wallace noted that European Alliance of Associations for Rheumatology (EULAR) recommendations consider the use of TDM in specific clinical scenarios, such as when treatment fails or to evaluate immunogenicity of a reaction, but they are limited. The American College of Rheumatology (ACR) does not have any recommendations for the use of TDM.

Based on the NOR-DRUM trials, rheumatologists in Norway have published their own guidelines for TDM for infliximab in rheumatologic disease, but they are in Norwegian and have not yet been taken up by EULAR, Brun noted. Publication of those recommendations in English is pending, she said.

“But for other subcutaneously administered TNF inhibitors, there’s a lack of data,” Brun added.
 

The State of the Evidence

NOR-DRUM A did not support the use of proactive TDM in the 30-week induction period as a way to improve disease remission in patients with chronic immune-mediated inflammatory disease. NOR-DRUM B, which evaluated TDM over a year, found the approach was more likely to lead to sustained disease control for that period.

Brun’s group recently published an analysis of the trials. “We did not find an overall effect during the initial phase of the treatment, the first 30 weeks,” she told Medscape Medical News.

“Then we looked at subgroups, and we found that the patients that developed antidrug antibodies [ADAs] had an effect, and ADA are associated with poorer outcomes as well as infusion reactions for patients treated with infliximab.

“So, it’s probably a benefit to be able to detect these ADA early before the patient experiences a disease flare or infusion reaction,” Brun added. “It facilitates for the clinician to take action to, for example, increase the dosing or switch therapy.”

However, the quality of the data supporting TDM in rheumatology is limited, Balevic said. “There’s very good observational data, but we have very few clinical trials that actually leverage TDM,” he said.

NOR-DRUM is the exception, he said. “Ideally, we need more of these dose-optimization trials to help guide clinical practice,” he said. But it stands alone.

Wallace noted several take-home messages from the NOR-DRUM trials, namely that using TDM to prevent ADA may be more effective during the maintenance phase of treatment than the induction phase. However, he said, the evidence is still emerging.

“It’s reasonable to say that we’re at an early stage of the evidence,” he said. “If you look at the large trials that have been done in rheumatology, they’ve combined patients with many different types of conditions, and a lot of our recommendations in rheumatology are disease-specific — in rheumatoid arthritis, in vasculitis. There’s a lack of data in specific diseases to guide or examine what the role of TDM might be.”

In the meantime, no fewer than four clinical trials evaluating TDM with tumor necrosis factor (TNF) inhibitors in rheumatologic diseases are ongoing or have completed but not yet released results, according to Wallace. Three Adalimumab Drug Optimization in Rheumatoid Arthritis trials are underway: The first is evaluating drug tapering vs disease activity score; the second is testing low or usual drug concentration; and the third is studying switches to etanercept or a non-TNF inhibitor drug (abatacept, rituximab, tocilizumab, or sarilumab) in patients failing treatment. Another trial called Tocilizumab Drug Levels to Optimized Treatment in RA is randomizing patients with high drug levels to dose maintenance or dose reduction. All four trials are sponsored by the Reade Rheumatology Research Institute, Amsterdam, the Netherlands.

Until clearer answers emerge from clinical trials, a number of barriers to and questions about the potential for TDM in rheumatology persist.
 

Barriers to Wider Use of TDM

“The biggest barrier with TDM is simply just a lack of what to do with the data,” Balevic said. “The clinician needs clear-cut guidance on what to do with the drug level. So, in other words, what is the target concentration for the drug? And if that target is not the goal, how should that dose be adjusted?”

The optimal drug levels, particularly for the older conventional synthetic DMARDs, simply have not been validated by clinical trials, he said.

“Different studies may report different target drug levels, and this could be due to different underlying population, or a different matrix — a measure of whole blood vs plasma — or even the timing of the sample,” he said. Balevic led a pharmacokinetic study earlier this year that proposed an algorithm for determining the number of missed hydroxychloroquine doses.

“This really goes back to the clinician needing to draw on a lot of pharmacology training to interpret the literature,” Balevic added.

That gets to the need for more education among rheumatologists, as Brun pointed out. “The physician needs to be educated about therapeutic ranges, when to assess concentrations of drug antibodies, and how to react to the results,” Brun said.

Which ADAs to identify is also problematic. “For antidrug antibodies, it’s especially challenging because there are so many assay formats in use, and it’s a bit complicated to analyze these antidrug antibodies,” Brun said. “There’s no consensus on what calibrators to use, and there’s no standardization of how to report the results, so you can’t really compare results from different assays. You need to know what your laboratory is using and how to interpret results from that particular assay, so that’s a challenge.”

Variability in drug tolerance also exists across assays, Wallace noted. “One of the challenges that have come up in the discussion of therapeutic drug monitoring is understanding what the target level is,” he said. “Defining what the target level might be for a specific condition is not something that’s well understood.”

Breaking down the science, he noted that an ADA can bind to a monoclonal antibody, forming an immune complex that avoids detection. Drug-sensitive assays may detect high concentrations of ADAs but miss low or moderate concentrations. Drug-tolerant assays may be more likely to detect low concentrations at ADAs, but the clinical significance is unclear.
 

Cost and Patient Trust as Barriers

“The costs vary a lot from assay to assay,” Brun said. “Some commercial assays can be really expensive.” In Norway, a dedicated lab with its own in-house assays helps to keep costs down, she said.

But that’s not the case in the United States, where insurance coverage can be a question mark, Shivani Garg, MD, a rheumatologist at the University of Wisconsin (UW)-Madison and director of the UW-Madison Health Lupus and Lupus Nephritis Clinics, told Medscape Medical News. “A lot of insurances are covering therapeutic drug monitoring, but for the high-deductible plans, there should be a way to offer these important tests to patients at a lower cost or figure out a way for coverage for those patients so that they can show that there are benefits of therapeutic drug monitoring without being sent a really big bill,” she said.

UW Health

Who May Benefit Most From TDM?

In the NOR-DRUM trials, patients at risk of developing ADA early on, before a disease flare or infusion reaction, seemed to benefit most from TDM. But who are those patients?

“We looked at risk factors for developing antidrug antibodies, and we found that patients with high disease activity when starting treatment, smokers, and patients with rheumatoid arthritis had a higher risk than other patients, as did patients who are not using concomitant immunosuppressive therapy,” Brun said.

“During treatment, we also found that low serum drug levels and drug holidays above 11 weeks were also risk factors,” she added.

The NOR-DRUM researchers also evaluated genetic risk factors and found that patients with the HLA-DQ2 gene variant were also at increased risk of developing ADA.

While NOR-DRUM evaluated only infliximab, some of its lessons may be applied to other DMARDs, Brun said. “We think that for other subcutaneously administered TNF inhibitors, you would probably see the same effect of proactive TDM, but we currently do not have data on that,” she said. A study similar to the NOR-DRUM design will evaluate this in Norway, Brun added.

She explained why the findings with infliximab may extend to adalimumab, which may be the second most immunogenic TNF inhibitor after infliximab. “The administration is different; it’s administered more often than infliximab; that would also make the results more uncertain to generalize to the other treatments, but I would guess there are also benefits of using TDM in other treatments.”
 

Potential Risks for TDM

Wallace has noted that TDM, with the current state of evidence, carries a number of potential risks. “The potential risks might be that you unnecessarily discontinue a medication because you detected an antibody, or the level seems low and you’re not able to get it higher, but the patient is otherwise doing fine,” he said. “You might end up increasing doses of the medicine that would put the patient at potentially increased risk of infection, as well as obviously more costs.”

That would also lead to more utilization of resources and costs, he said. “Some of those reasons are why there has been hesitation with therapeutic drug monitoring,” Wallace added.

A number of questions also surround the use of biosimilars and ADA levels, Wallace said. While a review of clinical trials found no meaningful differences in terms of immunogenicity between biosimilars and reference products, it did note discrepancies in how the agents were evaluated.
 

What DMARDs Are Most Suitable for TDM?

Petri said TDM would be useful for monitoring patients on mycophenolate mofetil. “A trough level can at least tell us if a patient is taking it,” she said. “Tacrolimus, used for lupus nephritis, has well-accepted peak and trough trends due to widespread use in transplant.”

Drugs with a wide variability in pharmacokinetics may also be suitable for TDM, Balevic said. That would include hydroxychloroquine, azathioprine, mycophenolate, or even cyclophosphamide. Drugs that have a narrow therapeutic index, such as tacrolimus, cyclosporine, or again, cyclophosphamide, might also be amenable to TDM, he said.
 

Why Do TDM?

“The two main reasons why somebody would go on to detect drug levels: The first may be to assess medication adherence, and this applies virtually to any drug that rheumatologists use; the second reason is to optimize dozing, either for efficacy purposes or to prevent toxicity,” Balevic said.

“When it comes to optimizing dosing, you should really think about TDM as one tool in our toolbelt,” he said.

Dose is “just a surrogate,” he said. “When we prescribe a drug, what truly matters is the amount of active unbound drug at the site of action. That’s what’s responsible for a drug’s pharmacologic effect.”

However, the same dose, or even the same weight-based dose, does not necessarily mean similar patients will achieve the same amount of exposure to the drug, but TDM can help determine that, he said.
 

What’s Next

Studies into the use of TDM in rheumatology are ongoing. Brun said her group is currently conducting a cost-effective analysis from the NOR-DRUM trials.

“There’s going to be more studies coming out in the next few years, looking at what impact the use of therapeutic drug monitoring might have on outcomes,” Wallace said.

“As we accumulate more and more evidence, we might see organizations like ACR and EULAR start to weigh in more on whether or not therapeutic drug monitoring can or should be used.”

Petri, Brun, and Garg had no relevant disclosures. Wallace disclosed financial relationships with Amgen, Alexion, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Medpace, Novartis, Sanofi, Viela Bio, Visterra, Xencor, and Zenas. Balevic disclosed relationships with the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, and UCB.
 

A version of this article appeared on Medscape.com.

Therapeutic drug monitoring (TDM) — the practice of using laboratory testing to measure blood levels of drugs — has garnered growing interest among rheumatologists in managing patients on disease-modifying antirheumatic drugs (DMARDs), but that hasn’t exactly translated to widespread practice.

While TDM has made some inroads with patients taking monoclonal antibodies, specifically infliximab, its uptake has encountered a number of headwinds, not the least of which is a lack of evidence and clinical guidelines, uneven access and standards of assays, and even an uncertainty about how to interpret laboratory results.

“In some fields, such as neurology, TDM is accepted for antiepileptics,” Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center, Baltimore, told Medscape Medical News. “In rheumatology, though, TDM is underutilized and not adequately championed by the American College of Rheumatology.”

Johns Hopkins University

Duke University

Reactive vs Proactive TDM

Among the few trials that examined TDM in rheumatology patients are the NOR-DRUM A and B trials in Norway. Marthe Brun, MD, PhD, a rheumatologist at the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and a coauthor of the NOR-DRUM trials, told Medscape Medical News that the trials found an overall benefit to TDM during infliximab maintenance therapy. The trials included not only patients with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) but also patients with inflammatory bowel disease and psoriasis, Brun said.

Nicolas Tourrenc

Brun explained that two types of TDM exist: Reactive and proactive. “Reactive TDM is when you use it to find the reason for a patient having a flare or disease worsening,” she told Medscape Medical News. “Proactive TDM would be regular testing to keep a patient within a therapeutic range to avoid flare because of low drug concentrations.”

Gastroenterologists are more inclined than rheumatologists and dermatologists to use reactive TDM, she said. “There have been no recommendations regarding proactive TDM because of the lack of data.”

In Europe, Wallace noted that European Alliance of Associations for Rheumatology (EULAR) recommendations consider the use of TDM in specific clinical scenarios, such as when treatment fails or to evaluate immunogenicity of a reaction, but they are limited. The American College of Rheumatology (ACR) does not have any recommendations for the use of TDM.

Based on the NOR-DRUM trials, rheumatologists in Norway have published their own guidelines for TDM for infliximab in rheumatologic disease, but they are in Norwegian and have not yet been taken up by EULAR, Brun noted. Publication of those recommendations in English is pending, she said.

“But for other subcutaneously administered TNF inhibitors, there’s a lack of data,” Brun added.
 

The State of the Evidence

NOR-DRUM A did not support the use of proactive TDM in the 30-week induction period as a way to improve disease remission in patients with chronic immune-mediated inflammatory disease. NOR-DRUM B, which evaluated TDM over a year, found the approach was more likely to lead to sustained disease control for that period.

Brun’s group recently published an analysis of the trials. “We did not find an overall effect during the initial phase of the treatment, the first 30 weeks,” she told Medscape Medical News.

“Then we looked at subgroups, and we found that the patients that developed antidrug antibodies [ADAs] had an effect, and ADA are associated with poorer outcomes as well as infusion reactions for patients treated with infliximab.

“So, it’s probably a benefit to be able to detect these ADA early before the patient experiences a disease flare or infusion reaction,” Brun added. “It facilitates for the clinician to take action to, for example, increase the dosing or switch therapy.”

However, the quality of the data supporting TDM in rheumatology is limited, Balevic said. “There’s very good observational data, but we have very few clinical trials that actually leverage TDM,” he said.

NOR-DRUM is the exception, he said. “Ideally, we need more of these dose-optimization trials to help guide clinical practice,” he said. But it stands alone.

Wallace noted several take-home messages from the NOR-DRUM trials, namely that using TDM to prevent ADA may be more effective during the maintenance phase of treatment than the induction phase. However, he said, the evidence is still emerging.

“It’s reasonable to say that we’re at an early stage of the evidence,” he said. “If you look at the large trials that have been done in rheumatology, they’ve combined patients with many different types of conditions, and a lot of our recommendations in rheumatology are disease-specific — in rheumatoid arthritis, in vasculitis. There’s a lack of data in specific diseases to guide or examine what the role of TDM might be.”

In the meantime, no fewer than four clinical trials evaluating TDM with tumor necrosis factor (TNF) inhibitors in rheumatologic diseases are ongoing or have completed but not yet released results, according to Wallace. Three Adalimumab Drug Optimization in Rheumatoid Arthritis trials are underway: The first is evaluating drug tapering vs disease activity score; the second is testing low or usual drug concentration; and the third is studying switches to etanercept or a non-TNF inhibitor drug (abatacept, rituximab, tocilizumab, or sarilumab) in patients failing treatment. Another trial called Tocilizumab Drug Levels to Optimized Treatment in RA is randomizing patients with high drug levels to dose maintenance or dose reduction. All four trials are sponsored by the Reade Rheumatology Research Institute, Amsterdam, the Netherlands.

Until clearer answers emerge from clinical trials, a number of barriers to and questions about the potential for TDM in rheumatology persist.
 

Barriers to Wider Use of TDM

“The biggest barrier with TDM is simply just a lack of what to do with the data,” Balevic said. “The clinician needs clear-cut guidance on what to do with the drug level. So, in other words, what is the target concentration for the drug? And if that target is not the goal, how should that dose be adjusted?”

The optimal drug levels, particularly for the older conventional synthetic DMARDs, simply have not been validated by clinical trials, he said.

“Different studies may report different target drug levels, and this could be due to different underlying population, or a different matrix — a measure of whole blood vs plasma — or even the timing of the sample,” he said. Balevic led a pharmacokinetic study earlier this year that proposed an algorithm for determining the number of missed hydroxychloroquine doses.

“This really goes back to the clinician needing to draw on a lot of pharmacology training to interpret the literature,” Balevic added.

That gets to the need for more education among rheumatologists, as Brun pointed out. “The physician needs to be educated about therapeutic ranges, when to assess concentrations of drug antibodies, and how to react to the results,” Brun said.

Which ADAs to identify is also problematic. “For antidrug antibodies, it’s especially challenging because there are so many assay formats in use, and it’s a bit complicated to analyze these antidrug antibodies,” Brun said. “There’s no consensus on what calibrators to use, and there’s no standardization of how to report the results, so you can’t really compare results from different assays. You need to know what your laboratory is using and how to interpret results from that particular assay, so that’s a challenge.”

Variability in drug tolerance also exists across assays, Wallace noted. “One of the challenges that have come up in the discussion of therapeutic drug monitoring is understanding what the target level is,” he said. “Defining what the target level might be for a specific condition is not something that’s well understood.”

Breaking down the science, he noted that an ADA can bind to a monoclonal antibody, forming an immune complex that avoids detection. Drug-sensitive assays may detect high concentrations of ADAs but miss low or moderate concentrations. Drug-tolerant assays may be more likely to detect low concentrations at ADAs, but the clinical significance is unclear.
 

Cost and Patient Trust as Barriers

“The costs vary a lot from assay to assay,” Brun said. “Some commercial assays can be really expensive.” In Norway, a dedicated lab with its own in-house assays helps to keep costs down, she said.

But that’s not the case in the United States, where insurance coverage can be a question mark, Shivani Garg, MD, a rheumatologist at the University of Wisconsin (UW)-Madison and director of the UW-Madison Health Lupus and Lupus Nephritis Clinics, told Medscape Medical News. “A lot of insurances are covering therapeutic drug monitoring, but for the high-deductible plans, there should be a way to offer these important tests to patients at a lower cost or figure out a way for coverage for those patients so that they can show that there are benefits of therapeutic drug monitoring without being sent a really big bill,” she said.

UW Health

Who May Benefit Most From TDM?

In the NOR-DRUM trials, patients at risk of developing ADA early on, before a disease flare or infusion reaction, seemed to benefit most from TDM. But who are those patients?

“We looked at risk factors for developing antidrug antibodies, and we found that patients with high disease activity when starting treatment, smokers, and patients with rheumatoid arthritis had a higher risk than other patients, as did patients who are not using concomitant immunosuppressive therapy,” Brun said.

“During treatment, we also found that low serum drug levels and drug holidays above 11 weeks were also risk factors,” she added.

The NOR-DRUM researchers also evaluated genetic risk factors and found that patients with the HLA-DQ2 gene variant were also at increased risk of developing ADA.

While NOR-DRUM evaluated only infliximab, some of its lessons may be applied to other DMARDs, Brun said. “We think that for other subcutaneously administered TNF inhibitors, you would probably see the same effect of proactive TDM, but we currently do not have data on that,” she said. A study similar to the NOR-DRUM design will evaluate this in Norway, Brun added.

She explained why the findings with infliximab may extend to adalimumab, which may be the second most immunogenic TNF inhibitor after infliximab. “The administration is different; it’s administered more often than infliximab; that would also make the results more uncertain to generalize to the other treatments, but I would guess there are also benefits of using TDM in other treatments.”
 

Potential Risks for TDM

Wallace has noted that TDM, with the current state of evidence, carries a number of potential risks. “The potential risks might be that you unnecessarily discontinue a medication because you detected an antibody, or the level seems low and you’re not able to get it higher, but the patient is otherwise doing fine,” he said. “You might end up increasing doses of the medicine that would put the patient at potentially increased risk of infection, as well as obviously more costs.”

That would also lead to more utilization of resources and costs, he said. “Some of those reasons are why there has been hesitation with therapeutic drug monitoring,” Wallace added.

A number of questions also surround the use of biosimilars and ADA levels, Wallace said. While a review of clinical trials found no meaningful differences in terms of immunogenicity between biosimilars and reference products, it did note discrepancies in how the agents were evaluated.
 

What DMARDs Are Most Suitable for TDM?

Petri said TDM would be useful for monitoring patients on mycophenolate mofetil. “A trough level can at least tell us if a patient is taking it,” she said. “Tacrolimus, used for lupus nephritis, has well-accepted peak and trough trends due to widespread use in transplant.”

Drugs with a wide variability in pharmacokinetics may also be suitable for TDM, Balevic said. That would include hydroxychloroquine, azathioprine, mycophenolate, or even cyclophosphamide. Drugs that have a narrow therapeutic index, such as tacrolimus, cyclosporine, or again, cyclophosphamide, might also be amenable to TDM, he said.
 

Why Do TDM?

“The two main reasons why somebody would go on to detect drug levels: The first may be to assess medication adherence, and this applies virtually to any drug that rheumatologists use; the second reason is to optimize dozing, either for efficacy purposes or to prevent toxicity,” Balevic said.

“When it comes to optimizing dosing, you should really think about TDM as one tool in our toolbelt,” he said.

Dose is “just a surrogate,” he said. “When we prescribe a drug, what truly matters is the amount of active unbound drug at the site of action. That’s what’s responsible for a drug’s pharmacologic effect.”

However, the same dose, or even the same weight-based dose, does not necessarily mean similar patients will achieve the same amount of exposure to the drug, but TDM can help determine that, he said.
 

What’s Next

Studies into the use of TDM in rheumatology are ongoing. Brun said her group is currently conducting a cost-effective analysis from the NOR-DRUM trials.

“There’s going to be more studies coming out in the next few years, looking at what impact the use of therapeutic drug monitoring might have on outcomes,” Wallace said.

“As we accumulate more and more evidence, we might see organizations like ACR and EULAR start to weigh in more on whether or not therapeutic drug monitoring can or should be used.”

Petri, Brun, and Garg had no relevant disclosures. Wallace disclosed financial relationships with Amgen, Alexion, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Medpace, Novartis, Sanofi, Viela Bio, Visterra, Xencor, and Zenas. Balevic disclosed relationships with the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, and UCB.
 

A version of this article appeared on Medscape.com.

Therapeutic drug monitoring (TDM) — the practice of using laboratory testing to measure blood levels of drugs — has garnered growing interest among rheumatologists in managing patients on disease-modifying antirheumatic drugs (DMARDs), but that hasn’t exactly translated to widespread practice.

While TDM has made some inroads with patients taking monoclonal antibodies, specifically infliximab, its uptake has encountered a number of headwinds, not the least of which is a lack of evidence and clinical guidelines, uneven access and standards of assays, and even an uncertainty about how to interpret laboratory results.

“In some fields, such as neurology, TDM is accepted for antiepileptics,” Michelle Petri, MD, MPH, director of the Johns Hopkins Lupus Center, Baltimore, told Medscape Medical News. “In rheumatology, though, TDM is underutilized and not adequately championed by the American College of Rheumatology.”

Johns Hopkins University

Duke University

Reactive vs Proactive TDM

Among the few trials that examined TDM in rheumatology patients are the NOR-DRUM A and B trials in Norway. Marthe Brun, MD, PhD, a rheumatologist at the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and a coauthor of the NOR-DRUM trials, told Medscape Medical News that the trials found an overall benefit to TDM during infliximab maintenance therapy. The trials included not only patients with inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis) but also patients with inflammatory bowel disease and psoriasis, Brun said.

Nicolas Tourrenc

Brun explained that two types of TDM exist: Reactive and proactive. “Reactive TDM is when you use it to find the reason for a patient having a flare or disease worsening,” she told Medscape Medical News. “Proactive TDM would be regular testing to keep a patient within a therapeutic range to avoid flare because of low drug concentrations.”

Gastroenterologists are more inclined than rheumatologists and dermatologists to use reactive TDM, she said. “There have been no recommendations regarding proactive TDM because of the lack of data.”

In Europe, Wallace noted that European Alliance of Associations for Rheumatology (EULAR) recommendations consider the use of TDM in specific clinical scenarios, such as when treatment fails or to evaluate immunogenicity of a reaction, but they are limited. The American College of Rheumatology (ACR) does not have any recommendations for the use of TDM.

Based on the NOR-DRUM trials, rheumatologists in Norway have published their own guidelines for TDM for infliximab in rheumatologic disease, but they are in Norwegian and have not yet been taken up by EULAR, Brun noted. Publication of those recommendations in English is pending, she said.

“But for other subcutaneously administered TNF inhibitors, there’s a lack of data,” Brun added.
 

The State of the Evidence

NOR-DRUM A did not support the use of proactive TDM in the 30-week induction period as a way to improve disease remission in patients with chronic immune-mediated inflammatory disease. NOR-DRUM B, which evaluated TDM over a year, found the approach was more likely to lead to sustained disease control for that period.

Brun’s group recently published an analysis of the trials. “We did not find an overall effect during the initial phase of the treatment, the first 30 weeks,” she told Medscape Medical News.

“Then we looked at subgroups, and we found that the patients that developed antidrug antibodies [ADAs] had an effect, and ADA are associated with poorer outcomes as well as infusion reactions for patients treated with infliximab.

“So, it’s probably a benefit to be able to detect these ADA early before the patient experiences a disease flare or infusion reaction,” Brun added. “It facilitates for the clinician to take action to, for example, increase the dosing or switch therapy.”

However, the quality of the data supporting TDM in rheumatology is limited, Balevic said. “There’s very good observational data, but we have very few clinical trials that actually leverage TDM,” he said.

NOR-DRUM is the exception, he said. “Ideally, we need more of these dose-optimization trials to help guide clinical practice,” he said. But it stands alone.

Wallace noted several take-home messages from the NOR-DRUM trials, namely that using TDM to prevent ADA may be more effective during the maintenance phase of treatment than the induction phase. However, he said, the evidence is still emerging.

“It’s reasonable to say that we’re at an early stage of the evidence,” he said. “If you look at the large trials that have been done in rheumatology, they’ve combined patients with many different types of conditions, and a lot of our recommendations in rheumatology are disease-specific — in rheumatoid arthritis, in vasculitis. There’s a lack of data in specific diseases to guide or examine what the role of TDM might be.”

In the meantime, no fewer than four clinical trials evaluating TDM with tumor necrosis factor (TNF) inhibitors in rheumatologic diseases are ongoing or have completed but not yet released results, according to Wallace. Three Adalimumab Drug Optimization in Rheumatoid Arthritis trials are underway: The first is evaluating drug tapering vs disease activity score; the second is testing low or usual drug concentration; and the third is studying switches to etanercept or a non-TNF inhibitor drug (abatacept, rituximab, tocilizumab, or sarilumab) in patients failing treatment. Another trial called Tocilizumab Drug Levels to Optimized Treatment in RA is randomizing patients with high drug levels to dose maintenance or dose reduction. All four trials are sponsored by the Reade Rheumatology Research Institute, Amsterdam, the Netherlands.

Until clearer answers emerge from clinical trials, a number of barriers to and questions about the potential for TDM in rheumatology persist.
 

Barriers to Wider Use of TDM

“The biggest barrier with TDM is simply just a lack of what to do with the data,” Balevic said. “The clinician needs clear-cut guidance on what to do with the drug level. So, in other words, what is the target concentration for the drug? And if that target is not the goal, how should that dose be adjusted?”

The optimal drug levels, particularly for the older conventional synthetic DMARDs, simply have not been validated by clinical trials, he said.

“Different studies may report different target drug levels, and this could be due to different underlying population, or a different matrix — a measure of whole blood vs plasma — or even the timing of the sample,” he said. Balevic led a pharmacokinetic study earlier this year that proposed an algorithm for determining the number of missed hydroxychloroquine doses.

“This really goes back to the clinician needing to draw on a lot of pharmacology training to interpret the literature,” Balevic added.

That gets to the need for more education among rheumatologists, as Brun pointed out. “The physician needs to be educated about therapeutic ranges, when to assess concentrations of drug antibodies, and how to react to the results,” Brun said.

Which ADAs to identify is also problematic. “For antidrug antibodies, it’s especially challenging because there are so many assay formats in use, and it’s a bit complicated to analyze these antidrug antibodies,” Brun said. “There’s no consensus on what calibrators to use, and there’s no standardization of how to report the results, so you can’t really compare results from different assays. You need to know what your laboratory is using and how to interpret results from that particular assay, so that’s a challenge.”

Variability in drug tolerance also exists across assays, Wallace noted. “One of the challenges that have come up in the discussion of therapeutic drug monitoring is understanding what the target level is,” he said. “Defining what the target level might be for a specific condition is not something that’s well understood.”

Breaking down the science, he noted that an ADA can bind to a monoclonal antibody, forming an immune complex that avoids detection. Drug-sensitive assays may detect high concentrations of ADAs but miss low or moderate concentrations. Drug-tolerant assays may be more likely to detect low concentrations at ADAs, but the clinical significance is unclear.
 

Cost and Patient Trust as Barriers

“The costs vary a lot from assay to assay,” Brun said. “Some commercial assays can be really expensive.” In Norway, a dedicated lab with its own in-house assays helps to keep costs down, she said.

But that’s not the case in the United States, where insurance coverage can be a question mark, Shivani Garg, MD, a rheumatologist at the University of Wisconsin (UW)-Madison and director of the UW-Madison Health Lupus and Lupus Nephritis Clinics, told Medscape Medical News. “A lot of insurances are covering therapeutic drug monitoring, but for the high-deductible plans, there should be a way to offer these important tests to patients at a lower cost or figure out a way for coverage for those patients so that they can show that there are benefits of therapeutic drug monitoring without being sent a really big bill,” she said.

UW Health

Who May Benefit Most From TDM?

In the NOR-DRUM trials, patients at risk of developing ADA early on, before a disease flare or infusion reaction, seemed to benefit most from TDM. But who are those patients?

“We looked at risk factors for developing antidrug antibodies, and we found that patients with high disease activity when starting treatment, smokers, and patients with rheumatoid arthritis had a higher risk than other patients, as did patients who are not using concomitant immunosuppressive therapy,” Brun said.

“During treatment, we also found that low serum drug levels and drug holidays above 11 weeks were also risk factors,” she added.

The NOR-DRUM researchers also evaluated genetic risk factors and found that patients with the HLA-DQ2 gene variant were also at increased risk of developing ADA.

While NOR-DRUM evaluated only infliximab, some of its lessons may be applied to other DMARDs, Brun said. “We think that for other subcutaneously administered TNF inhibitors, you would probably see the same effect of proactive TDM, but we currently do not have data on that,” she said. A study similar to the NOR-DRUM design will evaluate this in Norway, Brun added.

She explained why the findings with infliximab may extend to adalimumab, which may be the second most immunogenic TNF inhibitor after infliximab. “The administration is different; it’s administered more often than infliximab; that would also make the results more uncertain to generalize to the other treatments, but I would guess there are also benefits of using TDM in other treatments.”
 

Potential Risks for TDM

Wallace has noted that TDM, with the current state of evidence, carries a number of potential risks. “The potential risks might be that you unnecessarily discontinue a medication because you detected an antibody, or the level seems low and you’re not able to get it higher, but the patient is otherwise doing fine,” he said. “You might end up increasing doses of the medicine that would put the patient at potentially increased risk of infection, as well as obviously more costs.”

That would also lead to more utilization of resources and costs, he said. “Some of those reasons are why there has been hesitation with therapeutic drug monitoring,” Wallace added.

A number of questions also surround the use of biosimilars and ADA levels, Wallace said. While a review of clinical trials found no meaningful differences in terms of immunogenicity between biosimilars and reference products, it did note discrepancies in how the agents were evaluated.
 

What DMARDs Are Most Suitable for TDM?

Petri said TDM would be useful for monitoring patients on mycophenolate mofetil. “A trough level can at least tell us if a patient is taking it,” she said. “Tacrolimus, used for lupus nephritis, has well-accepted peak and trough trends due to widespread use in transplant.”

Drugs with a wide variability in pharmacokinetics may also be suitable for TDM, Balevic said. That would include hydroxychloroquine, azathioprine, mycophenolate, or even cyclophosphamide. Drugs that have a narrow therapeutic index, such as tacrolimus, cyclosporine, or again, cyclophosphamide, might also be amenable to TDM, he said.
 

Why Do TDM?

“The two main reasons why somebody would go on to detect drug levels: The first may be to assess medication adherence, and this applies virtually to any drug that rheumatologists use; the second reason is to optimize dozing, either for efficacy purposes or to prevent toxicity,” Balevic said.

“When it comes to optimizing dosing, you should really think about TDM as one tool in our toolbelt,” he said.

Dose is “just a surrogate,” he said. “When we prescribe a drug, what truly matters is the amount of active unbound drug at the site of action. That’s what’s responsible for a drug’s pharmacologic effect.”

However, the same dose, or even the same weight-based dose, does not necessarily mean similar patients will achieve the same amount of exposure to the drug, but TDM can help determine that, he said.
 

What’s Next

Studies into the use of TDM in rheumatology are ongoing. Brun said her group is currently conducting a cost-effective analysis from the NOR-DRUM trials.

“There’s going to be more studies coming out in the next few years, looking at what impact the use of therapeutic drug monitoring might have on outcomes,” Wallace said.

“As we accumulate more and more evidence, we might see organizations like ACR and EULAR start to weigh in more on whether or not therapeutic drug monitoring can or should be used.”

Petri, Brun, and Garg had no relevant disclosures. Wallace disclosed financial relationships with Amgen, Alexion, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Medpace, Novartis, Sanofi, Viela Bio, Visterra, Xencor, and Zenas. Balevic disclosed relationships with the National Institutes of Health, the Childhood Arthritis and Rheumatology Research Alliance, and UCB.
 

A version of this article appeared on Medscape.com.

Many patients use cannabis to manage their cancer-related symptoms. However, research indicates that patients often do so without speaking to their oncologists first, and oncologists may be hesitant to broach the topic with their patients.

Updated guidelines from the American Society of Clinical Oncology (ASCO) on the use of cannabis and cannabinoids in adults with cancer stress that it’s an important conversation to have.

According to the ASCO expert panel, access to and use of cannabis alongside cancer care have outpaced the science on evidence-based indications, and overall high-quality data on the effects of cannabis during cancer care are lacking. While several observational studies support cannabis use to help ease chemotherapy-related nausea and vomiting, the literature remains more divided on other potential benefits, such as alleviating cancer pain and sleep problems, and some evidence points to potential downsides of cannabis use.

Oncologists should “absolutely talk to patients” about cannabis, Brooke Worster, MD, medical director for the Master of Science in Medical Cannabis Science & Business program at Thomas Jefferson University, Philadelphia, told Medscape Medical News.

“Patients are interested, and they are going to find access to information. As a medical professional, it’s our job to help guide them through these spaces in a safe, nonjudgmental way.”

But, Worster noted, oncologists don’t have to be experts on cannabis to begin the conversation with patients.

So, “let yourself off the hook,” Worster urged.

Plus, avoiding the conversation won’t stop patients from using cannabis. In a recent study, Worster and her colleagues found that nearly one third of patients at 12 National Cancer Institute-designated cancer centers had used cannabis since their diagnosis — most often for sleep disturbance, pain, stress, and anxiety. Most (60%) felt somewhat or extremely comfortable talking to their healthcare provider about it, but only 21.5% said they had done so. Even fewer — about 10% — had talked to their treating oncologist.

Because patients may not discuss cannabis use, it’s especially important for oncologists to open up a line of communication, said Worster, also the enterprise director of supportive oncology at the Thomas Jefferson University.
 

Evidence on Cannabis During Cancer Care

A substantial proportion of people with cancer believe cannabis can help manage cancer-related symptoms.

In Worster’s recent survey study, regardless of whether patients had used cannabis, almost 90% of those surveyed reported a perceived benefit. Although 65% also reported perceived risks for cannabis use, including difficulty concentrating, lung damage, and impaired memory, the perceived benefits outweighed the risks.

Despite generally positive perceptions, the overall literature on the benefits of cannabis in patients with cancer paints a less clear picture.

The ASCO guidelines, which were based on 13 systematic reviews and five additional primary studies, reported that cannabis can improve refractory, chemotherapy-induced nausea or vomiting when added to guideline-concordant antiemetic regimens, but that there is no clear evidence of benefit or harm for other supportive care outcomes.

The “certainty of evidence for most outcomes was low or very low,” the ASCO authors wrote.

The ASCO experts explained that, outside the context of a clinical trial, the evidence is not sufficient to recommend cannabis or cannabinoids for managing cancer pain, sleep issues, appetite loss, or anxiety and depression. For these outcomes, some studies indicate a benefit, while others don’t.

Real-world data from a large registry study, for instance, have indicated that medical cannabis is “a safe and effective complementary treatment for pain relief in patients with cancer.” However, a 2020 meta-analysis found that, in studies with a low risk for bias, adding cannabinoids to opioids did not reduce cancer pain in adults with advanced cancer.

There can be downsides to cannabis use, too. In one recent study, some patients reported feeling worse physically and psychologically compared with those who didn’t use cannabis. Another study found that oral cannabis was associated with “bothersome” side effects, including sedation, dizziness, and transient anxiety.

The ASCO guidelines also made it clear that cannabis or cannabinoids should not be used as cancer-directed treatment, outside of a clinical trial.
 

Talking to Patients About Cannabis

Given the level of evidence and patient interest in cannabis, it is important for oncologists to raise the topic of cannabis use with their patients.

To help inform decision-making and approaches to care, the ASCO guidelines suggest that oncologists can guide care themselves or direct patients to appropriate “unbiased, evidence-based” resources. For those who use cannabis or cannabinoids outside of evidence-based indications or clinician recommendations, it’s important to explore patients’ goals, educate them, and try to minimize harm.

One strategy for broaching the topic, Worster suggested, is to simply ask patients if they have tried or considered trying cannabis to control symptoms like nausea and vomiting, loss of appetite, or cancer pain.

The conversation with patients should then include an overview of the potential benefits and potential risks for cannabis use as well as risk reduction strategies, Worster noted.

But “approach it in an open and nonjudgmental frame of mind,” she said. “Just have a conversation.”

Discussing the formulation and concentration of tetrahydrocannabinol (THC) and cannabidiol (CBD) in products matters as well.

Will the product be inhaled, ingested, or topical? Inhaled cannabis is not ideal but is sometimes what patients have access to, Worster explained. Inhaled formulations tend to have faster onset, which might be preferable for treating chemotherapy-related nausea and vomiting, whereas edible formulations may take a while to start working.

It’s also important to warn patients about taking too much, she said, explaining that inhaling THC at higher doses can increase the risk for cardiovascular effects, anxiety, paranoia, panic, and psychosis.

CBD, on the other hand, is anti-inflammatory, but early data suggest it may blunt immune responses in high doses and should be used cautiously by patients receiving immunotherapy.

Worster noted that as laws change and the science advances, new cannabis products and formulations will emerge, as will artificial intelligence tools for helping to guide patients and clinicians in optimal use of cannabis for cancer care. State websites are a particularly helpful tool for providing state-specific medical education related to cannabis laws and use, as well, she said.

The bottom line, she said, is that talking to patients about the ins and outs of cannabis use “really matters.”

Worster disclosed that she is a medical consultant for EO Care.
 

A version of this article appeared on Medscape.com.

Many patients use cannabis to manage their cancer-related symptoms. However, research indicates that patients often do so without speaking to their oncologists first, and oncologists may be hesitant to broach the topic with their patients.

Updated guidelines from the American Society of Clinical Oncology (ASCO) on the use of cannabis and cannabinoids in adults with cancer stress that it’s an important conversation to have.

According to the ASCO expert panel, access to and use of cannabis alongside cancer care have outpaced the science on evidence-based indications, and overall high-quality data on the effects of cannabis during cancer care are lacking. While several observational studies support cannabis use to help ease chemotherapy-related nausea and vomiting, the literature remains more divided on other potential benefits, such as alleviating cancer pain and sleep problems, and some evidence points to potential downsides of cannabis use.

Oncologists should “absolutely talk to patients” about cannabis, Brooke Worster, MD, medical director for the Master of Science in Medical Cannabis Science & Business program at Thomas Jefferson University, Philadelphia, told Medscape Medical News.

“Patients are interested, and they are going to find access to information. As a medical professional, it’s our job to help guide them through these spaces in a safe, nonjudgmental way.”

But, Worster noted, oncologists don’t have to be experts on cannabis to begin the conversation with patients.

So, “let yourself off the hook,” Worster urged.

Plus, avoiding the conversation won’t stop patients from using cannabis. In a recent study, Worster and her colleagues found that nearly one third of patients at 12 National Cancer Institute-designated cancer centers had used cannabis since their diagnosis — most often for sleep disturbance, pain, stress, and anxiety. Most (60%) felt somewhat or extremely comfortable talking to their healthcare provider about it, but only 21.5% said they had done so. Even fewer — about 10% — had talked to their treating oncologist.

Because patients may not discuss cannabis use, it’s especially important for oncologists to open up a line of communication, said Worster, also the enterprise director of supportive oncology at the Thomas Jefferson University.
 

Evidence on Cannabis During Cancer Care

A substantial proportion of people with cancer believe cannabis can help manage cancer-related symptoms.

In Worster’s recent survey study, regardless of whether patients had used cannabis, almost 90% of those surveyed reported a perceived benefit. Although 65% also reported perceived risks for cannabis use, including difficulty concentrating, lung damage, and impaired memory, the perceived benefits outweighed the risks.

Despite generally positive perceptions, the overall literature on the benefits of cannabis in patients with cancer paints a less clear picture.

The ASCO guidelines, which were based on 13 systematic reviews and five additional primary studies, reported that cannabis can improve refractory, chemotherapy-induced nausea or vomiting when added to guideline-concordant antiemetic regimens, but that there is no clear evidence of benefit or harm for other supportive care outcomes.

The “certainty of evidence for most outcomes was low or very low,” the ASCO authors wrote.

The ASCO experts explained that, outside the context of a clinical trial, the evidence is not sufficient to recommend cannabis or cannabinoids for managing cancer pain, sleep issues, appetite loss, or anxiety and depression. For these outcomes, some studies indicate a benefit, while others don’t.

Real-world data from a large registry study, for instance, have indicated that medical cannabis is “a safe and effective complementary treatment for pain relief in patients with cancer.” However, a 2020 meta-analysis found that, in studies with a low risk for bias, adding cannabinoids to opioids did not reduce cancer pain in adults with advanced cancer.

There can be downsides to cannabis use, too. In one recent study, some patients reported feeling worse physically and psychologically compared with those who didn’t use cannabis. Another study found that oral cannabis was associated with “bothersome” side effects, including sedation, dizziness, and transient anxiety.

The ASCO guidelines also made it clear that cannabis or cannabinoids should not be used as cancer-directed treatment, outside of a clinical trial.
 

Talking to Patients About Cannabis

Given the level of evidence and patient interest in cannabis, it is important for oncologists to raise the topic of cannabis use with their patients.

To help inform decision-making and approaches to care, the ASCO guidelines suggest that oncologists can guide care themselves or direct patients to appropriate “unbiased, evidence-based” resources. For those who use cannabis or cannabinoids outside of evidence-based indications or clinician recommendations, it’s important to explore patients’ goals, educate them, and try to minimize harm.

One strategy for broaching the topic, Worster suggested, is to simply ask patients if they have tried or considered trying cannabis to control symptoms like nausea and vomiting, loss of appetite, or cancer pain.

The conversation with patients should then include an overview of the potential benefits and potential risks for cannabis use as well as risk reduction strategies, Worster noted.

But “approach it in an open and nonjudgmental frame of mind,” she said. “Just have a conversation.”

Discussing the formulation and concentration of tetrahydrocannabinol (THC) and cannabidiol (CBD) in products matters as well.

Will the product be inhaled, ingested, or topical? Inhaled cannabis is not ideal but is sometimes what patients have access to, Worster explained. Inhaled formulations tend to have faster onset, which might be preferable for treating chemotherapy-related nausea and vomiting, whereas edible formulations may take a while to start working.

It’s also important to warn patients about taking too much, she said, explaining that inhaling THC at higher doses can increase the risk for cardiovascular effects, anxiety, paranoia, panic, and psychosis.

CBD, on the other hand, is anti-inflammatory, but early data suggest it may blunt immune responses in high doses and should be used cautiously by patients receiving immunotherapy.

Worster noted that as laws change and the science advances, new cannabis products and formulations will emerge, as will artificial intelligence tools for helping to guide patients and clinicians in optimal use of cannabis for cancer care. State websites are a particularly helpful tool for providing state-specific medical education related to cannabis laws and use, as well, she said.

The bottom line, she said, is that talking to patients about the ins and outs of cannabis use “really matters.”

Worster disclosed that she is a medical consultant for EO Care.
 

A version of this article appeared on Medscape.com.

Many patients use cannabis to manage their cancer-related symptoms. However, research indicates that patients often do so without speaking to their oncologists first, and oncologists may be hesitant to broach the topic with their patients.

Updated guidelines from the American Society of Clinical Oncology (ASCO) on the use of cannabis and cannabinoids in adults with cancer stress that it’s an important conversation to have.

According to the ASCO expert panel, access to and use of cannabis alongside cancer care have outpaced the science on evidence-based indications, and overall high-quality data on the effects of cannabis during cancer care are lacking. While several observational studies support cannabis use to help ease chemotherapy-related nausea and vomiting, the literature remains more divided on other potential benefits, such as alleviating cancer pain and sleep problems, and some evidence points to potential downsides of cannabis use.

Oncologists should “absolutely talk to patients” about cannabis, Brooke Worster, MD, medical director for the Master of Science in Medical Cannabis Science & Business program at Thomas Jefferson University, Philadelphia, told Medscape Medical News.

“Patients are interested, and they are going to find access to information. As a medical professional, it’s our job to help guide them through these spaces in a safe, nonjudgmental way.”

But, Worster noted, oncologists don’t have to be experts on cannabis to begin the conversation with patients.

So, “let yourself off the hook,” Worster urged.

Plus, avoiding the conversation won’t stop patients from using cannabis. In a recent study, Worster and her colleagues found that nearly one third of patients at 12 National Cancer Institute-designated cancer centers had used cannabis since their diagnosis — most often for sleep disturbance, pain, stress, and anxiety. Most (60%) felt somewhat or extremely comfortable talking to their healthcare provider about it, but only 21.5% said they had done so. Even fewer — about 10% — had talked to their treating oncologist.

Because patients may not discuss cannabis use, it’s especially important for oncologists to open up a line of communication, said Worster, also the enterprise director of supportive oncology at the Thomas Jefferson University.
 

Evidence on Cannabis During Cancer Care

A substantial proportion of people with cancer believe cannabis can help manage cancer-related symptoms.

In Worster’s recent survey study, regardless of whether patients had used cannabis, almost 90% of those surveyed reported a perceived benefit. Although 65% also reported perceived risks for cannabis use, including difficulty concentrating, lung damage, and impaired memory, the perceived benefits outweighed the risks.

Despite generally positive perceptions, the overall literature on the benefits of cannabis in patients with cancer paints a less clear picture.

The ASCO guidelines, which were based on 13 systematic reviews and five additional primary studies, reported that cannabis can improve refractory, chemotherapy-induced nausea or vomiting when added to guideline-concordant antiemetic regimens, but that there is no clear evidence of benefit or harm for other supportive care outcomes.

The “certainty of evidence for most outcomes was low or very low,” the ASCO authors wrote.

The ASCO experts explained that, outside the context of a clinical trial, the evidence is not sufficient to recommend cannabis or cannabinoids for managing cancer pain, sleep issues, appetite loss, or anxiety and depression. For these outcomes, some studies indicate a benefit, while others don’t.

Real-world data from a large registry study, for instance, have indicated that medical cannabis is “a safe and effective complementary treatment for pain relief in patients with cancer.” However, a 2020 meta-analysis found that, in studies with a low risk for bias, adding cannabinoids to opioids did not reduce cancer pain in adults with advanced cancer.

There can be downsides to cannabis use, too. In one recent study, some patients reported feeling worse physically and psychologically compared with those who didn’t use cannabis. Another study found that oral cannabis was associated with “bothersome” side effects, including sedation, dizziness, and transient anxiety.

The ASCO guidelines also made it clear that cannabis or cannabinoids should not be used as cancer-directed treatment, outside of a clinical trial.
 

Talking to Patients About Cannabis

Given the level of evidence and patient interest in cannabis, it is important for oncologists to raise the topic of cannabis use with their patients.

To help inform decision-making and approaches to care, the ASCO guidelines suggest that oncologists can guide care themselves or direct patients to appropriate “unbiased, evidence-based” resources. For those who use cannabis or cannabinoids outside of evidence-based indications or clinician recommendations, it’s important to explore patients’ goals, educate them, and try to minimize harm.

One strategy for broaching the topic, Worster suggested, is to simply ask patients if they have tried or considered trying cannabis to control symptoms like nausea and vomiting, loss of appetite, or cancer pain.

The conversation with patients should then include an overview of the potential benefits and potential risks for cannabis use as well as risk reduction strategies, Worster noted.

But “approach it in an open and nonjudgmental frame of mind,” she said. “Just have a conversation.”

Discussing the formulation and concentration of tetrahydrocannabinol (THC) and cannabidiol (CBD) in products matters as well.

Will the product be inhaled, ingested, or topical? Inhaled cannabis is not ideal but is sometimes what patients have access to, Worster explained. Inhaled formulations tend to have faster onset, which might be preferable for treating chemotherapy-related nausea and vomiting, whereas edible formulations may take a while to start working.

It’s also important to warn patients about taking too much, she said, explaining that inhaling THC at higher doses can increase the risk for cardiovascular effects, anxiety, paranoia, panic, and psychosis.

CBD, on the other hand, is anti-inflammatory, but early data suggest it may blunt immune responses in high doses and should be used cautiously by patients receiving immunotherapy.

Worster noted that as laws change and the science advances, new cannabis products and formulations will emerge, as will artificial intelligence tools for helping to guide patients and clinicians in optimal use of cannabis for cancer care. State websites are a particularly helpful tool for providing state-specific medical education related to cannabis laws and use, as well, she said.

The bottom line, she said, is that talking to patients about the ins and outs of cannabis use “really matters.”

Worster disclosed that she is a medical consultant for EO Care.
 

A version of this article appeared on Medscape.com.