Mixed Topics

Adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer, according to a new study of more than 44,000 individuals.

The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
 

What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

 What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
 

What Is the Takeaway Message for Clinical Practice?

The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded. 

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.

More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.

The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.

Adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer, according to a new study of more than 44,000 individuals.

The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
 

What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

 What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
 

What Is the Takeaway Message for Clinical Practice?

The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded. 

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.

More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.

The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.

Adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer, according to a new study of more than 44,000 individuals.

The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
 

What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

 What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
 

What Is the Takeaway Message for Clinical Practice?

The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded. 

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.

More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.

The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.

“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.

Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.

Despite confidently worded recommendations, the relationship between exercise and cancer risk is much less certain than the guidelines would suggest. The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.

What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?

Here’s an overview of the state of the evidence.

Exercise and Cancer Types: A Mixed Bag

When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.

For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.

The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.

The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”

Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations. 

“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.

That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.

“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”

And it’s challenging to put all the evidence together, Dr. Jones added.

The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.

Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.

In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.

The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.

Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).

What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.

Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).

The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.

But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.

How Big Is the Effect?

Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.

But how much of a difference can exercise make?

Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.

These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.

“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.

“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.

The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.

Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.

For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).

But there may be an exercise sweet spot that maximizes the cancer risk benefit.

Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.

The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.

Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.

Why Exercise May Lower Cancer Risk

Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.

Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.

The why remains unclear, though some studies offer clues.

“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.

That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.

A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.

Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.

Defining an Exercise ‘Prescription’

Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.

The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.

But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.

Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.

Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.

But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.

“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.

Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.

There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.

“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.

Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.

“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”

A version of this article appeared on Medscape.com.

“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.

Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.

Despite confidently worded recommendations, the relationship between exercise and cancer risk is much less certain than the guidelines would suggest. The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.

What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?

Here’s an overview of the state of the evidence.

Exercise and Cancer Types: A Mixed Bag

When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.

For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.

The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.

The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”

Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations. 

“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.

That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.

“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”

And it’s challenging to put all the evidence together, Dr. Jones added.

The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.

Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.

In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.

The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.

Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).

What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.

Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).

The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.

But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.

How Big Is the Effect?

Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.

But how much of a difference can exercise make?

Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.

These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.

“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.

“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.

The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.

Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.

For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).

But there may be an exercise sweet spot that maximizes the cancer risk benefit.

Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.

The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.

Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.

Why Exercise May Lower Cancer Risk

Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.

Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.

The why remains unclear, though some studies offer clues.

“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.

That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.

A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.

Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.

Defining an Exercise ‘Prescription’

Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.

The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.

But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.

Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.

Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.

But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.

“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.

Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.

There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.

“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.

Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.

“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”

A version of this article appeared on Medscape.com.

“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.

Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.

Despite confidently worded recommendations, the relationship between exercise and cancer risk is much less certain than the guidelines would suggest. The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.

What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?

Here’s an overview of the state of the evidence.

Exercise and Cancer Types: A Mixed Bag

When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.

For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.

The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.

The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”

Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations. 

“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.

That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.

“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”

And it’s challenging to put all the evidence together, Dr. Jones added.

The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.

Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.

In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.

The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.

Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).

What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.

Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).

The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.

But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.

How Big Is the Effect?

Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.

But how much of a difference can exercise make?

Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.

These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.

“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.

“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.

The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.

Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.

For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).

But there may be an exercise sweet spot that maximizes the cancer risk benefit.

Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.

The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.

Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.

Why Exercise May Lower Cancer Risk

Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.

Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.

The why remains unclear, though some studies offer clues.

“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.

That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.

A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.

Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.

Defining an Exercise ‘Prescription’

Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.

The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.

But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.

Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.

Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.

But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.

“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.

Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.

There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.

“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.

Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.

“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has approved nivolumab (Opdivo, Bristol-Myers Squibb) in combination with cisplatin and gemcitabine for first-line treatment of adults with unresectable or metastatic urothelial carcinoma.

Approval was based on the CHECKMATE-901 trial in 608 patients randomized equally to either cisplatin and gemcitabine for ≤ six cycles or nivolumab plus cisplatin and gemcitabine for ≤ six cycles, followed by nivolumab alone for ≤ 2 years. 

Median overall survival was 21.7 months with nivolumab add-on vs 18.9 months with cisplatin/gemcitabine alone (hazard ratio [HR], 0.78; P = .0171). The nivolumab group had a slightly higher median progression-free survival of 7.9 months vs 7.6 months in the cisplatin and gemcitabine group (HR, 0.72; P = .0012).

The most common adverse events, occurring in ≥ 15% of nivolumab patients, were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, peripheral neuropathy, urinary tract infection, diarrhea, edema, hypothyroidism, and pruritus.

Among numerous other oncology indications, nivolumab was previously approved for adjuvant treatment following urothelial carcinoma resection and for locally advanced or metastatic urothelial carcinoma that progresses during or following platinum-containing chemotherapy.
 

A version of this article appeared on Medscape.com .

The US Food and Drug Administration has approved nivolumab (Opdivo, Bristol-Myers Squibb) in combination with cisplatin and gemcitabine for first-line treatment of adults with unresectable or metastatic urothelial carcinoma.

Approval was based on the CHECKMATE-901 trial in 608 patients randomized equally to either cisplatin and gemcitabine for ≤ six cycles or nivolumab plus cisplatin and gemcitabine for ≤ six cycles, followed by nivolumab alone for ≤ 2 years. 

Median overall survival was 21.7 months with nivolumab add-on vs 18.9 months with cisplatin/gemcitabine alone (hazard ratio [HR], 0.78; P = .0171). The nivolumab group had a slightly higher median progression-free survival of 7.9 months vs 7.6 months in the cisplatin and gemcitabine group (HR, 0.72; P = .0012).

The most common adverse events, occurring in ≥ 15% of nivolumab patients, were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, peripheral neuropathy, urinary tract infection, diarrhea, edema, hypothyroidism, and pruritus.

Among numerous other oncology indications, nivolumab was previously approved for adjuvant treatment following urothelial carcinoma resection and for locally advanced or metastatic urothelial carcinoma that progresses during or following platinum-containing chemotherapy.
 

A version of this article appeared on Medscape.com .

The US Food and Drug Administration has approved nivolumab (Opdivo, Bristol-Myers Squibb) in combination with cisplatin and gemcitabine for first-line treatment of adults with unresectable or metastatic urothelial carcinoma.

Approval was based on the CHECKMATE-901 trial in 608 patients randomized equally to either cisplatin and gemcitabine for ≤ six cycles or nivolumab plus cisplatin and gemcitabine for ≤ six cycles, followed by nivolumab alone for ≤ 2 years. 

Median overall survival was 21.7 months with nivolumab add-on vs 18.9 months with cisplatin/gemcitabine alone (hazard ratio [HR], 0.78; P = .0171). The nivolumab group had a slightly higher median progression-free survival of 7.9 months vs 7.6 months in the cisplatin and gemcitabine group (HR, 0.72; P = .0012).

The most common adverse events, occurring in ≥ 15% of nivolumab patients, were nausea, fatigue, musculoskeletal pain, constipation, decreased appetite, rash, vomiting, peripheral neuropathy, urinary tract infection, diarrhea, edema, hypothyroidism, and pruritus.

Among numerous other oncology indications, nivolumab was previously approved for adjuvant treatment following urothelial carcinoma resection and for locally advanced or metastatic urothelial carcinoma that progresses during or following platinum-containing chemotherapy.
 

A version of this article appeared on Medscape.com .

Clinicians are navigating how to begin treating their patients with lifileucel (Amtagvi, Iovance Biotherapeutics Inc.), a new treatment for melanoma with a hefty price tag.

The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.

Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
 

Insurance Adjustments

The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.

Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.

Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.

The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.

Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.

At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.

Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.

Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.

 

Logistics and Infrastructure

A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.

The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
 

Docs Hope TIL Improves in Several Ways

Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.

More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”

Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.

“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.

“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.

“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”

“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.  

In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.

The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.

The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.

Clinicians are navigating how to begin treating their patients with lifileucel (Amtagvi, Iovance Biotherapeutics Inc.), a new treatment for melanoma with a hefty price tag.

The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.

Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
 

Insurance Adjustments

The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.

Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.

Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.

The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.

Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.

At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.

Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.

Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.

 

Logistics and Infrastructure

A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.

The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
 

Docs Hope TIL Improves in Several Ways

Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.

More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”

Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.

“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.

“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.

“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”

“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.  

In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.

The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.

The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.

Clinicians are navigating how to begin treating their patients with lifileucel (Amtagvi, Iovance Biotherapeutics Inc.), a new treatment for melanoma with a hefty price tag.

The US Food and Drug Administration (FDA) recently approved the tumor-infiltrating lymphocyte cell therapy (TIL) for use in certain adults with unresectable or metastatic melanoma. This marks the first time the FDA has allowed a cellular therapy to be marketed for a solid tumor cancer.

Lifileucel is made from a patient’s surgically removed tumor. Tissue from that tumor is then sent to a manufacturing center. Turnaround time to when the drug is ready to be sent back to the cancer center for use is approximately 34 days, according to the drug’s manufacturer, Iovance.
 

Insurance Adjustments

The cost of the one-time lifileucel treatment is $515,000, according to the manufacturer.

Two investigators in the clinical trials of lifileucel, Allison Betof Warner, MD, of Stanford University, Stanford, California, and Igor Puzanov, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, shared their expectations regarding factors that would contribute to how much a patient paid for the drug.

Given the drug’s recent approval, the logistical details are still being worked out between cancer centers and insurers regarding how much patients will pay out of pocket for lifileucel, said Dr. Betof Warner, who is assistant professor in the Department of Medicine, Division of Medical Oncology at Stanford University.

The associated costs, including the surgery that is needed to procure the TIL cells for expansion into the final drug product, will be different for each patient, she told this publication.

Patients’ costs for lifileucel will vary based on their insurance, explained Dr. Puzanov, chief of melanoma and professor of oncology at Roswell Park Comprehensive Cancer Center.

At Roswell Park, “we will work with our regionally-based payers on a case-by-case basis to seek approval for those patients we believe can most benefit from lifileucel,” he said in an interview. Preauthorization will be required, as is standard for many cancer treatments, he added.

Once payer approval is in place, Dr. Puzanov said, he did not anticipate significant delays in access for patients.

Certified centers such as the multidisciplinary team at Roswell Park are ready to treat patients now. Other centers are similarly prepared, especially those involved in the clinical trials of lifileucel, he said.

 

Logistics and Infrastructure

A position article and guidelines on the management of and best practices for TIL was published in the Journal for ImmunoTherapy of Cancer on February 29. The paper, of which both Dr. Betof Warner and Dr. Puzanov served as authors, noted that one of the barriers to the use of TIL cell therapy in clinical practice is the need for state-of-the art infrastructure at centers that want to offer the treatment. Scheduling, patient referrals, and surgery, as well as the production and infusion of TIL, must be organized and streamlined for successful treatment, the authors wrote.

The two supply chains involved in TIL — the transportation of the tumor tissue from the treatment center to the manufacturer and transport of the TIL infusion product back to the treatment center — must be timely and precise, they emphasized.
 

Docs Hope TIL Improves in Several Ways

Although the TIL technology is a breakthrough, “we hope to see even better efficacy and lower toxicity as further research looks at ways to improve on the current TIL standard,” Dr. Puzanov said.

More research and dose adjustments may impact patient costs and side effects, he noted. “I am looking to see TILs used in the front line, with or without checkpoint inhibitors.”

Research is needed to explore how to lower the chemotherapy doses and possibly the associated toxicity, he added. Finally, researchers must consider whether high-dose IL-2 therapy — given as part of the TIL cell therapy — could be replaced with other cytokines, or whether the number of doses could be lowered. Another avenue of exploration is engineering genes for cytokines into TILs, he said.

“The key is to think about TIL therapy before you need it — ideally, when the patient is still doing well on their frontline checkpoint inhibition immunotherapy,” Dr. Puzanov said in an interview. That is the time for evaluation, and specialty centers can provide an expert assessment, he said.

“We are constantly working to improve TIL therapy,” Dr. Betof Warner told this publication. More research is needed optimize the regimen to reduce side effects, which would not only make treatment easier for currently eligible patients, but might allow treatment for patients not currently eligible.

“For example, we are looking for ways to reduce the dose of preparative chemotherapy, which prepares the body for the cells to maximize their longevity and efficacy, and to reduce or eliminate the need to give IL-2 after the cell administration,” continued Dr. Betof Warner, who is also Director of Melanoma Medical Oncology, Director of Solid Tumor Cellular Therapy, and Codirector of the Pigmented Lesion and Melanoma Program at Stanford University. “We are also actively studying next-generation TIL therapies to try to increase the efficacy.”

“Lifileucel has about a 30% success rate for melanoma that has progressed after standard therapy; we are working hard to do better than that,” she noted.  

In a press release, Iovance summarized the results of the trial that supported the FDA’s accelerated approval of lifileucel. In an open-label single-arm study, including multiple sites worldwide, 73 adults with unresectable or metastatic melanoma who had received at least one previous systemic therapy underwent a lymphodepleting regimen followed by treatments with fludarabine and aldesleukin. Patients then received lifileucel at a median dose of 21.1 x 109 viable cells; the recommended dose ranges from 7.5 x 109 to 72 x 109 cells.

The primary efficacy outcome was objective response rate (ORR). The ORR in the study was 31.5%, and the median time to initial lifileucel response was 1.5 months.

The clinical trials of lifileucel for which Dr. Betof Warner and Dr. Puzanov served as investigators were sponsored by Iovance.

TOPLINE:

Women with daily exposure to spironolactone for dermatologic conditions showed no higher risk of developing breast or gynecologic cancer than that of unexposed women.

METHODOLOGY:

• Spironolactone, used off-label for several skin conditions in women, carries a warning about an increased tumor risk associated with high doses in rat models, and its antiandrogen properties have prompted hypotheses about a possible increased risk for breast or gynecologic cancers.
• The researchers reviewed data on 420 women with a history of spironolactone use for acne, hair loss, and hirsutism and 3272 women with no spironolactone use at the authors› institution. Their mean age ranged from 42 to 63 years; the majority were White, and 38% were non-White.
• Median spironolactone doses ranged from 25 mg to 225 mg; chart reviews included 5-year follow-up data from the first spironolactone exposure to allow time for tumor development.

TAKEAWAY:

• A total of 37 of the 420 women exposed to spironolactone developed any tumors, as did 546 of the 3272 with no spironolactone exposure.
• After the researchers controlled for age and race, women exposed to spironolactone were no more likely to develop a malignant tumor than a benign tumor, compared with unexposed women (odds ratio [OR], 0.48, P = .2).
• The risk for breast or uterine cancer was not significantly different in the spironolactone and non-spironolactone groups (OR, 0.95, P > .9).

IN PRACTICE:

“Women taking spironolactone for acne, hair loss, and hirsutism and who are at low risk of breast or gynecologic cancers may be counseled to have regular gynecology follow-up, but no more frequently than the general population,” but more studies are needed to evaluate risk over longer periods of time, the researchers wrote.

SOURCE:

The lead author of the study was Rachel C. Hill, BS, a student at Weill Cornell Medical College, New York City, and Shari R. Lipner, MD, PhD, of the department of dermatology at Weill Cornell Medical College, was the corresponding author. The study was published online in The Journal of the American Academy of Dermatology.

LIMITATIONS:

The findings were limited by the retrospective design, as well as the small number of spironolactone patients analyzed, the short follow-up period, the lack of information about spironolactone courses, and the inability to control for family history of malignancy.

DISCLOSURES:

The study was supported by the National Center for Advancing Translational Sciences and a grant from the Clinical and Translational Science Center at Weill Cornell Medical College awarded to Ms. Hill. None of the authors had relevant disclosures; Dr. Lipner disclosed serving as a consultant for Ortho-Dermatologics, Eli Lilly, Moberg Pharmaceuticals, and BelleTorus Corporation.

A version of this article appeared on Medscape.com.

TOPLINE:

Women with daily exposure to spironolactone for dermatologic conditions showed no higher risk of developing breast or gynecologic cancer than that of unexposed women.

METHODOLOGY:

• Spironolactone, used off-label for several skin conditions in women, carries a warning about an increased tumor risk associated with high doses in rat models, and its antiandrogen properties have prompted hypotheses about a possible increased risk for breast or gynecologic cancers.
• The researchers reviewed data on 420 women with a history of spironolactone use for acne, hair loss, and hirsutism and 3272 women with no spironolactone use at the authors› institution. Their mean age ranged from 42 to 63 years; the majority were White, and 38% were non-White.
• Median spironolactone doses ranged from 25 mg to 225 mg; chart reviews included 5-year follow-up data from the first spironolactone exposure to allow time for tumor development.

TAKEAWAY:

• A total of 37 of the 420 women exposed to spironolactone developed any tumors, as did 546 of the 3272 with no spironolactone exposure.
• After the researchers controlled for age and race, women exposed to spironolactone were no more likely to develop a malignant tumor than a benign tumor, compared with unexposed women (odds ratio [OR], 0.48, P = .2).
• The risk for breast or uterine cancer was not significantly different in the spironolactone and non-spironolactone groups (OR, 0.95, P > .9).

IN PRACTICE:

“Women taking spironolactone for acne, hair loss, and hirsutism and who are at low risk of breast or gynecologic cancers may be counseled to have regular gynecology follow-up, but no more frequently than the general population,” but more studies are needed to evaluate risk over longer periods of time, the researchers wrote.

SOURCE:

The lead author of the study was Rachel C. Hill, BS, a student at Weill Cornell Medical College, New York City, and Shari R. Lipner, MD, PhD, of the department of dermatology at Weill Cornell Medical College, was the corresponding author. The study was published online in The Journal of the American Academy of Dermatology.

LIMITATIONS:

The findings were limited by the retrospective design, as well as the small number of spironolactone patients analyzed, the short follow-up period, the lack of information about spironolactone courses, and the inability to control for family history of malignancy.

DISCLOSURES:

The study was supported by the National Center for Advancing Translational Sciences and a grant from the Clinical and Translational Science Center at Weill Cornell Medical College awarded to Ms. Hill. None of the authors had relevant disclosures; Dr. Lipner disclosed serving as a consultant for Ortho-Dermatologics, Eli Lilly, Moberg Pharmaceuticals, and BelleTorus Corporation.

A version of this article appeared on Medscape.com.

TOPLINE:

Women with daily exposure to spironolactone for dermatologic conditions showed no higher risk of developing breast or gynecologic cancer than that of unexposed women.

METHODOLOGY:

• Spironolactone, used off-label for several skin conditions in women, carries a warning about an increased tumor risk associated with high doses in rat models, and its antiandrogen properties have prompted hypotheses about a possible increased risk for breast or gynecologic cancers.
• The researchers reviewed data on 420 women with a history of spironolactone use for acne, hair loss, and hirsutism and 3272 women with no spironolactone use at the authors› institution. Their mean age ranged from 42 to 63 years; the majority were White, and 38% were non-White.
• Median spironolactone doses ranged from 25 mg to 225 mg; chart reviews included 5-year follow-up data from the first spironolactone exposure to allow time for tumor development.

TAKEAWAY:

• A total of 37 of the 420 women exposed to spironolactone developed any tumors, as did 546 of the 3272 with no spironolactone exposure.
• After the researchers controlled for age and race, women exposed to spironolactone were no more likely to develop a malignant tumor than a benign tumor, compared with unexposed women (odds ratio [OR], 0.48, P = .2).
• The risk for breast or uterine cancer was not significantly different in the spironolactone and non-spironolactone groups (OR, 0.95, P > .9).

IN PRACTICE:

“Women taking spironolactone for acne, hair loss, and hirsutism and who are at low risk of breast or gynecologic cancers may be counseled to have regular gynecology follow-up, but no more frequently than the general population,” but more studies are needed to evaluate risk over longer periods of time, the researchers wrote.

SOURCE:

The lead author of the study was Rachel C. Hill, BS, a student at Weill Cornell Medical College, New York City, and Shari R. Lipner, MD, PhD, of the department of dermatology at Weill Cornell Medical College, was the corresponding author. The study was published online in The Journal of the American Academy of Dermatology.

LIMITATIONS:

The findings were limited by the retrospective design, as well as the small number of spironolactone patients analyzed, the short follow-up period, the lack of information about spironolactone courses, and the inability to control for family history of malignancy.

DISCLOSURES:

The study was supported by the National Center for Advancing Translational Sciences and a grant from the Clinical and Translational Science Center at Weill Cornell Medical College awarded to Ms. Hill. None of the authors had relevant disclosures; Dr. Lipner disclosed serving as a consultant for Ortho-Dermatologics, Eli Lilly, Moberg Pharmaceuticals, and BelleTorus Corporation.

A version of this article appeared on Medscape.com.

TOPLINE: 

In patients with type 2 diabetes, there was no difference in risk of developing autoimmune disease if prescribed glucagon-like peptide 1 receptor agonists (GLP-1-RAs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, or dipeptidyl peptidase-4 (DPP-4) inhibitors.

METHODOLOGY:

• The effect of GLP-1-RAs and SGLT2 inhibitors on autoimmune rheumatic disease (ARD) is understudied, though previous case reports and one study have hinted at increased risk.
• Researchers used administrative health data from 2014 to 2021 to identify 34,400 patients prescribed GLP-1-RAs and 83,500 patients prescribed SGLT2 inhibitors.
• They compared patients prescribed GLP-1-RAs or SGLT2 inhibitors with 68,400 patients prescribed DPP-4 inhibitors, which previous studies suggest do not increase ARD risk.
• Primary outcome was ARD incidence, defined by diagnostic codes.

TAKEAWAY:

• There were no significant differences in incident ARDs between the three groups.
• Mean follow-up time was 0.88-1.53 years.
• The hazard ratio (HR) for developing ARDs with GLP-1-RAs exposure was 0.93 (95% CI, 0.66-1.30) compared with DPP-4 inhibitors.
• The HR for developing ARDs with SGLT2 inhibitor exposure was 0.97 (95% CI, 0.76-1.24).

IN PRACTICE: 

“Extended longitudinal data are needed to assess risk and benefit with longer-term exposure,” the authors wrote.

SOURCE: 

First author Derin Karacabeyli, MD, of the University of British Columbia, Vancouver, Canada, presented the study in abstract form at the Canadian Rheumatology Association (CRA) 2024 Annual Meeting in Winnipeg on February 29.

LIMITATIONS: 

The study was observational, which could have some residual or unmeasured confounding of data. The researchers relied on diagnostic codes and the average follow-up time was short. 

DISCLOSURES:

The study was funded by the Canadian Institutes of Health Research. The authors had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE: 

In patients with type 2 diabetes, there was no difference in risk of developing autoimmune disease if prescribed glucagon-like peptide 1 receptor agonists (GLP-1-RAs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, or dipeptidyl peptidase-4 (DPP-4) inhibitors.

METHODOLOGY:

• The effect of GLP-1-RAs and SGLT2 inhibitors on autoimmune rheumatic disease (ARD) is understudied, though previous case reports and one study have hinted at increased risk.
• Researchers used administrative health data from 2014 to 2021 to identify 34,400 patients prescribed GLP-1-RAs and 83,500 patients prescribed SGLT2 inhibitors.
• They compared patients prescribed GLP-1-RAs or SGLT2 inhibitors with 68,400 patients prescribed DPP-4 inhibitors, which previous studies suggest do not increase ARD risk.
• Primary outcome was ARD incidence, defined by diagnostic codes.

TAKEAWAY:

• There were no significant differences in incident ARDs between the three groups.
• Mean follow-up time was 0.88-1.53 years.
• The hazard ratio (HR) for developing ARDs with GLP-1-RAs exposure was 0.93 (95% CI, 0.66-1.30) compared with DPP-4 inhibitors.
• The HR for developing ARDs with SGLT2 inhibitor exposure was 0.97 (95% CI, 0.76-1.24).

IN PRACTICE: 

“Extended longitudinal data are needed to assess risk and benefit with longer-term exposure,” the authors wrote.

SOURCE: 

First author Derin Karacabeyli, MD, of the University of British Columbia, Vancouver, Canada, presented the study in abstract form at the Canadian Rheumatology Association (CRA) 2024 Annual Meeting in Winnipeg on February 29.

LIMITATIONS: 

The study was observational, which could have some residual or unmeasured confounding of data. The researchers relied on diagnostic codes and the average follow-up time was short. 

DISCLOSURES:

The study was funded by the Canadian Institutes of Health Research. The authors had no disclosures.

A version of this article appeared on Medscape.com.

TOPLINE: 

In patients with type 2 diabetes, there was no difference in risk of developing autoimmune disease if prescribed glucagon-like peptide 1 receptor agonists (GLP-1-RAs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, or dipeptidyl peptidase-4 (DPP-4) inhibitors.

METHODOLOGY:

• The effect of GLP-1-RAs and SGLT2 inhibitors on autoimmune rheumatic disease (ARD) is understudied, though previous case reports and one study have hinted at increased risk.
• Researchers used administrative health data from 2014 to 2021 to identify 34,400 patients prescribed GLP-1-RAs and 83,500 patients prescribed SGLT2 inhibitors.
• They compared patients prescribed GLP-1-RAs or SGLT2 inhibitors with 68,400 patients prescribed DPP-4 inhibitors, which previous studies suggest do not increase ARD risk.
• Primary outcome was ARD incidence, defined by diagnostic codes.

TAKEAWAY:

• There were no significant differences in incident ARDs between the three groups.
• Mean follow-up time was 0.88-1.53 years.
• The hazard ratio (HR) for developing ARDs with GLP-1-RAs exposure was 0.93 (95% CI, 0.66-1.30) compared with DPP-4 inhibitors.
• The HR for developing ARDs with SGLT2 inhibitor exposure was 0.97 (95% CI, 0.76-1.24).

IN PRACTICE: 

“Extended longitudinal data are needed to assess risk and benefit with longer-term exposure,” the authors wrote.

SOURCE: 

First author Derin Karacabeyli, MD, of the University of British Columbia, Vancouver, Canada, presented the study in abstract form at the Canadian Rheumatology Association (CRA) 2024 Annual Meeting in Winnipeg on February 29.

LIMITATIONS: 

The study was observational, which could have some residual or unmeasured confounding of data. The researchers relied on diagnostic codes and the average follow-up time was short. 

DISCLOSURES:

The study was funded by the Canadian Institutes of Health Research. The authors had no disclosures.

A version of this article appeared on Medscape.com.

Vulvar lichen sclerosus (VLS) is an underserved area in medicine and dermatology. We discuss updates in VLS, which include the following: (1) development of core outcome domains to include in all future clinical trials, with current efforts focused on determining outcome measurements for each domain; (2) increased understanding of the impact VLS has on quality-of-life (QOL) outcomes; (3) expanded disease associations; (4) clinical and histologic variants, including vestibular sclerosis and nonsclerotic VLS; and (5) updates in management of VLS.

Core Outcomes Measures

The burden of VLS is challenging to quantify, with little agreement among experts.¹ Recently there has been a focus on developing scoring scales to measure disease progression and treatment response. Simpson et al² pioneered the development of a core outcome set to be included in all future clinical trials for genital lichen sclerosus (LS)—clinical (visible) signs, symptoms, and LS-specific QOL.

Although there is no standardized method for assessing disease severity, various scales have been proposed to measure clinical findings in VLS, such as the vulvar architecture severity scale³ as well as the clinical LS score,⁴ which is the only validated scale to incorporate the signs and architectural changes identified by a 2018 Delphi consensus group of the International Society for the Study of Vulvovaginal Disease.⁵ Work is ongoing to identify and evaluate outcome measurement instruments for each of the 3 core outcome domains.

Increased Understanding of QOL Impacts

Pain, pruritus, impairment of sexual function, genitourinary complications, architectural changes, and risk for squamous cell carcinoma (SCC) all have been well established as VLS sequelae.^6,7 Recent studies have focused on the QOL impact and associations with psychiatric comorbidities. A matched case-control study found that LS was significantly associated with depression and anxiety among US women (P<.001), and individuals with LS had a more than 2-fold increased odds of receiving a diagnosis of depression or anxiety.⁸

A review evaluating QOL outcomes in LS found that overall QOL was impaired. Female patients reported worse QOL in the work-school domain of the dermatology life quality index compared with male counterparts.⁹

Finally, a study exploring the experiences of patients living with VLS highlighted the secrecy and stigma of the condition,¹⁰ which serves as a call to action to improve the general population’s knowledge about vulvar anatomy and create change in societal attitudes on vulvar conditions.

Although there are several instruments assessing vulvar-specific QOL, most are for patients with vulvar cancer and focus on sexual function. In 2020, Saunderson et al¹¹ published the 15-item vulvar quality of life index (VQLI), which has broad implications for measuring vulvar disease burden and is an important tool for standardizing vulvar disease measurements and outcomes for clinical research.¹² The VQLI, though not specific to VLS, consists of 4 domains to assess vulvar QOL including symptoms, anxiety, activities of daily living, and sexuality. Studies have evaluated this scoring system in patients with VLS, with 1 study finding that VQLI correlated with clinician-rated severity scores (P=.01) and overall patient itch/discomfort score (P<.001) in VLS.^13,14

Expanded Disease Associations

Lichen sclerosus has a well-known association with vulvar SCC and other autoimmune conditions, including thyroid disease and bullous pemphigoid.^15-17 Recent studies also have revealed an association between LS and psoriasis.¹⁸ A case-control study from a single center found VLS was associated with elevated body mass index, statin usage, and cholecystectomy.¹⁹ Gynecologic pain syndromes, interstitial cystitis, urinary incontinence, and some gastrointestinal tract disorders including celiac disease also have been found to be increased in patients with VLS.²⁰ Finally, the incidence of cutaneous immune-related adverse events such as LS has increased as the use of immune checkpoint therapies as anticancer treatments has expanded.²¹ Clinicians should be aware of these potential disease associations when caring for patients with VLS.

The incidence of VLS is higher in lower estrogen states throughout the lifespan, and a recent case-control study evaluated the cutaneous hormonal and microbial landscapes in postmenopausal patients (6 patients with VLS; 12 controls).²² Levels of the following cutaneous hormones in the groin were found to be altered in patients with VLS compared with controls: estrone (lower; P=.006), progesterone (higher; P<.0001), and testosterone (lower; P=.02). The authors found that most hormone levels normalized following treatment with a topical steroid. Additionally, bacterial microbiome alterations were seen in patients with VLS compared with controls. Thus, cutaneous sex hormone and skin microbiome alterations may be associated with VLS.²²

Updates in Clinical and Histologic Variants

Less-recognized variants of VLS have been characterized in recent years. Vestibular sclerosis is a variant of VLS with unique clinical and histopathologic features; it is characterized by involvement localized to the anterior vestibule and either an absent or sparse lymphocytic infiltrate on histopathology.^23,24 Nonsclerotic VLS is a variant with clinical features consistent with VLS that does not exhibit dermal sclerosis on histopathology. Thus, a diagnosis of nonsclerotic VLS requires clinicopathologic correlation. Four nonsclerotic histopathologic subtypes are proposed: lichenoid, hypertrophic lichenoid, dermal fibrosis without acanthosis, and dermal fibrosis with acanthosis.²⁵ Longitudinal studies that correlate duration, signs, and symptoms will be important to further understand these variants.

Management Updates

First-line treatment of VLS still consists of ultrapotent topical corticosteroids with chronic maintenance therapy (usually lifetime) to decrease the risk for SCC and architectural changes.²⁶ However, a survey across social media platforms found steroid phobia is common in patients with VLS (N=865), with approximately 40% of respondents endorsing waiting as long as they could before using topical corticosteroids and stopping as soon as possible.²⁷ Clinicians should be aware of possible patient perceptions in the use of chronic steroids when discussing this therapy.

Randomized controlled trials utilizing fractional CO₂ devices for VLS have been performed with conflicting results and no consensus regarding outcome measurement.^28,29 Additionally, long-term disease outcomes following laser use have not been investigated. Although there is evidence that both ablative and nonablative devices can improve symptoms and signs, there is no evidence that they offer a cure for a chronic inflammatory skin condition. Current evidence suggests that even for patients undergoing these procedures, maintenance therapy is still essential to prevent sequelae.³⁰ Future studies incorporating standardized outcome measures will be important for assessing the benefits of laser therapy in VLS. Finally, the reasons why topical corticosteroids may fail in an individual patient are multifaceted and should be explored thoroughly when considering laser therapy for VLS.

Studies evaluating the role of systemic therapies for refractory cases of VLS have expanded. A systematic review of systemic therapies for both genital and extragenital LS found oral corticosteroids and methotrexate were the most-reported systemic treatment regimens.³¹ Use of biologics in LS has been reported, with cases utilizing adalimumab for VLS and dupilumab for extragenital LS. Use of Janus kinase inhibitors including abrocitinib and baricitinib also has been reported for LS.³¹ A clinical trial to evaluate the safety and efficacy of topical ruxolitinib in VLS was recently completed (ClinicalTrials.govidentifier NCT05593445). Future research studies likely will focus on the safety and efficacy of targeted and steroid-sparing therapies for patients with VLS.

Final Thoughts

Vulvar lichen sclerosus increasingly is becoming recognized as a chronic genital skin condition that impacts QOL and health outcomes, with a need to develop more effective and safe evidence-based therapies. Recent literature has focused on the importance of developing and standardizing disease outcomes; identifying disease associations including the role of cutaneous hormones and microbiome alterations; characterizing histologic and clinical variants; and staying up-to-date on management, including the need for understanding patient perceptions of chronic topical steroid therapy. Each of these are important updates for clinicians to consider when caring for patients with VLS. Future studies likely will focus on elucidating disease etiology and mechanisms to gain a better understanding of VLS pathogenesis and potential targets for therapies as well as implementation of clinical trials that incorporate standardized outcome domains to test efficacy and safety of additional therapies.

Vulvar lichen sclerosus (VLS) is an underserved area in medicine and dermatology. We discuss updates in VLS, which include the following: (1) development of core outcome domains to include in all future clinical trials, with current efforts focused on determining outcome measurements for each domain; (2) increased understanding of the impact VLS has on quality-of-life (QOL) outcomes; (3) expanded disease associations; (4) clinical and histologic variants, including vestibular sclerosis and nonsclerotic VLS; and (5) updates in management of VLS.

Core Outcomes Measures

The burden of VLS is challenging to quantify, with little agreement among experts.¹ Recently there has been a focus on developing scoring scales to measure disease progression and treatment response. Simpson et al² pioneered the development of a core outcome set to be included in all future clinical trials for genital lichen sclerosus (LS)—clinical (visible) signs, symptoms, and LS-specific QOL.

Although there is no standardized method for assessing disease severity, various scales have been proposed to measure clinical findings in VLS, such as the vulvar architecture severity scale³ as well as the clinical LS score,⁴ which is the only validated scale to incorporate the signs and architectural changes identified by a 2018 Delphi consensus group of the International Society for the Study of Vulvovaginal Disease.⁵ Work is ongoing to identify and evaluate outcome measurement instruments for each of the 3 core outcome domains.

Increased Understanding of QOL Impacts

Pain, pruritus, impairment of sexual function, genitourinary complications, architectural changes, and risk for squamous cell carcinoma (SCC) all have been well established as VLS sequelae.^6,7 Recent studies have focused on the QOL impact and associations with psychiatric comorbidities. A matched case-control study found that LS was significantly associated with depression and anxiety among US women (P<.001), and individuals with LS had a more than 2-fold increased odds of receiving a diagnosis of depression or anxiety.⁸

A review evaluating QOL outcomes in LS found that overall QOL was impaired. Female patients reported worse QOL in the work-school domain of the dermatology life quality index compared with male counterparts.⁹

Finally, a study exploring the experiences of patients living with VLS highlighted the secrecy and stigma of the condition,¹⁰ which serves as a call to action to improve the general population’s knowledge about vulvar anatomy and create change in societal attitudes on vulvar conditions.

Although there are several instruments assessing vulvar-specific QOL, most are for patients with vulvar cancer and focus on sexual function. In 2020, Saunderson et al¹¹ published the 15-item vulvar quality of life index (VQLI), which has broad implications for measuring vulvar disease burden and is an important tool for standardizing vulvar disease measurements and outcomes for clinical research.¹² The VQLI, though not specific to VLS, consists of 4 domains to assess vulvar QOL including symptoms, anxiety, activities of daily living, and sexuality. Studies have evaluated this scoring system in patients with VLS, with 1 study finding that VQLI correlated with clinician-rated severity scores (P=.01) and overall patient itch/discomfort score (P<.001) in VLS.^13,14

Expanded Disease Associations

Lichen sclerosus has a well-known association with vulvar SCC and other autoimmune conditions, including thyroid disease and bullous pemphigoid.^15-17 Recent studies also have revealed an association between LS and psoriasis.¹⁸ A case-control study from a single center found VLS was associated with elevated body mass index, statin usage, and cholecystectomy.¹⁹ Gynecologic pain syndromes, interstitial cystitis, urinary incontinence, and some gastrointestinal tract disorders including celiac disease also have been found to be increased in patients with VLS.²⁰ Finally, the incidence of cutaneous immune-related adverse events such as LS has increased as the use of immune checkpoint therapies as anticancer treatments has expanded.²¹ Clinicians should be aware of these potential disease associations when caring for patients with VLS.

The incidence of VLS is higher in lower estrogen states throughout the lifespan, and a recent case-control study evaluated the cutaneous hormonal and microbial landscapes in postmenopausal patients (6 patients with VLS; 12 controls).²² Levels of the following cutaneous hormones in the groin were found to be altered in patients with VLS compared with controls: estrone (lower; P=.006), progesterone (higher; P<.0001), and testosterone (lower; P=.02). The authors found that most hormone levels normalized following treatment with a topical steroid. Additionally, bacterial microbiome alterations were seen in patients with VLS compared with controls. Thus, cutaneous sex hormone and skin microbiome alterations may be associated with VLS.²²

Updates in Clinical and Histologic Variants

Less-recognized variants of VLS have been characterized in recent years. Vestibular sclerosis is a variant of VLS with unique clinical and histopathologic features; it is characterized by involvement localized to the anterior vestibule and either an absent or sparse lymphocytic infiltrate on histopathology.^23,24 Nonsclerotic VLS is a variant with clinical features consistent with VLS that does not exhibit dermal sclerosis on histopathology. Thus, a diagnosis of nonsclerotic VLS requires clinicopathologic correlation. Four nonsclerotic histopathologic subtypes are proposed: lichenoid, hypertrophic lichenoid, dermal fibrosis without acanthosis, and dermal fibrosis with acanthosis.²⁵ Longitudinal studies that correlate duration, signs, and symptoms will be important to further understand these variants.

Management Updates

First-line treatment of VLS still consists of ultrapotent topical corticosteroids with chronic maintenance therapy (usually lifetime) to decrease the risk for SCC and architectural changes.²⁶ However, a survey across social media platforms found steroid phobia is common in patients with VLS (N=865), with approximately 40% of respondents endorsing waiting as long as they could before using topical corticosteroids and stopping as soon as possible.²⁷ Clinicians should be aware of possible patient perceptions in the use of chronic steroids when discussing this therapy.

Randomized controlled trials utilizing fractional CO₂ devices for VLS have been performed with conflicting results and no consensus regarding outcome measurement.^28,29 Additionally, long-term disease outcomes following laser use have not been investigated. Although there is evidence that both ablative and nonablative devices can improve symptoms and signs, there is no evidence that they offer a cure for a chronic inflammatory skin condition. Current evidence suggests that even for patients undergoing these procedures, maintenance therapy is still essential to prevent sequelae.³⁰ Future studies incorporating standardized outcome measures will be important for assessing the benefits of laser therapy in VLS. Finally, the reasons why topical corticosteroids may fail in an individual patient are multifaceted and should be explored thoroughly when considering laser therapy for VLS.

Studies evaluating the role of systemic therapies for refractory cases of VLS have expanded. A systematic review of systemic therapies for both genital and extragenital LS found oral corticosteroids and methotrexate were the most-reported systemic treatment regimens.³¹ Use of biologics in LS has been reported, with cases utilizing adalimumab for VLS and dupilumab for extragenital LS. Use of Janus kinase inhibitors including abrocitinib and baricitinib also has been reported for LS.³¹ A clinical trial to evaluate the safety and efficacy of topical ruxolitinib in VLS was recently completed (ClinicalTrials.govidentifier NCT05593445). Future research studies likely will focus on the safety and efficacy of targeted and steroid-sparing therapies for patients with VLS.

Final Thoughts

Vulvar lichen sclerosus increasingly is becoming recognized as a chronic genital skin condition that impacts QOL and health outcomes, with a need to develop more effective and safe evidence-based therapies. Recent literature has focused on the importance of developing and standardizing disease outcomes; identifying disease associations including the role of cutaneous hormones and microbiome alterations; characterizing histologic and clinical variants; and staying up-to-date on management, including the need for understanding patient perceptions of chronic topical steroid therapy. Each of these are important updates for clinicians to consider when caring for patients with VLS. Future studies likely will focus on elucidating disease etiology and mechanisms to gain a better understanding of VLS pathogenesis and potential targets for therapies as well as implementation of clinical trials that incorporate standardized outcome domains to test efficacy and safety of additional therapies.

Vulvar lichen sclerosus (VLS) is an underserved area in medicine and dermatology. We discuss updates in VLS, which include the following: (1) development of core outcome domains to include in all future clinical trials, with current efforts focused on determining outcome measurements for each domain; (2) increased understanding of the impact VLS has on quality-of-life (QOL) outcomes; (3) expanded disease associations; (4) clinical and histologic variants, including vestibular sclerosis and nonsclerotic VLS; and (5) updates in management of VLS.

Core Outcomes Measures

The burden of VLS is challenging to quantify, with little agreement among experts.¹ Recently there has been a focus on developing scoring scales to measure disease progression and treatment response. Simpson et al² pioneered the development of a core outcome set to be included in all future clinical trials for genital lichen sclerosus (LS)—clinical (visible) signs, symptoms, and LS-specific QOL.

Although there is no standardized method for assessing disease severity, various scales have been proposed to measure clinical findings in VLS, such as the vulvar architecture severity scale³ as well as the clinical LS score,⁴ which is the only validated scale to incorporate the signs and architectural changes identified by a 2018 Delphi consensus group of the International Society for the Study of Vulvovaginal Disease.⁵ Work is ongoing to identify and evaluate outcome measurement instruments for each of the 3 core outcome domains.

Increased Understanding of QOL Impacts

Pain, pruritus, impairment of sexual function, genitourinary complications, architectural changes, and risk for squamous cell carcinoma (SCC) all have been well established as VLS sequelae.^6,7 Recent studies have focused on the QOL impact and associations with psychiatric comorbidities. A matched case-control study found that LS was significantly associated with depression and anxiety among US women (P<.001), and individuals with LS had a more than 2-fold increased odds of receiving a diagnosis of depression or anxiety.⁸

A review evaluating QOL outcomes in LS found that overall QOL was impaired. Female patients reported worse QOL in the work-school domain of the dermatology life quality index compared with male counterparts.⁹

Finally, a study exploring the experiences of patients living with VLS highlighted the secrecy and stigma of the condition,¹⁰ which serves as a call to action to improve the general population’s knowledge about vulvar anatomy and create change in societal attitudes on vulvar conditions.

Although there are several instruments assessing vulvar-specific QOL, most are for patients with vulvar cancer and focus on sexual function. In 2020, Saunderson et al¹¹ published the 15-item vulvar quality of life index (VQLI), which has broad implications for measuring vulvar disease burden and is an important tool for standardizing vulvar disease measurements and outcomes for clinical research.¹² The VQLI, though not specific to VLS, consists of 4 domains to assess vulvar QOL including symptoms, anxiety, activities of daily living, and sexuality. Studies have evaluated this scoring system in patients with VLS, with 1 study finding that VQLI correlated with clinician-rated severity scores (P=.01) and overall patient itch/discomfort score (P<.001) in VLS.^13,14

Expanded Disease Associations

Lichen sclerosus has a well-known association with vulvar SCC and other autoimmune conditions, including thyroid disease and bullous pemphigoid.^15-17 Recent studies also have revealed an association between LS and psoriasis.¹⁸ A case-control study from a single center found VLS was associated with elevated body mass index, statin usage, and cholecystectomy.¹⁹ Gynecologic pain syndromes, interstitial cystitis, urinary incontinence, and some gastrointestinal tract disorders including celiac disease also have been found to be increased in patients with VLS.²⁰ Finally, the incidence of cutaneous immune-related adverse events such as LS has increased as the use of immune checkpoint therapies as anticancer treatments has expanded.²¹ Clinicians should be aware of these potential disease associations when caring for patients with VLS.

The incidence of VLS is higher in lower estrogen states throughout the lifespan, and a recent case-control study evaluated the cutaneous hormonal and microbial landscapes in postmenopausal patients (6 patients with VLS; 12 controls).²² Levels of the following cutaneous hormones in the groin were found to be altered in patients with VLS compared with controls: estrone (lower; P=.006), progesterone (higher; P<.0001), and testosterone (lower; P=.02). The authors found that most hormone levels normalized following treatment with a topical steroid. Additionally, bacterial microbiome alterations were seen in patients with VLS compared with controls. Thus, cutaneous sex hormone and skin microbiome alterations may be associated with VLS.²²

Updates in Clinical and Histologic Variants

Less-recognized variants of VLS have been characterized in recent years. Vestibular sclerosis is a variant of VLS with unique clinical and histopathologic features; it is characterized by involvement localized to the anterior vestibule and either an absent or sparse lymphocytic infiltrate on histopathology.^23,24 Nonsclerotic VLS is a variant with clinical features consistent with VLS that does not exhibit dermal sclerosis on histopathology. Thus, a diagnosis of nonsclerotic VLS requires clinicopathologic correlation. Four nonsclerotic histopathologic subtypes are proposed: lichenoid, hypertrophic lichenoid, dermal fibrosis without acanthosis, and dermal fibrosis with acanthosis.²⁵ Longitudinal studies that correlate duration, signs, and symptoms will be important to further understand these variants.

Management Updates

First-line treatment of VLS still consists of ultrapotent topical corticosteroids with chronic maintenance therapy (usually lifetime) to decrease the risk for SCC and architectural changes.²⁶ However, a survey across social media platforms found steroid phobia is common in patients with VLS (N=865), with approximately 40% of respondents endorsing waiting as long as they could before using topical corticosteroids and stopping as soon as possible.²⁷ Clinicians should be aware of possible patient perceptions in the use of chronic steroids when discussing this therapy.

Randomized controlled trials utilizing fractional CO₂ devices for VLS have been performed with conflicting results and no consensus regarding outcome measurement.^28,29 Additionally, long-term disease outcomes following laser use have not been investigated. Although there is evidence that both ablative and nonablative devices can improve symptoms and signs, there is no evidence that they offer a cure for a chronic inflammatory skin condition. Current evidence suggests that even for patients undergoing these procedures, maintenance therapy is still essential to prevent sequelae.³⁰ Future studies incorporating standardized outcome measures will be important for assessing the benefits of laser therapy in VLS. Finally, the reasons why topical corticosteroids may fail in an individual patient are multifaceted and should be explored thoroughly when considering laser therapy for VLS.

Studies evaluating the role of systemic therapies for refractory cases of VLS have expanded. A systematic review of systemic therapies for both genital and extragenital LS found oral corticosteroids and methotrexate were the most-reported systemic treatment regimens.³¹ Use of biologics in LS has been reported, with cases utilizing adalimumab for VLS and dupilumab for extragenital LS. Use of Janus kinase inhibitors including abrocitinib and baricitinib also has been reported for LS.³¹ A clinical trial to evaluate the safety and efficacy of topical ruxolitinib in VLS was recently completed (ClinicalTrials.govidentifier NCT05593445). Future research studies likely will focus on the safety and efficacy of targeted and steroid-sparing therapies for patients with VLS.

Final Thoughts

Vulvar lichen sclerosus increasingly is becoming recognized as a chronic genital skin condition that impacts QOL and health outcomes, with a need to develop more effective and safe evidence-based therapies. Recent literature has focused on the importance of developing and standardizing disease outcomes; identifying disease associations including the role of cutaneous hormones and microbiome alterations; characterizing histologic and clinical variants; and staying up-to-date on management, including the need for understanding patient perceptions of chronic topical steroid therapy. Each of these are important updates for clinicians to consider when caring for patients with VLS. Future studies likely will focus on elucidating disease etiology and mechanisms to gain a better understanding of VLS pathogenesis and potential targets for therapies as well as implementation of clinical trials that incorporate standardized outcome domains to test efficacy and safety of additional therapies.

The Diagnosis: Granular Parakeratosis

Histopathology demonstrated diffuse parakeratosis with retention of keratohyalin granules throughout the stratum corneum consistent with a diagnosis of granular parakeratosis (Figure), a rare benign cutaneous condition that is thought to occur due to a defect in epidermal differentiation. The lesion resolved without additional treatment.

The pathogenesis of granular parakeratosis is unclear, but a reactive process in which locoregional irritation or occlusion prompts increased cell turnover and prevention of profilaggrin breakdown has been proposed.^1,2 The diagnosis is linked to various precipitating agents, most commonly topical products (eg, zinc oxide, antiperspirants) and products with benzalkonium chloride (eg, laundry rinses). These agents are thought to cause retention of keratohyalin granules in the stratum corneum during epidermal differentiation.^1,2

Most affected patients are middle-aged women (mean age at diagnosis, 37.8 years).² Patients present with eruptions of erythematous, brown, hyperkeratotic patches and papules that coalesce into plaques.^1,2 These lesions can be pruritic and painful or asymptomatic. They often manifest bilaterally in intertriginous sites, most commonly the axillae, groin, or inguinal folds.^1,2

Treatment involves identification and removal of potential triggers including changing antiperspirants, limiting use of irritating agents (eg, topical products with strong fragrances), and reducing heat and moisture in the affected areas. If the lesion persists, stepwise treatment can be initiated with topical agents (eg, corticosteroids, vitamin D analogues, retinoids, keratolytics, calcineurin inhibitors) followed by systemic medications (eg, antibiotics, isotretinoin, antifungals, dexamethasone) and procedures (eg, botulinum toxin injections, surgery, laser, cryotherapy).^1,2

Unilateral granular parakeratosis, as seen in our patient, is an uncommon manifestation. Our case supports the theory that occlusion is a precipitating factor for this condition, given persistent axillary exposure to heat, sweat, and friction in the setting of limb immobilization.³

Granular parakeratosis is a challenge to diagnose due to clinical overlap with several other cutaneous conditions; histopathologic confirmation is required. Fox- Fordyce disease is a rare condition that is thought to result from keratin buildup or occlusion of apocrine or apoeccrine sweat ducts leading to duct rupture and surrounding inflammation.⁴ Common triggers include laser hair removal, hormonal changes, and living conditions that promote hot and humid environments.⁵ It can manifest similarly to granular parakeratosis, with eruptions of multiple red-violet papules that appear bilaterally in aprocine gland–rich areas, including the axillae and less commonly the genital, periareolar, thoracic, abdominal, and facial areas.^4,5 However, most patients with Fox-Fordyce disease tend to be younger females (aged 13–35 years) with severely pruritic lesions,^4,5 unlike our patient. In addition, histopathology shows hyperkeratosis, hair follicle plugging, and sweat gland and duct dilation.⁴

Seborrheic keratoses are common benign epidermal tumors caused by an overproliferation of immature keratinocytes.^6,7 Similar to granular parakeratosis, they commonly manifest in older adults as hyperpigmented, well-demarcated, verrucous plaques with a hyperkeratotic surface.⁶ However, they are more common on the face, neck, trunk, and extremities, and they tend to be asymptomatic, differentiating them from granular parakerosis.⁶ Histopathology demonstrates a papillomatous epidermal surface, large capillaries in the dermal papillae, and intraepidermal and pseudohorn epidermal cysts.⁷

Inverse lichen planus, a variant of lichen planus, is a rare inflammatory condition that involves the lysis of basal keratinocytes by CD8+ lymphocytes.⁸ Similar to granular parakeratosis, lichen planus commonly affects middle-aged women (aged 30–60 years), and this particular variant manifests with asymptomatic or mildly pruritic, hyperpigmented patches and plaques in intertriginous areas. Although it also shows hyperkeratosis on histopathology, it can be differentiated from granular parakeratosis by the additional findings of epidermal hypergranulosis, sawtooth acanthosis of rete ridges, apoptotic keratinocytes in the dermoepidermal junction, and lymphocytic infiltrate in the upper dermis.⁸

Hailey-Hailey disease (also known as familial benign pemphigus) is a rare condition caused by an autosomaldominant mutation affecting intracellular calcium signaling that impairs keratinocyte adhesion.⁹ Similar to granular parakeratosis, it is most common in middle-aged adults (aged 30–40 years) and manifests as pruritic and burning lesions in symmetric intertriginous areas that also can be triggered by heat and sweating. However, patients present with recurrent blistering and vesicular lesions that may lead to erosions and secondary infections, which reduced clinical suspicion for this diagnosis in our patient. Histopathology shows suprabasilar and intraepidermal clefts, full-thickness acantholysis, protruding dermal papillae, and a perivascular lymphocytic infiltrate in the superficial dermis.⁹

The Diagnosis: Granular Parakeratosis

Histopathology demonstrated diffuse parakeratosis with retention of keratohyalin granules throughout the stratum corneum consistent with a diagnosis of granular parakeratosis (Figure), a rare benign cutaneous condition that is thought to occur due to a defect in epidermal differentiation. The lesion resolved without additional treatment.

The pathogenesis of granular parakeratosis is unclear, but a reactive process in which locoregional irritation or occlusion prompts increased cell turnover and prevention of profilaggrin breakdown has been proposed.^1,2 The diagnosis is linked to various precipitating agents, most commonly topical products (eg, zinc oxide, antiperspirants) and products with benzalkonium chloride (eg, laundry rinses). These agents are thought to cause retention of keratohyalin granules in the stratum corneum during epidermal differentiation.^1,2

Most affected patients are middle-aged women (mean age at diagnosis, 37.8 years).² Patients present with eruptions of erythematous, brown, hyperkeratotic patches and papules that coalesce into plaques.^1,2 These lesions can be pruritic and painful or asymptomatic. They often manifest bilaterally in intertriginous sites, most commonly the axillae, groin, or inguinal folds.^1,2

Treatment involves identification and removal of potential triggers including changing antiperspirants, limiting use of irritating agents (eg, topical products with strong fragrances), and reducing heat and moisture in the affected areas. If the lesion persists, stepwise treatment can be initiated with topical agents (eg, corticosteroids, vitamin D analogues, retinoids, keratolytics, calcineurin inhibitors) followed by systemic medications (eg, antibiotics, isotretinoin, antifungals, dexamethasone) and procedures (eg, botulinum toxin injections, surgery, laser, cryotherapy).^1,2

Unilateral granular parakeratosis, as seen in our patient, is an uncommon manifestation. Our case supports the theory that occlusion is a precipitating factor for this condition, given persistent axillary exposure to heat, sweat, and friction in the setting of limb immobilization.³

Granular parakeratosis is a challenge to diagnose due to clinical overlap with several other cutaneous conditions; histopathologic confirmation is required. Fox- Fordyce disease is a rare condition that is thought to result from keratin buildup or occlusion of apocrine or apoeccrine sweat ducts leading to duct rupture and surrounding inflammation.⁴ Common triggers include laser hair removal, hormonal changes, and living conditions that promote hot and humid environments.⁵ It can manifest similarly to granular parakeratosis, with eruptions of multiple red-violet papules that appear bilaterally in aprocine gland–rich areas, including the axillae and less commonly the genital, periareolar, thoracic, abdominal, and facial areas.^4,5 However, most patients with Fox-Fordyce disease tend to be younger females (aged 13–35 years) with severely pruritic lesions,^4,5 unlike our patient. In addition, histopathology shows hyperkeratosis, hair follicle plugging, and sweat gland and duct dilation.⁴

Seborrheic keratoses are common benign epidermal tumors caused by an overproliferation of immature keratinocytes.^6,7 Similar to granular parakeratosis, they commonly manifest in older adults as hyperpigmented, well-demarcated, verrucous plaques with a hyperkeratotic surface.⁶ However, they are more common on the face, neck, trunk, and extremities, and they tend to be asymptomatic, differentiating them from granular parakerosis.⁶ Histopathology demonstrates a papillomatous epidermal surface, large capillaries in the dermal papillae, and intraepidermal and pseudohorn epidermal cysts.⁷

Inverse lichen planus, a variant of lichen planus, is a rare inflammatory condition that involves the lysis of basal keratinocytes by CD8+ lymphocytes.⁸ Similar to granular parakeratosis, lichen planus commonly affects middle-aged women (aged 30–60 years), and this particular variant manifests with asymptomatic or mildly pruritic, hyperpigmented patches and plaques in intertriginous areas. Although it also shows hyperkeratosis on histopathology, it can be differentiated from granular parakeratosis by the additional findings of epidermal hypergranulosis, sawtooth acanthosis of rete ridges, apoptotic keratinocytes in the dermoepidermal junction, and lymphocytic infiltrate in the upper dermis.⁸

Hailey-Hailey disease (also known as familial benign pemphigus) is a rare condition caused by an autosomaldominant mutation affecting intracellular calcium signaling that impairs keratinocyte adhesion.⁹ Similar to granular parakeratosis, it is most common in middle-aged adults (aged 30–40 years) and manifests as pruritic and burning lesions in symmetric intertriginous areas that also can be triggered by heat and sweating. However, patients present with recurrent blistering and vesicular lesions that may lead to erosions and secondary infections, which reduced clinical suspicion for this diagnosis in our patient. Histopathology shows suprabasilar and intraepidermal clefts, full-thickness acantholysis, protruding dermal papillae, and a perivascular lymphocytic infiltrate in the superficial dermis.⁹

The Diagnosis: Granular Parakeratosis

Histopathology demonstrated diffuse parakeratosis with retention of keratohyalin granules throughout the stratum corneum consistent with a diagnosis of granular parakeratosis (Figure), a rare benign cutaneous condition that is thought to occur due to a defect in epidermal differentiation. The lesion resolved without additional treatment.

The pathogenesis of granular parakeratosis is unclear, but a reactive process in which locoregional irritation or occlusion prompts increased cell turnover and prevention of profilaggrin breakdown has been proposed.^1,2 The diagnosis is linked to various precipitating agents, most commonly topical products (eg, zinc oxide, antiperspirants) and products with benzalkonium chloride (eg, laundry rinses). These agents are thought to cause retention of keratohyalin granules in the stratum corneum during epidermal differentiation.^1,2

Most affected patients are middle-aged women (mean age at diagnosis, 37.8 years).² Patients present with eruptions of erythematous, brown, hyperkeratotic patches and papules that coalesce into plaques.^1,2 These lesions can be pruritic and painful or asymptomatic. They often manifest bilaterally in intertriginous sites, most commonly the axillae, groin, or inguinal folds.^1,2

Treatment involves identification and removal of potential triggers including changing antiperspirants, limiting use of irritating agents (eg, topical products with strong fragrances), and reducing heat and moisture in the affected areas. If the lesion persists, stepwise treatment can be initiated with topical agents (eg, corticosteroids, vitamin D analogues, retinoids, keratolytics, calcineurin inhibitors) followed by systemic medications (eg, antibiotics, isotretinoin, antifungals, dexamethasone) and procedures (eg, botulinum toxin injections, surgery, laser, cryotherapy).^1,2

Unilateral granular parakeratosis, as seen in our patient, is an uncommon manifestation. Our case supports the theory that occlusion is a precipitating factor for this condition, given persistent axillary exposure to heat, sweat, and friction in the setting of limb immobilization.³

Granular parakeratosis is a challenge to diagnose due to clinical overlap with several other cutaneous conditions; histopathologic confirmation is required. Fox- Fordyce disease is a rare condition that is thought to result from keratin buildup or occlusion of apocrine or apoeccrine sweat ducts leading to duct rupture and surrounding inflammation.⁴ Common triggers include laser hair removal, hormonal changes, and living conditions that promote hot and humid environments.⁵ It can manifest similarly to granular parakeratosis, with eruptions of multiple red-violet papules that appear bilaterally in aprocine gland–rich areas, including the axillae and less commonly the genital, periareolar, thoracic, abdominal, and facial areas.^4,5 However, most patients with Fox-Fordyce disease tend to be younger females (aged 13–35 years) with severely pruritic lesions,^4,5 unlike our patient. In addition, histopathology shows hyperkeratosis, hair follicle plugging, and sweat gland and duct dilation.⁴

Seborrheic keratoses are common benign epidermal tumors caused by an overproliferation of immature keratinocytes.^6,7 Similar to granular parakeratosis, they commonly manifest in older adults as hyperpigmented, well-demarcated, verrucous plaques with a hyperkeratotic surface.⁶ However, they are more common on the face, neck, trunk, and extremities, and they tend to be asymptomatic, differentiating them from granular parakerosis.⁶ Histopathology demonstrates a papillomatous epidermal surface, large capillaries in the dermal papillae, and intraepidermal and pseudohorn epidermal cysts.⁷

Inverse lichen planus, a variant of lichen planus, is a rare inflammatory condition that involves the lysis of basal keratinocytes by CD8+ lymphocytes.⁸ Similar to granular parakeratosis, lichen planus commonly affects middle-aged women (aged 30–60 years), and this particular variant manifests with asymptomatic or mildly pruritic, hyperpigmented patches and plaques in intertriginous areas. Although it also shows hyperkeratosis on histopathology, it can be differentiated from granular parakeratosis by the additional findings of epidermal hypergranulosis, sawtooth acanthosis of rete ridges, apoptotic keratinocytes in the dermoepidermal junction, and lymphocytic infiltrate in the upper dermis.⁸

Hailey-Hailey disease (also known as familial benign pemphigus) is a rare condition caused by an autosomaldominant mutation affecting intracellular calcium signaling that impairs keratinocyte adhesion.⁹ Similar to granular parakeratosis, it is most common in middle-aged adults (aged 30–40 years) and manifests as pruritic and burning lesions in symmetric intertriginous areas that also can be triggered by heat and sweating. However, patients present with recurrent blistering and vesicular lesions that may lead to erosions and secondary infections, which reduced clinical suspicion for this diagnosis in our patient. Histopathology shows suprabasilar and intraepidermal clefts, full-thickness acantholysis, protruding dermal papillae, and a perivascular lymphocytic infiltrate in the superficial dermis.⁹