AVAHO

A new U.K. study shows no link between brain tumors and cell phone use, even among individuals who used their phones every day and/or had used them for over 10 years.

“These results support the accumulating evidence that mobile phone use under usual conditions does not increase brain tumor risk,” study author Kirstin Pirie, MSc, from the cancer epidemiology unit at Oxford (England) Population Health, said in a statement.

However, an important limitation of the study is that it involved only women who were middle-aged and older; these people generally use cell phones less than younger women or men, the authors noted. In this study’s cohort, mobile phone use was low, with only 18% of users talking on the phone for 30 minutes or more each week.

The results were published in the Journal of the National Cancer Institute.

This study is a “welcome addition to the body of knowledge looking at the risk from mobile phones, and specifically in relation to certain types of tumor genesis. It is a well-designed, prospective study that identifies no causal link,” commented Malcolm Sperrin from Oxford University Hospitals, who was not involved in the research.

“There is always a need for further research work, especially as phones, wireless, etc., become ubiquitous, but this study should allay many existing concerns,” he commented on the UK Science Media Centre.

Concerns about a cancer risk, particularly brain tumors, have been circulating for decades, and to date, there have been some 30 epidemiologic studies on this issue.

In 2011, the International Agency for Research on Cancer announced that cell phones are “possibly carcinogenic.” That conclusion was based largely on the results of the large INTERPHONE international case-control study and a series of Swedish studies led by Hardell Lennart, MD.

In the latest article, the U.K. researchers suggest that a “likely explanation for the previous positive results is that for a very slow growing tumor, there may be detection bias if cellular telephone users seek medical advice because of awareness of typical symptoms of acoustic neuroma, such as unilateral hearing problems, earlier than nonusers.

“The totality of human evidence, from observational studies, time trends, and bioassays, suggests little or no increase in the risk of cellular telephone users developing a brain tumor,” the U.K. researchers concluded.

Commenting on the U.K. study, Joachim Schüz, PhD, branch head of the section of environment and radiation at the IARC, noted that “mobile technologies are improving all the time, so that the more recent generations emit substantially lower output power.

“Nevertheless, given the lack of evidence for heavy users, advising mobile phone users to reduce unnecessary exposures remains a good precautionary approach,” Dr. Schuz said in a statement.
 

Details of U.K. study

The U.K. study was conducted by researchers from Oxford Population Health and IARC, who used data from the ongoing UK Million Women Study. This study began in 1996 and has recruited 1.3 million women born from 1935 to 1950 (which amounts to 1 in every 4 women) through the U.K. National Health Service Breast Screening Programme. These women complete regular postal questionnaires about sociodemographic, medical, and lifestyle factors.

Questions about cell phone use were completed by about 776,000 women in 2001 (when they were 50-65 years old). About half of these women also answered these questions about mobile phone use 10 years later, in 2011 (when they were aged 60-75).

The answers indicated that by 2011, the majority of women (75%) aged between 60 and 64 years used a mobile phone, while just under half of those aged between 75 and 79 years used one.

These women were then followed for an average of 14 years through linkage to their NHS records.

The researchers looked for any mention of brain tumors, including glioma, acoustic neuroma, meningioma, and pituitary gland tumors, as well as eye tumors.

During the 14 year follow-up period, 3,268 (0.42%) of the participants developed a brain tumor, but there was no significant difference in that risk between individuals who had never used a mobile phone and those who were mobile phone users. These included tumors in the temporal and parietal lobes, which are the most exposed areas of the brain.

There was also no difference in the risk of developing tumors between women who reported using a mobile phone daily, those who used them for at least 20 minutes a week, and those who had used a mobile phone for over 10 years.

In addition, among the individuals who did develop a tumor, the incidence of right- and left-sided tumors was similar among mobile phone users, even though mobile phone use tends to involve the right side considerably more than the left side, the researchers noted.

The study was funded by the UK Medical Research Council and Cancer Research UK.

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

A new U.K. study shows no link between brain tumors and cell phone use, even among individuals who used their phones every day and/or had used them for over 10 years.

“These results support the accumulating evidence that mobile phone use under usual conditions does not increase brain tumor risk,” study author Kirstin Pirie, MSc, from the cancer epidemiology unit at Oxford (England) Population Health, said in a statement.

However, an important limitation of the study is that it involved only women who were middle-aged and older; these people generally use cell phones less than younger women or men, the authors noted. In this study’s cohort, mobile phone use was low, with only 18% of users talking on the phone for 30 minutes or more each week.

The results were published in the Journal of the National Cancer Institute.

This study is a “welcome addition to the body of knowledge looking at the risk from mobile phones, and specifically in relation to certain types of tumor genesis. It is a well-designed, prospective study that identifies no causal link,” commented Malcolm Sperrin from Oxford University Hospitals, who was not involved in the research.

“There is always a need for further research work, especially as phones, wireless, etc., become ubiquitous, but this study should allay many existing concerns,” he commented on the UK Science Media Centre.

Concerns about a cancer risk, particularly brain tumors, have been circulating for decades, and to date, there have been some 30 epidemiologic studies on this issue.

In 2011, the International Agency for Research on Cancer announced that cell phones are “possibly carcinogenic.” That conclusion was based largely on the results of the large INTERPHONE international case-control study and a series of Swedish studies led by Hardell Lennart, MD.

In the latest article, the U.K. researchers suggest that a “likely explanation for the previous positive results is that for a very slow growing tumor, there may be detection bias if cellular telephone users seek medical advice because of awareness of typical symptoms of acoustic neuroma, such as unilateral hearing problems, earlier than nonusers.

“The totality of human evidence, from observational studies, time trends, and bioassays, suggests little or no increase in the risk of cellular telephone users developing a brain tumor,” the U.K. researchers concluded.

Commenting on the U.K. study, Joachim Schüz, PhD, branch head of the section of environment and radiation at the IARC, noted that “mobile technologies are improving all the time, so that the more recent generations emit substantially lower output power.

“Nevertheless, given the lack of evidence for heavy users, advising mobile phone users to reduce unnecessary exposures remains a good precautionary approach,” Dr. Schuz said in a statement.
 

Details of U.K. study

The U.K. study was conducted by researchers from Oxford Population Health and IARC, who used data from the ongoing UK Million Women Study. This study began in 1996 and has recruited 1.3 million women born from 1935 to 1950 (which amounts to 1 in every 4 women) through the U.K. National Health Service Breast Screening Programme. These women complete regular postal questionnaires about sociodemographic, medical, and lifestyle factors.

Questions about cell phone use were completed by about 776,000 women in 2001 (when they were 50-65 years old). About half of these women also answered these questions about mobile phone use 10 years later, in 2011 (when they were aged 60-75).

The answers indicated that by 2011, the majority of women (75%) aged between 60 and 64 years used a mobile phone, while just under half of those aged between 75 and 79 years used one.

These women were then followed for an average of 14 years through linkage to their NHS records.

The researchers looked for any mention of brain tumors, including glioma, acoustic neuroma, meningioma, and pituitary gland tumors, as well as eye tumors.

During the 14 year follow-up period, 3,268 (0.42%) of the participants developed a brain tumor, but there was no significant difference in that risk between individuals who had never used a mobile phone and those who were mobile phone users. These included tumors in the temporal and parietal lobes, which are the most exposed areas of the brain.

There was also no difference in the risk of developing tumors between women who reported using a mobile phone daily, those who used them for at least 20 minutes a week, and those who had used a mobile phone for over 10 years.

In addition, among the individuals who did develop a tumor, the incidence of right- and left-sided tumors was similar among mobile phone users, even though mobile phone use tends to involve the right side considerably more than the left side, the researchers noted.

The study was funded by the UK Medical Research Council and Cancer Research UK.

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

A new U.K. study shows no link between brain tumors and cell phone use, even among individuals who used their phones every day and/or had used them for over 10 years.

“These results support the accumulating evidence that mobile phone use under usual conditions does not increase brain tumor risk,” study author Kirstin Pirie, MSc, from the cancer epidemiology unit at Oxford (England) Population Health, said in a statement.

However, an important limitation of the study is that it involved only women who were middle-aged and older; these people generally use cell phones less than younger women or men, the authors noted. In this study’s cohort, mobile phone use was low, with only 18% of users talking on the phone for 30 minutes or more each week.

The results were published in the Journal of the National Cancer Institute.

This study is a “welcome addition to the body of knowledge looking at the risk from mobile phones, and specifically in relation to certain types of tumor genesis. It is a well-designed, prospective study that identifies no causal link,” commented Malcolm Sperrin from Oxford University Hospitals, who was not involved in the research.

“There is always a need for further research work, especially as phones, wireless, etc., become ubiquitous, but this study should allay many existing concerns,” he commented on the UK Science Media Centre.

Concerns about a cancer risk, particularly brain tumors, have been circulating for decades, and to date, there have been some 30 epidemiologic studies on this issue.

In 2011, the International Agency for Research on Cancer announced that cell phones are “possibly carcinogenic.” That conclusion was based largely on the results of the large INTERPHONE international case-control study and a series of Swedish studies led by Hardell Lennart, MD.

In the latest article, the U.K. researchers suggest that a “likely explanation for the previous positive results is that for a very slow growing tumor, there may be detection bias if cellular telephone users seek medical advice because of awareness of typical symptoms of acoustic neuroma, such as unilateral hearing problems, earlier than nonusers.

“The totality of human evidence, from observational studies, time trends, and bioassays, suggests little or no increase in the risk of cellular telephone users developing a brain tumor,” the U.K. researchers concluded.

Commenting on the U.K. study, Joachim Schüz, PhD, branch head of the section of environment and radiation at the IARC, noted that “mobile technologies are improving all the time, so that the more recent generations emit substantially lower output power.

“Nevertheless, given the lack of evidence for heavy users, advising mobile phone users to reduce unnecessary exposures remains a good precautionary approach,” Dr. Schuz said in a statement.
 

Details of U.K. study

The U.K. study was conducted by researchers from Oxford Population Health and IARC, who used data from the ongoing UK Million Women Study. This study began in 1996 and has recruited 1.3 million women born from 1935 to 1950 (which amounts to 1 in every 4 women) through the U.K. National Health Service Breast Screening Programme. These women complete regular postal questionnaires about sociodemographic, medical, and lifestyle factors.

Questions about cell phone use were completed by about 776,000 women in 2001 (when they were 50-65 years old). About half of these women also answered these questions about mobile phone use 10 years later, in 2011 (when they were aged 60-75).

The answers indicated that by 2011, the majority of women (75%) aged between 60 and 64 years used a mobile phone, while just under half of those aged between 75 and 79 years used one.

These women were then followed for an average of 14 years through linkage to their NHS records.

The researchers looked for any mention of brain tumors, including glioma, acoustic neuroma, meningioma, and pituitary gland tumors, as well as eye tumors.

During the 14 year follow-up period, 3,268 (0.42%) of the participants developed a brain tumor, but there was no significant difference in that risk between individuals who had never used a mobile phone and those who were mobile phone users. These included tumors in the temporal and parietal lobes, which are the most exposed areas of the brain.

There was also no difference in the risk of developing tumors between women who reported using a mobile phone daily, those who used them for at least 20 minutes a week, and those who had used a mobile phone for over 10 years.

In addition, among the individuals who did develop a tumor, the incidence of right- and left-sided tumors was similar among mobile phone users, even though mobile phone use tends to involve the right side considerably more than the left side, the researchers noted.

The study was funded by the UK Medical Research Council and Cancer Research UK.

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

The link between obesity and cancer has increasingly been emphasized in public health messages, but is the current message correct?

“Being overweight or having obesity increases your risk of getting cancer,” warns the U.S. Centers for Disease Control and Prevention. It warns that overweight/obesity is “linked with a higher risk of getting 13 types of cancer ... [which] make up 40% of all cancers diagnosed in the United States each year.”

But that message, which is also promulgated by many cancer organizations, is based on data from observational studies, which have many limitations.

A new study based on Mendelian randomization studies has come to a slightly different conclusion and has found a potential causal association with just six cancers.

In addition, it found an inverse relationship for breast cancer, in which early-life obesity was associated with a reduced risk of breast cancer, and the relationship with obesity was “complicated” for lung and prostate cancer.

The study, headed by Zhe Fang, MBBS, Harvard T. H. Chan School of Public Health, Boston, Mass., was published in the Journal of the National Cancer Institute

“For a seemingly straightforward question of whether excessive body fatness causes cancer, the answer may not be straightforward after all,” writes Song Yao, PhD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., in an accompanying editorial

“How to craft a simple public health message to convey the complexity and nuances of the relationships may be a challenge to be grappled with going forward,” he added.

In an interview, Dr. Yao said that it “really depends on what kind of message you want to get out.”

“If you want to talk about cancer overall, as one disease, we all know that a clear association with obesity does not exist,” he said. “It’s not that simple.”

“You really cannot say that obesity increases cancer risk overall,” he said.

For some cancers included in the study, Dr. Yao continued, it was “very clear that obesity increased the risk ... but for some other cancer types, we either don’t have enough data yet or the association is not as consistent.”

This, he said, is especially the case for prostate and lung cancer.

All of this indicates that there is a complex relationship between obesity and cancer risk, he maintains.

“We always think obesity is bad, not only for cancer but also for more common conditions, like hypertension, diabetes, and cardiovascular disease,” Dr. Yao noted. This points to the link between obesity and chronic inflammation, he added.

However, there are also other hypotheses, including synthesis of estrogen in adipose tissue, which may explain the link between obesity and breast cancer risk in older women.

However, in younger women, obesity protects against breast cancer, and “we really don’t know why,” Dr. Yao said.

The new study used Mendelian randomization to examine these relationships. This is a “new tool that we have developed over the past 20 years or so, largely because there is so much data coming from genome-wide association studies,” Dr. Yao explained.

It has “advantages” over other methods, including observational studies. One of its strengths is that it is “not impacted by reverse causality,” because genetic risk does not change over time.

However, he said, it is “quite straightforward to think that the genetics do not change, but at the same time, the environment we live in throughout our life course changes,” and the impact of genetic variants may be “washed out.”

How genetics influences cancer risk may therefore change over time, and it is a “dynamic process,” Dr. Yao commented.

In addition, this approach has its own limitations, he said, because it depends on how much of the variation in a given measure can be attributed to genetic factors.
 

New conclusions

In their study, Dr. Fang and colleagues reviewed 204 meta-analyses of 2,179 individual estimates from 507 cohort or case-control studies. They found “strong evidence” that supports the association between obesity and 11 cancers.

These are esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

They note, however, that the associations “may be causal for some malignancies” but that the co-occurrence of obesity with various cancer risk factors means that others may be “susceptible to potential confounding bias.”

To overcome some of these limitations, the team looked to Mendelian randomization studies that examined the association between genetic variants linked to body mass index (BMI), indicating lifetime risk of high BMI, and cancer risk for a range of cancer types.

These Mendelian randomization studies were then compared with the results of large-scale conventional observational studies, as well as with evidence in reports from the International Agency for Research on Cancer and the World Cancer Research Fund–American Institute of Cancer Research, which also include experimental studies.

The researchers say that, overall, the Mendelian randomization studies “further establish the causality of obesity” with six cancer types: colorectal, endometrial, ovarian, kidney, and pancreatic cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship of early-life obesity with breast cancer.

However, the approach could not confirm a positive association between obesity and gallbladder and gastric cardia cancer, as well as multiple myeloma.

“This could be due to low power,” the team suggests, “and larger studies are required.”

With respect to lung cancer, the Mendelian randomization identified a positive association with obesity that supports the inverse association identified in observational studies, that is, that obesity may reduce the risk for lung cancer.

The researchers suggest this may reflect reverse causality related to the loss of lean body mass before diagnosis, as well as confounding by smoking.

For prostate cancer, the evidence was “conflicting” and “implies a complicated role of obesity,” Dr. Zhang and colleagues comment.

The link between obesity and lower prostate-specific antigen levels, they suggest, may result in a detection bias by masking the presence of prostate cancer, or it “could be biological” in origin, owing to reduced androgen levels.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were stronger than those seen in conventional studies, with the magnitude of risk ranging from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

In another editorial accompanying the new study, Graham A. Colditz, MD, DrPH, from Washington University School of Medicine, St. Louis, underlined that childhood and adolescent obesity and their contribution to cancer risk need further attention.

“To reap the reward from past research, we must act to implement effective strategies to reduce childhood and adolescent adiposity, reduce excess weight gain in adult years, and maintain a healthy weight,” he writes.

“This will require us to change the way we live, but COVID-19 has shown we can make changes to how we live and work. Let us keep the changes we have already made, or take on new ones, that will cut our collective cancer toll,” he implores.

No funding for the study was described. Dr. Colditz is supported by the Breast Cancer Research Foundation. No other relevant financial relationships were described.

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

The link between obesity and cancer has increasingly been emphasized in public health messages, but is the current message correct?

“Being overweight or having obesity increases your risk of getting cancer,” warns the U.S. Centers for Disease Control and Prevention. It warns that overweight/obesity is “linked with a higher risk of getting 13 types of cancer ... [which] make up 40% of all cancers diagnosed in the United States each year.”

But that message, which is also promulgated by many cancer organizations, is based on data from observational studies, which have many limitations.

A new study based on Mendelian randomization studies has come to a slightly different conclusion and has found a potential causal association with just six cancers.

In addition, it found an inverse relationship for breast cancer, in which early-life obesity was associated with a reduced risk of breast cancer, and the relationship with obesity was “complicated” for lung and prostate cancer.

The study, headed by Zhe Fang, MBBS, Harvard T. H. Chan School of Public Health, Boston, Mass., was published in the Journal of the National Cancer Institute

“For a seemingly straightforward question of whether excessive body fatness causes cancer, the answer may not be straightforward after all,” writes Song Yao, PhD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., in an accompanying editorial

“How to craft a simple public health message to convey the complexity and nuances of the relationships may be a challenge to be grappled with going forward,” he added.

In an interview, Dr. Yao said that it “really depends on what kind of message you want to get out.”

“If you want to talk about cancer overall, as one disease, we all know that a clear association with obesity does not exist,” he said. “It’s not that simple.”

“You really cannot say that obesity increases cancer risk overall,” he said.

For some cancers included in the study, Dr. Yao continued, it was “very clear that obesity increased the risk ... but for some other cancer types, we either don’t have enough data yet or the association is not as consistent.”

This, he said, is especially the case for prostate and lung cancer.

All of this indicates that there is a complex relationship between obesity and cancer risk, he maintains.

“We always think obesity is bad, not only for cancer but also for more common conditions, like hypertension, diabetes, and cardiovascular disease,” Dr. Yao noted. This points to the link between obesity and chronic inflammation, he added.

However, there are also other hypotheses, including synthesis of estrogen in adipose tissue, which may explain the link between obesity and breast cancer risk in older women.

However, in younger women, obesity protects against breast cancer, and “we really don’t know why,” Dr. Yao said.

The new study used Mendelian randomization to examine these relationships. This is a “new tool that we have developed over the past 20 years or so, largely because there is so much data coming from genome-wide association studies,” Dr. Yao explained.

It has “advantages” over other methods, including observational studies. One of its strengths is that it is “not impacted by reverse causality,” because genetic risk does not change over time.

However, he said, it is “quite straightforward to think that the genetics do not change, but at the same time, the environment we live in throughout our life course changes,” and the impact of genetic variants may be “washed out.”

How genetics influences cancer risk may therefore change over time, and it is a “dynamic process,” Dr. Yao commented.

In addition, this approach has its own limitations, he said, because it depends on how much of the variation in a given measure can be attributed to genetic factors.
 

New conclusions

In their study, Dr. Fang and colleagues reviewed 204 meta-analyses of 2,179 individual estimates from 507 cohort or case-control studies. They found “strong evidence” that supports the association between obesity and 11 cancers.

These are esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

They note, however, that the associations “may be causal for some malignancies” but that the co-occurrence of obesity with various cancer risk factors means that others may be “susceptible to potential confounding bias.”

To overcome some of these limitations, the team looked to Mendelian randomization studies that examined the association between genetic variants linked to body mass index (BMI), indicating lifetime risk of high BMI, and cancer risk for a range of cancer types.

These Mendelian randomization studies were then compared with the results of large-scale conventional observational studies, as well as with evidence in reports from the International Agency for Research on Cancer and the World Cancer Research Fund–American Institute of Cancer Research, which also include experimental studies.

The researchers say that, overall, the Mendelian randomization studies “further establish the causality of obesity” with six cancer types: colorectal, endometrial, ovarian, kidney, and pancreatic cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship of early-life obesity with breast cancer.

However, the approach could not confirm a positive association between obesity and gallbladder and gastric cardia cancer, as well as multiple myeloma.

“This could be due to low power,” the team suggests, “and larger studies are required.”

With respect to lung cancer, the Mendelian randomization identified a positive association with obesity that supports the inverse association identified in observational studies, that is, that obesity may reduce the risk for lung cancer.

The researchers suggest this may reflect reverse causality related to the loss of lean body mass before diagnosis, as well as confounding by smoking.

For prostate cancer, the evidence was “conflicting” and “implies a complicated role of obesity,” Dr. Zhang and colleagues comment.

The link between obesity and lower prostate-specific antigen levels, they suggest, may result in a detection bias by masking the presence of prostate cancer, or it “could be biological” in origin, owing to reduced androgen levels.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were stronger than those seen in conventional studies, with the magnitude of risk ranging from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

In another editorial accompanying the new study, Graham A. Colditz, MD, DrPH, from Washington University School of Medicine, St. Louis, underlined that childhood and adolescent obesity and their contribution to cancer risk need further attention.

“To reap the reward from past research, we must act to implement effective strategies to reduce childhood and adolescent adiposity, reduce excess weight gain in adult years, and maintain a healthy weight,” he writes.

“This will require us to change the way we live, but COVID-19 has shown we can make changes to how we live and work. Let us keep the changes we have already made, or take on new ones, that will cut our collective cancer toll,” he implores.

No funding for the study was described. Dr. Colditz is supported by the Breast Cancer Research Foundation. No other relevant financial relationships were described.

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

The link between obesity and cancer has increasingly been emphasized in public health messages, but is the current message correct?

“Being overweight or having obesity increases your risk of getting cancer,” warns the U.S. Centers for Disease Control and Prevention. It warns that overweight/obesity is “linked with a higher risk of getting 13 types of cancer ... [which] make up 40% of all cancers diagnosed in the United States each year.”

But that message, which is also promulgated by many cancer organizations, is based on data from observational studies, which have many limitations.

A new study based on Mendelian randomization studies has come to a slightly different conclusion and has found a potential causal association with just six cancers.

In addition, it found an inverse relationship for breast cancer, in which early-life obesity was associated with a reduced risk of breast cancer, and the relationship with obesity was “complicated” for lung and prostate cancer.

The study, headed by Zhe Fang, MBBS, Harvard T. H. Chan School of Public Health, Boston, Mass., was published in the Journal of the National Cancer Institute

“For a seemingly straightforward question of whether excessive body fatness causes cancer, the answer may not be straightforward after all,” writes Song Yao, PhD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., in an accompanying editorial

“How to craft a simple public health message to convey the complexity and nuances of the relationships may be a challenge to be grappled with going forward,” he added.

In an interview, Dr. Yao said that it “really depends on what kind of message you want to get out.”

“If you want to talk about cancer overall, as one disease, we all know that a clear association with obesity does not exist,” he said. “It’s not that simple.”

“You really cannot say that obesity increases cancer risk overall,” he said.

For some cancers included in the study, Dr. Yao continued, it was “very clear that obesity increased the risk ... but for some other cancer types, we either don’t have enough data yet or the association is not as consistent.”

This, he said, is especially the case for prostate and lung cancer.

All of this indicates that there is a complex relationship between obesity and cancer risk, he maintains.

“We always think obesity is bad, not only for cancer but also for more common conditions, like hypertension, diabetes, and cardiovascular disease,” Dr. Yao noted. This points to the link between obesity and chronic inflammation, he added.

However, there are also other hypotheses, including synthesis of estrogen in adipose tissue, which may explain the link between obesity and breast cancer risk in older women.

However, in younger women, obesity protects against breast cancer, and “we really don’t know why,” Dr. Yao said.

The new study used Mendelian randomization to examine these relationships. This is a “new tool that we have developed over the past 20 years or so, largely because there is so much data coming from genome-wide association studies,” Dr. Yao explained.

It has “advantages” over other methods, including observational studies. One of its strengths is that it is “not impacted by reverse causality,” because genetic risk does not change over time.

However, he said, it is “quite straightforward to think that the genetics do not change, but at the same time, the environment we live in throughout our life course changes,” and the impact of genetic variants may be “washed out.”

How genetics influences cancer risk may therefore change over time, and it is a “dynamic process,” Dr. Yao commented.

In addition, this approach has its own limitations, he said, because it depends on how much of the variation in a given measure can be attributed to genetic factors.
 

New conclusions

In their study, Dr. Fang and colleagues reviewed 204 meta-analyses of 2,179 individual estimates from 507 cohort or case-control studies. They found “strong evidence” that supports the association between obesity and 11 cancers.

These are esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

They note, however, that the associations “may be causal for some malignancies” but that the co-occurrence of obesity with various cancer risk factors means that others may be “susceptible to potential confounding bias.”

To overcome some of these limitations, the team looked to Mendelian randomization studies that examined the association between genetic variants linked to body mass index (BMI), indicating lifetime risk of high BMI, and cancer risk for a range of cancer types.

These Mendelian randomization studies were then compared with the results of large-scale conventional observational studies, as well as with evidence in reports from the International Agency for Research on Cancer and the World Cancer Research Fund–American Institute of Cancer Research, which also include experimental studies.

The researchers say that, overall, the Mendelian randomization studies “further establish the causality of obesity” with six cancer types: colorectal, endometrial, ovarian, kidney, and pancreatic cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship of early-life obesity with breast cancer.

However, the approach could not confirm a positive association between obesity and gallbladder and gastric cardia cancer, as well as multiple myeloma.

“This could be due to low power,” the team suggests, “and larger studies are required.”

With respect to lung cancer, the Mendelian randomization identified a positive association with obesity that supports the inverse association identified in observational studies, that is, that obesity may reduce the risk for lung cancer.

The researchers suggest this may reflect reverse causality related to the loss of lean body mass before diagnosis, as well as confounding by smoking.

For prostate cancer, the evidence was “conflicting” and “implies a complicated role of obesity,” Dr. Zhang and colleagues comment.

The link between obesity and lower prostate-specific antigen levels, they suggest, may result in a detection bias by masking the presence of prostate cancer, or it “could be biological” in origin, owing to reduced androgen levels.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were stronger than those seen in conventional studies, with the magnitude of risk ranging from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

In another editorial accompanying the new study, Graham A. Colditz, MD, DrPH, from Washington University School of Medicine, St. Louis, underlined that childhood and adolescent obesity and their contribution to cancer risk need further attention.

“To reap the reward from past research, we must act to implement effective strategies to reduce childhood and adolescent adiposity, reduce excess weight gain in adult years, and maintain a healthy weight,” he writes.

“This will require us to change the way we live, but COVID-19 has shown we can make changes to how we live and work. Let us keep the changes we have already made, or take on new ones, that will cut our collective cancer toll,” he implores.

No funding for the study was described. Dr. Colditz is supported by the Breast Cancer Research Foundation. No other relevant financial relationships were described.

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

Federal Practitioner, in collaboration with the Association of VA Hematology/Oncology (AVAHO), present the 2022 edition of Cancer Data Trends (click to view the digital edition). This special issue provides updates on some of the top cancers and related concerns affecting veterans through original infographics and visual storytelling.

In this issue:

• Exposure-Related Cancers
• Cancer in Women
• Genitourinary Cancers
• Gastrointestinal Cancers
• Telehealth in Oncology
•  Precision Oncology
•  Palliative and Hospice Care
•  Alcohol and Cancer
•  Lung Cancer
•  Oropharyngeal Cancer
• Hematologic Cancers

Federal Practitioner and AVAHO would like to thank the following experts for their contributions to this issue:

Anita Aggarwal, DO, PhD; Sara Ahmed, PhD; Katherine Faricy-Anderson, MD; Apar Kishor Ganti, MD, MS; Solomon A Graf, MD; Kate Hendricks Thomas, PhD; Michael Kelley, MD; Mark Klein, MD, Gina McWhirter, MSN, MBA, RN; Bruce Montgomery, MD; Vida Almario Passero, MD, MBA; Thomas D Rodgers, MD; Vlad C Sandulache, MD, PhD; David H Wang, MD, PhD.

Federal Practitioner, in collaboration with the Association of VA Hematology/Oncology (AVAHO), present the 2022 edition of Cancer Data Trends (click to view the digital edition). This special issue provides updates on some of the top cancers and related concerns affecting veterans through original infographics and visual storytelling.

In this issue:

• Exposure-Related Cancers
• Cancer in Women
• Genitourinary Cancers
• Gastrointestinal Cancers
• Telehealth in Oncology
•  Precision Oncology
•  Palliative and Hospice Care
•  Alcohol and Cancer
•  Lung Cancer
•  Oropharyngeal Cancer
• Hematologic Cancers

Federal Practitioner and AVAHO would like to thank the following experts for their contributions to this issue:

Anita Aggarwal, DO, PhD; Sara Ahmed, PhD; Katherine Faricy-Anderson, MD; Apar Kishor Ganti, MD, MS; Solomon A Graf, MD; Kate Hendricks Thomas, PhD; Michael Kelley, MD; Mark Klein, MD, Gina McWhirter, MSN, MBA, RN; Bruce Montgomery, MD; Vida Almario Passero, MD, MBA; Thomas D Rodgers, MD; Vlad C Sandulache, MD, PhD; David H Wang, MD, PhD.

Federal Practitioner, in collaboration with the Association of VA Hematology/Oncology (AVAHO), present the 2022 edition of Cancer Data Trends (click to view the digital edition). This special issue provides updates on some of the top cancers and related concerns affecting veterans through original infographics and visual storytelling.

In this issue:

• Exposure-Related Cancers
• Cancer in Women
• Genitourinary Cancers
• Gastrointestinal Cancers
• Telehealth in Oncology
•  Precision Oncology
•  Palliative and Hospice Care
•  Alcohol and Cancer
•  Lung Cancer
•  Oropharyngeal Cancer
• Hematologic Cancers

Federal Practitioner and AVAHO would like to thank the following experts for their contributions to this issue:

Anita Aggarwal, DO, PhD; Sara Ahmed, PhD; Katherine Faricy-Anderson, MD; Apar Kishor Ganti, MD, MS; Solomon A Graf, MD; Kate Hendricks Thomas, PhD; Michael Kelley, MD; Mark Klein, MD, Gina McWhirter, MSN, MBA, RN; Bruce Montgomery, MD; Vida Almario Passero, MD, MBA; Thomas D Rodgers, MD; Vlad C Sandulache, MD, PhD; David H Wang, MD, PhD.

Is this the most controversial topic in breast oncology? Quite likely: the results of a recent online poll show split votes and no consensus.

The topic is the use of chemotherapy for premenopausal women with early-stage hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer.

Is the use of chemo in this patient population merely a “graceless” means of achieving ovarian function suppression, as one expert argued in a recent debate?

Or does it offer a distinct cytotoxic benefit, as the other expert countered?

The debate was held during the recent San Antonio Breast Cancer Symposium (SABCS), at which new results were presented that increased the controversy.

The controversy had arisen the previous year over results from the RxPONDER trial.

Five-year follow-up data from RxPONDER showed that adding chemotherapy to endocrine therapy did not improve outcomes over endocrine therapy alone for postmenopausal women with low-risk, node-positive HR+, HER2- breast cancer. This suggests that older women with early-stage breast cancer may safely forgo chemotherapy.

However, the same trial included premenopausal women with the same disease profile, and the results in this subgroup showed that there was benefit from chemotherapy, with a 5-year invasive disease-free survival (IDFS) rate of 94.2%, versus 89.0% for endocrine therapy alone (P = .0004).

The results were immediately controversial.

Some experts suggested the effect was due to the chemotherapy incidentally causing ovarian suppression, not the cytotoxic effect of the drugs on cancer cells. These experts were skeptical about the suggestion that chemotherapy works differently in premenopausal women than it does in postmenopausal women.

Some clinicians feel the lack of clarity creates an opportunity for greater discussion with women when making the treatment decision.

“When I have this conversation with patients, it’s really nuanced,” Stephanie L. Graff, MD, director of breast oncology, Lifespan Cancer Institute, Providence, R.I., told this news organization.

“I would choose chemotherapy for myself, but I’m a chemotherapy doctor, so I’m very comfortable with these medications and their side effects, and I am also very familiar with the slow burn of the side effects of endocrine therapy,” she said.

But for patients who are hearing their options for the first time, the idea of chemotherapy “feels scary,” and there is “a lot of stigma” associated with it, she commented.

Ultimately, she believes in offering patients as much information as possible, inasmuch as “knowledge is power.”

For Dr. Graff, the message from RxPONDER was that, in premenopausal patients with lymph node positive, HR+ breast cancer, “all comers benefited from chemotherapy.”

“And so if the goal is to be maximally aggressive and optimally lower your risk of distant recurrence, which is a life-threatening event, chemotherapy should offered.”

But chemotherapy comes with side effects, so it’s an important conversation to have with patients; RxPONDER showed that the absolute difference in the rate of distant recurrence with chemotherapy was relatively minor, she added.
 

Debate rages on

The debate at SABCS was moderated by Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute, Boston, who commented that if this was “a compelling question last week in clinic, it has now become red hot.”

At the meeting, held in December 2021, new longer-term data from the SOFT and TEXT clinical trials were presented, showing that ovarian suppression with tamoxifen plus an aromatase inhibitor provides a greater reduction in long-term risk of recurrence than tamoxifen alone.

Moreover, updated results from RxPONDER presented at the same session revealed that chemoendocrine therapy was associated with longer IDFS and distant relapse-free survival than endocrine therapy alone for women with one to three positive lymph nodes and a recurrence score of 25 or lower on the Oncotype DX (Genomic Health) 21-gene breast cancer assay.

Dr. Burstein said the debate over the use of chemotherapy in premenopausal women “is the most interesting question right now in early-stage breast cancer.”

The debate focused on the effect of chemotherapy in these patients – was it all down to ovarian function suppression?

Yes, argued Michael Gnant, MD, from the Medical University of Vienna.

Data from “modern adjuvant chemotherapy trials” suggest that chemo offers a 2%-3% benefit in distant disease-free survival at 5 years for premenopausal women, he noted. But the effect is much larger with ovarian function suppression via endocrine therapy, which provides 5-year disease-free and overall survival benefits of 9%-13%.

Older studies have shown that the benefit with chemotherapy is seen only in women who experience amenorrhea with the cytotoxic drugs, Dr. Gnant noted.

“In short, if you give adjuvant chemotherapy and you induce amenorrhea, then there is going to be a survival difference,” he said. “But if you give adjuvant chemotherapy and there is no amenorrhea, there won’t be an outcome difference.”

The ABSCG-05 trial, which compared endocrine therapy with chemotherapy, showed that “in the presence of optimal endocrine adjuvant treatment, adjuvant chemotherapy doesn’t add anything, because you have already achieved the effect of treatment-induced amenorrhea.”

So Dr. Gnant argued that the effect of chemotherapy in RxPONDER was due to ovarian function suppression.

But the real question is: “What does it mean for clinical practice?”

Dr. Gnant asserted that for the “large group of lower-risk premenopausal patients, tamoxifen will be good enough,” while those at moderate or intermediate risk should receive ovarian function suppression with either tamoxifen or an aromatase inhibitor, with the choice dictated by their adverse effects.

Chemotherapy “is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine nonresponsive disease,” he argued.

On the other side of the debate, Sibylle Loibl, MD, PhD, from the Centre of Hematology and Oncology, Bethanien, Frankfurt, argued that the effect is not all due to ovarian function suppression and that chemotherapy also has a cytotoxic effect in these patients.

“We need chemotherapy” because “cancer in young women is biologically different,” she asserted.

Dr. Loibl pointed to data currently awaiting publication in the Journal of the National Cancer Institute that suggest that younger women have “higher immune gene expression” that may make them more chemotherapy sensitive, and lower expression of hormone receptor genes, which “could make them less endocrine sensitive.”

She also cited data from a study from her own group that showed that pathologic complete response rates to neoadjuvant chemotherapy were higher in younger women with HR+, HER2- breast cancer, indicating a direct effect of chemotherapy on the disease and that age was an important prognostic factor.

The data on the induction of amenorrhea by chemotherapy is also not as clearcut as it seems, she commented. Chemotherapy does not achieve 100% amenorrhea, and gonadotropin-releasing hormone analogues are unable to suppress ovarian function in 20% of women.

Dr. Loibl concluded that the “chemotherapy effect is there, it is higher in young women with HR+, HER2- breast cancer,” and that the effect has two components.

“There is a direct cytotoxic effect which cannot be neglected, and there is an endocrine effect on the ovarian function suppression,” she argued.

“I think both are needed in young premenopausal patients,” she added.
 

Audience responses

After the debate, the audience was polled on what effect they thought chemotherapy was having in lower-risk HR+, HER2- breast cancer patients. About two-thirds responded that it was all or mostly due to ovarian function suppression.

However, the next question split the audience. They were presented with a clinical scenario: a 43-year-old woman with a mammographically detected 1.4-cm, intermediate grade, HR+, HER2- breast cancer who also had metastatic disease in one of three sentinel lymph nodes and whose recurrence score was 13.

When asked about the treatment plan they would choose for this patient, the audience was split over whether to opt for chemoendocrine therapy or endocrine therapy alone.

A similar clinical question was posited recently on Twitter, when Angela Toss, MD, PhD, from the University of Modena and Reggio Emilia, Italy, asked respondents which they would chose from among three options.

From the 815 votes that were cast, 46% chose Oncotype DX testing to determine the likely benefit of chemotherapy, 48% chose chemotherapy, and 6% picked ovarian function suppression and an aromatase inhibitor.

In response, Paolo Tarantino, MD, from the Dana-Farber Cancer Institute, commented: “If you had any doubt of which is the most controversial topic in breast oncology, doubt no more. 815 votes, no consensus.”

Approached for comment, Eric Winer, MD, director of the Yale Cancer Center, New Haven, Conn., said that the data from RxPONDER “in many ways was helpful, but ... it created about as many questions as it answered, if not more.”

Because the results showed a benefit from chemotherapy for premenopausal women but not for postmenopausal women with breast cancer, Dr. Winer told this news organization that one of the outstanding questions is “whether premenopausal women are fundamentally different from postmenopausal women ... and my answer to that is that is very unlikely.”

Dr. Winer added that the “real tragedy” of this trial was that it did not include women with more than three positive nodes, particularly those who have a low recurrence score, he said.

Clinicians are therefore left either “extrapolating” data from those with fewer nodes or “marching down a path that we’ve taken for years of just giving those people chemotherapy routinely,” even though there may be no benefit, Dr. Winer commented.

Another expert who was approached for comment had a different take on the data. Matteo Lambertini, MD, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, agreed with Loibl’s argument that chemotherapy has a cytotoxic effect in premenopausal women with HR+, HER2- breast cancer in addition to its effect on ovarian function suppression.

He did not agree, however, that there is a question mark over what to do for patients with more than three positive lymph nodes.

Dr. Lambertini said in an interview that he thinks “too much” trust is placed in genomic testing and that there is a “risk of forgetting about all the other factors that we normally use to make our treatment choices.”

A patient with five positive nodes will benefit from chemotherapy, “even if she had a very low recurrence score,” he said, “because there is a very high clinical risk of disease recurrence,” and chemotherapy “is of benefit” in these situations, he asserted.

Dr. Lambertini said that the RxPONDER results – and also studies such as TAILORx, which demonstrated the ability of Oncotype DX to identify which patients with early breast cancer could skip chemotherapy – show that “chemotherapy has a role to play” and that most patients should receive it.

He suggested, however, that “probably the benefit of chemotherapy is smaller” in real life than was seen in these trials, because in the trials, they did not use optimal adjuvant endocrine therapy.
 

Treating individual patients

When it comes to making treatment decisions for individual patients, Dr. Winer said he has a “conversation with people about what the results of the study showed and what [he believes] that they need.”

For patients whose Oncotype DX score is in the “very low range, I do not recommend chemotherapy,” he said, preferring instead to use endocrine therapy for ovarian function suppression.

For women with a more intermediate score, “I explain that I don’t think we have an answer and that, if they would want to take the most traditional and conservative path, it would be to get chemotherapy.

“But I’m certainly not rigid about my recommendations, and I’m particularly open” to ovarian function suppression for a premenopausal woman with an Onctyope DX score of 20 and two positive nodes who does not have “other adverse features.”

“Ultimately, what pushes me in one direction or another,” Dr. Winer said, aside from number of positive nodes or the size of the tumor, “is the patient’s preferences.”

This was a theme taken up by Kim Sabelko, PhD, vice-president of scientific strategy and programs at Susan G. Komen, Dallas.

The results from RxPONDER and similar studies are “really interesting,” as researchers are “working out how to individualize treatment,” and that it is not a matter of “one size fits all.”

“We need to understand when to use chemotherapy and other drugs, and more importantly, when not to, because we don’t want to overtreat people who don’t necessarily need these drugs,” she commented.

Dr. Sabelko emphasized that treatment decisions “should be shared” between the patient and their doctor, and she noted that there “will be some people who are going to refuse chemotherapy for different reasons.”

These clinical trial results help clinicians to explain the risks and benefits of treatment options, but the treatment decision should be taken “together” with the patient, she emphasized.

Dr. Gnant has relationships with Sandoz, Amge, Daiichi Sankyo, AstraZeneca, Eli Lilly, Nanostring, Novartis, Pierre Fabre, TLC Pharmaceuticals, and Life Brain. Dr. Loibl has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Meyers Squibb, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Medscape, Puma, Roche, Samsung, Seagen, VM Scope, and GBG Forschungs.

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

Is this the most controversial topic in breast oncology? Quite likely: the results of a recent online poll show split votes and no consensus.

The topic is the use of chemotherapy for premenopausal women with early-stage hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer.

Is the use of chemo in this patient population merely a “graceless” means of achieving ovarian function suppression, as one expert argued in a recent debate?

Or does it offer a distinct cytotoxic benefit, as the other expert countered?

The debate was held during the recent San Antonio Breast Cancer Symposium (SABCS), at which new results were presented that increased the controversy.

The controversy had arisen the previous year over results from the RxPONDER trial.

Five-year follow-up data from RxPONDER showed that adding chemotherapy to endocrine therapy did not improve outcomes over endocrine therapy alone for postmenopausal women with low-risk, node-positive HR+, HER2- breast cancer. This suggests that older women with early-stage breast cancer may safely forgo chemotherapy.

However, the same trial included premenopausal women with the same disease profile, and the results in this subgroup showed that there was benefit from chemotherapy, with a 5-year invasive disease-free survival (IDFS) rate of 94.2%, versus 89.0% for endocrine therapy alone (P = .0004).

The results were immediately controversial.

Some experts suggested the effect was due to the chemotherapy incidentally causing ovarian suppression, not the cytotoxic effect of the drugs on cancer cells. These experts were skeptical about the suggestion that chemotherapy works differently in premenopausal women than it does in postmenopausal women.

Some clinicians feel the lack of clarity creates an opportunity for greater discussion with women when making the treatment decision.

“When I have this conversation with patients, it’s really nuanced,” Stephanie L. Graff, MD, director of breast oncology, Lifespan Cancer Institute, Providence, R.I., told this news organization.

“I would choose chemotherapy for myself, but I’m a chemotherapy doctor, so I’m very comfortable with these medications and their side effects, and I am also very familiar with the slow burn of the side effects of endocrine therapy,” she said.

But for patients who are hearing their options for the first time, the idea of chemotherapy “feels scary,” and there is “a lot of stigma” associated with it, she commented.

Ultimately, she believes in offering patients as much information as possible, inasmuch as “knowledge is power.”

For Dr. Graff, the message from RxPONDER was that, in premenopausal patients with lymph node positive, HR+ breast cancer, “all comers benefited from chemotherapy.”

“And so if the goal is to be maximally aggressive and optimally lower your risk of distant recurrence, which is a life-threatening event, chemotherapy should offered.”

But chemotherapy comes with side effects, so it’s an important conversation to have with patients; RxPONDER showed that the absolute difference in the rate of distant recurrence with chemotherapy was relatively minor, she added.
 

Debate rages on

The debate at SABCS was moderated by Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute, Boston, who commented that if this was “a compelling question last week in clinic, it has now become red hot.”

At the meeting, held in December 2021, new longer-term data from the SOFT and TEXT clinical trials were presented, showing that ovarian suppression with tamoxifen plus an aromatase inhibitor provides a greater reduction in long-term risk of recurrence than tamoxifen alone.

Moreover, updated results from RxPONDER presented at the same session revealed that chemoendocrine therapy was associated with longer IDFS and distant relapse-free survival than endocrine therapy alone for women with one to three positive lymph nodes and a recurrence score of 25 or lower on the Oncotype DX (Genomic Health) 21-gene breast cancer assay.

Dr. Burstein said the debate over the use of chemotherapy in premenopausal women “is the most interesting question right now in early-stage breast cancer.”

The debate focused on the effect of chemotherapy in these patients – was it all down to ovarian function suppression?

Yes, argued Michael Gnant, MD, from the Medical University of Vienna.

Data from “modern adjuvant chemotherapy trials” suggest that chemo offers a 2%-3% benefit in distant disease-free survival at 5 years for premenopausal women, he noted. But the effect is much larger with ovarian function suppression via endocrine therapy, which provides 5-year disease-free and overall survival benefits of 9%-13%.

Older studies have shown that the benefit with chemotherapy is seen only in women who experience amenorrhea with the cytotoxic drugs, Dr. Gnant noted.

“In short, if you give adjuvant chemotherapy and you induce amenorrhea, then there is going to be a survival difference,” he said. “But if you give adjuvant chemotherapy and there is no amenorrhea, there won’t be an outcome difference.”

The ABSCG-05 trial, which compared endocrine therapy with chemotherapy, showed that “in the presence of optimal endocrine adjuvant treatment, adjuvant chemotherapy doesn’t add anything, because you have already achieved the effect of treatment-induced amenorrhea.”

So Dr. Gnant argued that the effect of chemotherapy in RxPONDER was due to ovarian function suppression.

But the real question is: “What does it mean for clinical practice?”

Dr. Gnant asserted that for the “large group of lower-risk premenopausal patients, tamoxifen will be good enough,” while those at moderate or intermediate risk should receive ovarian function suppression with either tamoxifen or an aromatase inhibitor, with the choice dictated by their adverse effects.

Chemotherapy “is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine nonresponsive disease,” he argued.

On the other side of the debate, Sibylle Loibl, MD, PhD, from the Centre of Hematology and Oncology, Bethanien, Frankfurt, argued that the effect is not all due to ovarian function suppression and that chemotherapy also has a cytotoxic effect in these patients.

“We need chemotherapy” because “cancer in young women is biologically different,” she asserted.

Dr. Loibl pointed to data currently awaiting publication in the Journal of the National Cancer Institute that suggest that younger women have “higher immune gene expression” that may make them more chemotherapy sensitive, and lower expression of hormone receptor genes, which “could make them less endocrine sensitive.”

She also cited data from a study from her own group that showed that pathologic complete response rates to neoadjuvant chemotherapy were higher in younger women with HR+, HER2- breast cancer, indicating a direct effect of chemotherapy on the disease and that age was an important prognostic factor.

The data on the induction of amenorrhea by chemotherapy is also not as clearcut as it seems, she commented. Chemotherapy does not achieve 100% amenorrhea, and gonadotropin-releasing hormone analogues are unable to suppress ovarian function in 20% of women.

Dr. Loibl concluded that the “chemotherapy effect is there, it is higher in young women with HR+, HER2- breast cancer,” and that the effect has two components.

“There is a direct cytotoxic effect which cannot be neglected, and there is an endocrine effect on the ovarian function suppression,” she argued.

“I think both are needed in young premenopausal patients,” she added.
 

Audience responses

After the debate, the audience was polled on what effect they thought chemotherapy was having in lower-risk HR+, HER2- breast cancer patients. About two-thirds responded that it was all or mostly due to ovarian function suppression.

However, the next question split the audience. They were presented with a clinical scenario: a 43-year-old woman with a mammographically detected 1.4-cm, intermediate grade, HR+, HER2- breast cancer who also had metastatic disease in one of three sentinel lymph nodes and whose recurrence score was 13.

When asked about the treatment plan they would choose for this patient, the audience was split over whether to opt for chemoendocrine therapy or endocrine therapy alone.

A similar clinical question was posited recently on Twitter, when Angela Toss, MD, PhD, from the University of Modena and Reggio Emilia, Italy, asked respondents which they would chose from among three options.

From the 815 votes that were cast, 46% chose Oncotype DX testing to determine the likely benefit of chemotherapy, 48% chose chemotherapy, and 6% picked ovarian function suppression and an aromatase inhibitor.

In response, Paolo Tarantino, MD, from the Dana-Farber Cancer Institute, commented: “If you had any doubt of which is the most controversial topic in breast oncology, doubt no more. 815 votes, no consensus.”

Approached for comment, Eric Winer, MD, director of the Yale Cancer Center, New Haven, Conn., said that the data from RxPONDER “in many ways was helpful, but ... it created about as many questions as it answered, if not more.”

Because the results showed a benefit from chemotherapy for premenopausal women but not for postmenopausal women with breast cancer, Dr. Winer told this news organization that one of the outstanding questions is “whether premenopausal women are fundamentally different from postmenopausal women ... and my answer to that is that is very unlikely.”

Dr. Winer added that the “real tragedy” of this trial was that it did not include women with more than three positive nodes, particularly those who have a low recurrence score, he said.

Clinicians are therefore left either “extrapolating” data from those with fewer nodes or “marching down a path that we’ve taken for years of just giving those people chemotherapy routinely,” even though there may be no benefit, Dr. Winer commented.

Another expert who was approached for comment had a different take on the data. Matteo Lambertini, MD, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, agreed with Loibl’s argument that chemotherapy has a cytotoxic effect in premenopausal women with HR+, HER2- breast cancer in addition to its effect on ovarian function suppression.

He did not agree, however, that there is a question mark over what to do for patients with more than three positive lymph nodes.

Dr. Lambertini said in an interview that he thinks “too much” trust is placed in genomic testing and that there is a “risk of forgetting about all the other factors that we normally use to make our treatment choices.”

A patient with five positive nodes will benefit from chemotherapy, “even if she had a very low recurrence score,” he said, “because there is a very high clinical risk of disease recurrence,” and chemotherapy “is of benefit” in these situations, he asserted.

Dr. Lambertini said that the RxPONDER results – and also studies such as TAILORx, which demonstrated the ability of Oncotype DX to identify which patients with early breast cancer could skip chemotherapy – show that “chemotherapy has a role to play” and that most patients should receive it.

He suggested, however, that “probably the benefit of chemotherapy is smaller” in real life than was seen in these trials, because in the trials, they did not use optimal adjuvant endocrine therapy.
 

Treating individual patients

When it comes to making treatment decisions for individual patients, Dr. Winer said he has a “conversation with people about what the results of the study showed and what [he believes] that they need.”

For patients whose Oncotype DX score is in the “very low range, I do not recommend chemotherapy,” he said, preferring instead to use endocrine therapy for ovarian function suppression.

For women with a more intermediate score, “I explain that I don’t think we have an answer and that, if they would want to take the most traditional and conservative path, it would be to get chemotherapy.

“But I’m certainly not rigid about my recommendations, and I’m particularly open” to ovarian function suppression for a premenopausal woman with an Onctyope DX score of 20 and two positive nodes who does not have “other adverse features.”

“Ultimately, what pushes me in one direction or another,” Dr. Winer said, aside from number of positive nodes or the size of the tumor, “is the patient’s preferences.”

This was a theme taken up by Kim Sabelko, PhD, vice-president of scientific strategy and programs at Susan G. Komen, Dallas.

The results from RxPONDER and similar studies are “really interesting,” as researchers are “working out how to individualize treatment,” and that it is not a matter of “one size fits all.”

“We need to understand when to use chemotherapy and other drugs, and more importantly, when not to, because we don’t want to overtreat people who don’t necessarily need these drugs,” she commented.

Dr. Sabelko emphasized that treatment decisions “should be shared” between the patient and their doctor, and she noted that there “will be some people who are going to refuse chemotherapy for different reasons.”

These clinical trial results help clinicians to explain the risks and benefits of treatment options, but the treatment decision should be taken “together” with the patient, she emphasized.

Dr. Gnant has relationships with Sandoz, Amge, Daiichi Sankyo, AstraZeneca, Eli Lilly, Nanostring, Novartis, Pierre Fabre, TLC Pharmaceuticals, and Life Brain. Dr. Loibl has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Meyers Squibb, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Medscape, Puma, Roche, Samsung, Seagen, VM Scope, and GBG Forschungs.

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

Is this the most controversial topic in breast oncology? Quite likely: the results of a recent online poll show split votes and no consensus.

The topic is the use of chemotherapy for premenopausal women with early-stage hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer.

Is the use of chemo in this patient population merely a “graceless” means of achieving ovarian function suppression, as one expert argued in a recent debate?

Or does it offer a distinct cytotoxic benefit, as the other expert countered?

The debate was held during the recent San Antonio Breast Cancer Symposium (SABCS), at which new results were presented that increased the controversy.

The controversy had arisen the previous year over results from the RxPONDER trial.

Five-year follow-up data from RxPONDER showed that adding chemotherapy to endocrine therapy did not improve outcomes over endocrine therapy alone for postmenopausal women with low-risk, node-positive HR+, HER2- breast cancer. This suggests that older women with early-stage breast cancer may safely forgo chemotherapy.

However, the same trial included premenopausal women with the same disease profile, and the results in this subgroup showed that there was benefit from chemotherapy, with a 5-year invasive disease-free survival (IDFS) rate of 94.2%, versus 89.0% for endocrine therapy alone (P = .0004).

The results were immediately controversial.

Some experts suggested the effect was due to the chemotherapy incidentally causing ovarian suppression, not the cytotoxic effect of the drugs on cancer cells. These experts were skeptical about the suggestion that chemotherapy works differently in premenopausal women than it does in postmenopausal women.

Some clinicians feel the lack of clarity creates an opportunity for greater discussion with women when making the treatment decision.

“When I have this conversation with patients, it’s really nuanced,” Stephanie L. Graff, MD, director of breast oncology, Lifespan Cancer Institute, Providence, R.I., told this news organization.

“I would choose chemotherapy for myself, but I’m a chemotherapy doctor, so I’m very comfortable with these medications and their side effects, and I am also very familiar with the slow burn of the side effects of endocrine therapy,” she said.

But for patients who are hearing their options for the first time, the idea of chemotherapy “feels scary,” and there is “a lot of stigma” associated with it, she commented.

Ultimately, she believes in offering patients as much information as possible, inasmuch as “knowledge is power.”

For Dr. Graff, the message from RxPONDER was that, in premenopausal patients with lymph node positive, HR+ breast cancer, “all comers benefited from chemotherapy.”

“And so if the goal is to be maximally aggressive and optimally lower your risk of distant recurrence, which is a life-threatening event, chemotherapy should offered.”

But chemotherapy comes with side effects, so it’s an important conversation to have with patients; RxPONDER showed that the absolute difference in the rate of distant recurrence with chemotherapy was relatively minor, she added.
 

Debate rages on

The debate at SABCS was moderated by Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute, Boston, who commented that if this was “a compelling question last week in clinic, it has now become red hot.”

At the meeting, held in December 2021, new longer-term data from the SOFT and TEXT clinical trials were presented, showing that ovarian suppression with tamoxifen plus an aromatase inhibitor provides a greater reduction in long-term risk of recurrence than tamoxifen alone.

Moreover, updated results from RxPONDER presented at the same session revealed that chemoendocrine therapy was associated with longer IDFS and distant relapse-free survival than endocrine therapy alone for women with one to three positive lymph nodes and a recurrence score of 25 or lower on the Oncotype DX (Genomic Health) 21-gene breast cancer assay.

Dr. Burstein said the debate over the use of chemotherapy in premenopausal women “is the most interesting question right now in early-stage breast cancer.”

The debate focused on the effect of chemotherapy in these patients – was it all down to ovarian function suppression?

Yes, argued Michael Gnant, MD, from the Medical University of Vienna.

Data from “modern adjuvant chemotherapy trials” suggest that chemo offers a 2%-3% benefit in distant disease-free survival at 5 years for premenopausal women, he noted. But the effect is much larger with ovarian function suppression via endocrine therapy, which provides 5-year disease-free and overall survival benefits of 9%-13%.

Older studies have shown that the benefit with chemotherapy is seen only in women who experience amenorrhea with the cytotoxic drugs, Dr. Gnant noted.

“In short, if you give adjuvant chemotherapy and you induce amenorrhea, then there is going to be a survival difference,” he said. “But if you give adjuvant chemotherapy and there is no amenorrhea, there won’t be an outcome difference.”

The ABSCG-05 trial, which compared endocrine therapy with chemotherapy, showed that “in the presence of optimal endocrine adjuvant treatment, adjuvant chemotherapy doesn’t add anything, because you have already achieved the effect of treatment-induced amenorrhea.”

So Dr. Gnant argued that the effect of chemotherapy in RxPONDER was due to ovarian function suppression.

But the real question is: “What does it mean for clinical practice?”

Dr. Gnant asserted that for the “large group of lower-risk premenopausal patients, tamoxifen will be good enough,” while those at moderate or intermediate risk should receive ovarian function suppression with either tamoxifen or an aromatase inhibitor, with the choice dictated by their adverse effects.

Chemotherapy “is just a graceless method of ovarian function suppression and should only be given to high-risk patients and to patients with endocrine nonresponsive disease,” he argued.

On the other side of the debate, Sibylle Loibl, MD, PhD, from the Centre of Hematology and Oncology, Bethanien, Frankfurt, argued that the effect is not all due to ovarian function suppression and that chemotherapy also has a cytotoxic effect in these patients.

“We need chemotherapy” because “cancer in young women is biologically different,” she asserted.

Dr. Loibl pointed to data currently awaiting publication in the Journal of the National Cancer Institute that suggest that younger women have “higher immune gene expression” that may make them more chemotherapy sensitive, and lower expression of hormone receptor genes, which “could make them less endocrine sensitive.”

She also cited data from a study from her own group that showed that pathologic complete response rates to neoadjuvant chemotherapy were higher in younger women with HR+, HER2- breast cancer, indicating a direct effect of chemotherapy on the disease and that age was an important prognostic factor.

The data on the induction of amenorrhea by chemotherapy is also not as clearcut as it seems, she commented. Chemotherapy does not achieve 100% amenorrhea, and gonadotropin-releasing hormone analogues are unable to suppress ovarian function in 20% of women.

Dr. Loibl concluded that the “chemotherapy effect is there, it is higher in young women with HR+, HER2- breast cancer,” and that the effect has two components.

“There is a direct cytotoxic effect which cannot be neglected, and there is an endocrine effect on the ovarian function suppression,” she argued.

“I think both are needed in young premenopausal patients,” she added.
 

Audience responses

After the debate, the audience was polled on what effect they thought chemotherapy was having in lower-risk HR+, HER2- breast cancer patients. About two-thirds responded that it was all or mostly due to ovarian function suppression.

However, the next question split the audience. They were presented with a clinical scenario: a 43-year-old woman with a mammographically detected 1.4-cm, intermediate grade, HR+, HER2- breast cancer who also had metastatic disease in one of three sentinel lymph nodes and whose recurrence score was 13.

When asked about the treatment plan they would choose for this patient, the audience was split over whether to opt for chemoendocrine therapy or endocrine therapy alone.

A similar clinical question was posited recently on Twitter, when Angela Toss, MD, PhD, from the University of Modena and Reggio Emilia, Italy, asked respondents which they would chose from among three options.

From the 815 votes that were cast, 46% chose Oncotype DX testing to determine the likely benefit of chemotherapy, 48% chose chemotherapy, and 6% picked ovarian function suppression and an aromatase inhibitor.

In response, Paolo Tarantino, MD, from the Dana-Farber Cancer Institute, commented: “If you had any doubt of which is the most controversial topic in breast oncology, doubt no more. 815 votes, no consensus.”

Approached for comment, Eric Winer, MD, director of the Yale Cancer Center, New Haven, Conn., said that the data from RxPONDER “in many ways was helpful, but ... it created about as many questions as it answered, if not more.”

Because the results showed a benefit from chemotherapy for premenopausal women but not for postmenopausal women with breast cancer, Dr. Winer told this news organization that one of the outstanding questions is “whether premenopausal women are fundamentally different from postmenopausal women ... and my answer to that is that is very unlikely.”

Dr. Winer added that the “real tragedy” of this trial was that it did not include women with more than three positive nodes, particularly those who have a low recurrence score, he said.

Clinicians are therefore left either “extrapolating” data from those with fewer nodes or “marching down a path that we’ve taken for years of just giving those people chemotherapy routinely,” even though there may be no benefit, Dr. Winer commented.

Another expert who was approached for comment had a different take on the data. Matteo Lambertini, MD, IRCCS Ospedale Policlinico San Martino, Genoa, Italy, agreed with Loibl’s argument that chemotherapy has a cytotoxic effect in premenopausal women with HR+, HER2- breast cancer in addition to its effect on ovarian function suppression.

He did not agree, however, that there is a question mark over what to do for patients with more than three positive lymph nodes.

Dr. Lambertini said in an interview that he thinks “too much” trust is placed in genomic testing and that there is a “risk of forgetting about all the other factors that we normally use to make our treatment choices.”

A patient with five positive nodes will benefit from chemotherapy, “even if she had a very low recurrence score,” he said, “because there is a very high clinical risk of disease recurrence,” and chemotherapy “is of benefit” in these situations, he asserted.

Dr. Lambertini said that the RxPONDER results – and also studies such as TAILORx, which demonstrated the ability of Oncotype DX to identify which patients with early breast cancer could skip chemotherapy – show that “chemotherapy has a role to play” and that most patients should receive it.

He suggested, however, that “probably the benefit of chemotherapy is smaller” in real life than was seen in these trials, because in the trials, they did not use optimal adjuvant endocrine therapy.
 

Treating individual patients

When it comes to making treatment decisions for individual patients, Dr. Winer said he has a “conversation with people about what the results of the study showed and what [he believes] that they need.”

For patients whose Oncotype DX score is in the “very low range, I do not recommend chemotherapy,” he said, preferring instead to use endocrine therapy for ovarian function suppression.

For women with a more intermediate score, “I explain that I don’t think we have an answer and that, if they would want to take the most traditional and conservative path, it would be to get chemotherapy.

“But I’m certainly not rigid about my recommendations, and I’m particularly open” to ovarian function suppression for a premenopausal woman with an Onctyope DX score of 20 and two positive nodes who does not have “other adverse features.”

“Ultimately, what pushes me in one direction or another,” Dr. Winer said, aside from number of positive nodes or the size of the tumor, “is the patient’s preferences.”

This was a theme taken up by Kim Sabelko, PhD, vice-president of scientific strategy and programs at Susan G. Komen, Dallas.

The results from RxPONDER and similar studies are “really interesting,” as researchers are “working out how to individualize treatment,” and that it is not a matter of “one size fits all.”

“We need to understand when to use chemotherapy and other drugs, and more importantly, when not to, because we don’t want to overtreat people who don’t necessarily need these drugs,” she commented.

Dr. Sabelko emphasized that treatment decisions “should be shared” between the patient and their doctor, and she noted that there “will be some people who are going to refuse chemotherapy for different reasons.”

These clinical trial results help clinicians to explain the risks and benefits of treatment options, but the treatment decision should be taken “together” with the patient, she emphasized.

Dr. Gnant has relationships with Sandoz, Amge, Daiichi Sankyo, AstraZeneca, Eli Lilly, Nanostring, Novartis, Pierre Fabre, TLC Pharmaceuticals, and Life Brain. Dr. Loibl has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Meyers Squibb, Celgene, Daiichi Sankyo, Eirgenix, GSK, Gilead, Lilly, Merck, Novartis, Pfizer, Pierre Fabre, Medscape, Puma, Roche, Samsung, Seagen, VM Scope, and GBG Forschungs.

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

Breast cancer screening modality has less effect on the probability of false-positive results than screening interval, patient age, and breast density according to a new study comparing digital breast tomosynthesis (DBT) with digital mammography.

Although DBT was associated with a modest improvement in recalls for false-positive results compared with mammography, about half of women in both groups received at least one false-positive result over a 10-year period of annual screening, reported senior author Diana L. Miglioretti, PhD, from the University of California, Davis, and colleagues.

By contrast, the authors reported “substantial reductions” in false-positive recalls with biennial screening. Specifically, while annual mammography and DBT resulted in cumulative 10-year false-positive recall rates of 56.3% and 49.6% respectively, biennial rates were 38.1% and 35.7%.

The comparative effectiveness study, published in JAMA Network Open, included 903,495 women who underwent 10 years of breast cancer screening at 126 radiology facilities in the Breast Cancer Surveillance Consortium. The mean age of participants was 57.6 years, and 46% of them had dense breasts. A total of 2,969,055 screening exams were performed (15% DBT), with each woman receiving a mean of 3.3 exams over 10 years. Most participants (71.8%) had annual exams, while 16.8% had biennial, with the remainder being performed at intervals of 3 years or more.

Investigators looked at the cumulative rate of three kinds of false-positive results over 10 years: false-positive recalls for further imaging, false-positive short-interval follow-up recommendations, and false-positive biopsy recommendations. A result was considered false positive if there was no diagnosis of invasive carcinoma or ductal carcinoma in situ within 1 year of the screening examination and before the next screening examination.

Overall, across all screening intervals, and after adjusting for age and breast density, the percentage of false-positive results was slightly lower for DBT vs. mammography: 7.6% vs. 9.0%, respectively, for false-positive recalls; 1.8% vs. 2.1%, respectively, for false-positive short-interval follow-up recommendations; and 1.1% vs. 1.2% for false-positive biopsy recommendations. “We did not observe consistent clinically meaningful differences in the cumulative probabilities of false-positive short-interval follow-up or biopsy recommendation by screening modality,” they noted, adding that, although DBT provided “modest” reductions in false-positive recalls, compared with mammography (2.4% less for biennial screening and 6.7% less for annual screening), “nonetheless, this percentage equates to many thousands of individuals in absolute numbers, especially for annual screening, which is the dominant practice in the U.S.”

The authors also noted that, regardless of screening modality, all three types of false-positive results were substantially lower for biennial versus annual mammograph, and depended on age and breast density. The highest cumulative rates of false-positive results occurred in women aged 40-49 years (68.0% with annual digital mammography and 60.8% with annual DBT). Women with extremely dense breasts had the highest probability of all three types of false positive, which “may be due to the lack of interspersed fat within dense fibroglandular tissue, with the contrast between the fat and tissue being a requirement for more accurate detection of suspicious features by interpreting radiologists.”

The study findings “offer new information about the potential harms of repeated screening, which may be used to inform screening guidelines and decision-making between individuals and their physicians. However, it is important to weigh these and other potential harms with potential benefits of earlier diagnosis. … Women at high risk of an advanced cancer under biennial screening, including some women with dense breasts, may reduce their risk with annual screening,” they suggested.

Although DBT is now widely used in the United States, amid growing optimism about its superiority over digital mammography, this study reminds clinicians to counsel patients appropriately, according to Lydia E. Pace, MD, from Brigham and Women’s Hospital in Boston. “Unfortunately, the growing availability of DBT does not substantially change the likelihood that women will experience a false-positive result over years of regular mammograms,” she wrote in an invited commentary published with the study. She noted that, although many women tolerate false-positive results, “they are associated with at least transient anxiety as well as time, inconvenience, and expense. More information is needed to understand the association of DBT with overdiagnosis, which is the more clinically important harm of screening.”

The study was funded by the National Cancer Institute. Dr. Miglioretti and Dr. Pace reported no conflicts of interest. One coauthor of the study is an unpaid consultant for Grail, for the STRIVE study, and another coauthor receives personal fees from Grail for work on a data safety monitoring board. No other disclosures were reported.

Breast cancer screening modality has less effect on the probability of false-positive results than screening interval, patient age, and breast density according to a new study comparing digital breast tomosynthesis (DBT) with digital mammography.

Although DBT was associated with a modest improvement in recalls for false-positive results compared with mammography, about half of women in both groups received at least one false-positive result over a 10-year period of annual screening, reported senior author Diana L. Miglioretti, PhD, from the University of California, Davis, and colleagues.

By contrast, the authors reported “substantial reductions” in false-positive recalls with biennial screening. Specifically, while annual mammography and DBT resulted in cumulative 10-year false-positive recall rates of 56.3% and 49.6% respectively, biennial rates were 38.1% and 35.7%.

The comparative effectiveness study, published in JAMA Network Open, included 903,495 women who underwent 10 years of breast cancer screening at 126 radiology facilities in the Breast Cancer Surveillance Consortium. The mean age of participants was 57.6 years, and 46% of them had dense breasts. A total of 2,969,055 screening exams were performed (15% DBT), with each woman receiving a mean of 3.3 exams over 10 years. Most participants (71.8%) had annual exams, while 16.8% had biennial, with the remainder being performed at intervals of 3 years or more.

Investigators looked at the cumulative rate of three kinds of false-positive results over 10 years: false-positive recalls for further imaging, false-positive short-interval follow-up recommendations, and false-positive biopsy recommendations. A result was considered false positive if there was no diagnosis of invasive carcinoma or ductal carcinoma in situ within 1 year of the screening examination and before the next screening examination.

Overall, across all screening intervals, and after adjusting for age and breast density, the percentage of false-positive results was slightly lower for DBT vs. mammography: 7.6% vs. 9.0%, respectively, for false-positive recalls; 1.8% vs. 2.1%, respectively, for false-positive short-interval follow-up recommendations; and 1.1% vs. 1.2% for false-positive biopsy recommendations. “We did not observe consistent clinically meaningful differences in the cumulative probabilities of false-positive short-interval follow-up or biopsy recommendation by screening modality,” they noted, adding that, although DBT provided “modest” reductions in false-positive recalls, compared with mammography (2.4% less for biennial screening and 6.7% less for annual screening), “nonetheless, this percentage equates to many thousands of individuals in absolute numbers, especially for annual screening, which is the dominant practice in the U.S.”

The authors also noted that, regardless of screening modality, all three types of false-positive results were substantially lower for biennial versus annual mammograph, and depended on age and breast density. The highest cumulative rates of false-positive results occurred in women aged 40-49 years (68.0% with annual digital mammography and 60.8% with annual DBT). Women with extremely dense breasts had the highest probability of all three types of false positive, which “may be due to the lack of interspersed fat within dense fibroglandular tissue, with the contrast between the fat and tissue being a requirement for more accurate detection of suspicious features by interpreting radiologists.”

The study findings “offer new information about the potential harms of repeated screening, which may be used to inform screening guidelines and decision-making between individuals and their physicians. However, it is important to weigh these and other potential harms with potential benefits of earlier diagnosis. … Women at high risk of an advanced cancer under biennial screening, including some women with dense breasts, may reduce their risk with annual screening,” they suggested.

Although DBT is now widely used in the United States, amid growing optimism about its superiority over digital mammography, this study reminds clinicians to counsel patients appropriately, according to Lydia E. Pace, MD, from Brigham and Women’s Hospital in Boston. “Unfortunately, the growing availability of DBT does not substantially change the likelihood that women will experience a false-positive result over years of regular mammograms,” she wrote in an invited commentary published with the study. She noted that, although many women tolerate false-positive results, “they are associated with at least transient anxiety as well as time, inconvenience, and expense. More information is needed to understand the association of DBT with overdiagnosis, which is the more clinically important harm of screening.”

The study was funded by the National Cancer Institute. Dr. Miglioretti and Dr. Pace reported no conflicts of interest. One coauthor of the study is an unpaid consultant for Grail, for the STRIVE study, and another coauthor receives personal fees from Grail for work on a data safety monitoring board. No other disclosures were reported.

Breast cancer screening modality has less effect on the probability of false-positive results than screening interval, patient age, and breast density according to a new study comparing digital breast tomosynthesis (DBT) with digital mammography.

Although DBT was associated with a modest improvement in recalls for false-positive results compared with mammography, about half of women in both groups received at least one false-positive result over a 10-year period of annual screening, reported senior author Diana L. Miglioretti, PhD, from the University of California, Davis, and colleagues.

By contrast, the authors reported “substantial reductions” in false-positive recalls with biennial screening. Specifically, while annual mammography and DBT resulted in cumulative 10-year false-positive recall rates of 56.3% and 49.6% respectively, biennial rates were 38.1% and 35.7%.

The comparative effectiveness study, published in JAMA Network Open, included 903,495 women who underwent 10 years of breast cancer screening at 126 radiology facilities in the Breast Cancer Surveillance Consortium. The mean age of participants was 57.6 years, and 46% of them had dense breasts. A total of 2,969,055 screening exams were performed (15% DBT), with each woman receiving a mean of 3.3 exams over 10 years. Most participants (71.8%) had annual exams, while 16.8% had biennial, with the remainder being performed at intervals of 3 years or more.

Investigators looked at the cumulative rate of three kinds of false-positive results over 10 years: false-positive recalls for further imaging, false-positive short-interval follow-up recommendations, and false-positive biopsy recommendations. A result was considered false positive if there was no diagnosis of invasive carcinoma or ductal carcinoma in situ within 1 year of the screening examination and before the next screening examination.

Overall, across all screening intervals, and after adjusting for age and breast density, the percentage of false-positive results was slightly lower for DBT vs. mammography: 7.6% vs. 9.0%, respectively, for false-positive recalls; 1.8% vs. 2.1%, respectively, for false-positive short-interval follow-up recommendations; and 1.1% vs. 1.2% for false-positive biopsy recommendations. “We did not observe consistent clinically meaningful differences in the cumulative probabilities of false-positive short-interval follow-up or biopsy recommendation by screening modality,” they noted, adding that, although DBT provided “modest” reductions in false-positive recalls, compared with mammography (2.4% less for biennial screening and 6.7% less for annual screening), “nonetheless, this percentage equates to many thousands of individuals in absolute numbers, especially for annual screening, which is the dominant practice in the U.S.”

The authors also noted that, regardless of screening modality, all three types of false-positive results were substantially lower for biennial versus annual mammograph, and depended on age and breast density. The highest cumulative rates of false-positive results occurred in women aged 40-49 years (68.0% with annual digital mammography and 60.8% with annual DBT). Women with extremely dense breasts had the highest probability of all three types of false positive, which “may be due to the lack of interspersed fat within dense fibroglandular tissue, with the contrast between the fat and tissue being a requirement for more accurate detection of suspicious features by interpreting radiologists.”

The study findings “offer new information about the potential harms of repeated screening, which may be used to inform screening guidelines and decision-making between individuals and their physicians. However, it is important to weigh these and other potential harms with potential benefits of earlier diagnosis. … Women at high risk of an advanced cancer under biennial screening, including some women with dense breasts, may reduce their risk with annual screening,” they suggested.

Although DBT is now widely used in the United States, amid growing optimism about its superiority over digital mammography, this study reminds clinicians to counsel patients appropriately, according to Lydia E. Pace, MD, from Brigham and Women’s Hospital in Boston. “Unfortunately, the growing availability of DBT does not substantially change the likelihood that women will experience a false-positive result over years of regular mammograms,” she wrote in an invited commentary published with the study. She noted that, although many women tolerate false-positive results, “they are associated with at least transient anxiety as well as time, inconvenience, and expense. More information is needed to understand the association of DBT with overdiagnosis, which is the more clinically important harm of screening.”

The study was funded by the National Cancer Institute. Dr. Miglioretti and Dr. Pace reported no conflicts of interest. One coauthor of the study is an unpaid consultant for Grail, for the STRIVE study, and another coauthor receives personal fees from Grail for work on a data safety monitoring board. No other disclosures were reported.

During a recent virtual medical malpractice trial, the judge called a break, and the participants left their screens. When the trial resumed a short time later, one juror was missing. The court called his phone, but there was no answer.

“Everyone had to keep waiting and waiting while the bailiff kept trying to call,” recalled Elizabeth Leedom, a medical malpractice defense attorney based in Seattle. “The juror fell asleep.”

The sleeping juror caused a significant delay in the trial, Ms. Leedom said. Finally, he woke up, and the trial was able to continue.

In another instance, a potential juror showed up drunk to a virtual jury selection. The man was slurring his words as he answered questions, Ms. Leedom said, and when asked if he was okay, he admitted that he had a drinking problem. The judge asked whether he had consumed alcohol, and the man admitted that he’d been drinking that day. He was excused from jury selection.

These alarming incidents are among the mishaps that happen during virtual medical malpractice trials. Since the pandemic started, many courts have moved to virtual settings to slow the spread of COVID-19. Although some courts have now shifted back to in-person trials, some areas continue to mandate virtual malpractice trials, hearings, and depositions.

Such trials can save money and are convenient, but legal experts say virtual trials present serious challenges for physicians and raise concerns about fairness. Some jurors are not taking virtual cases seriously or do not stay focused on the subject matter, according to attorneys.

“Virtual trials are not as fair to physicians as in-person trials,” said Andrew DeSimone, a medical malpractice defense attorney based in Lexington, Ky. “It’s too easy not to pay attention in a virtual setting. And when you are dealing with complex medical topics, juror attention is a paramount issue.”
 

Casual settings, constant interruptions during jury selections

Understanding and reaching the jury have been the greatest challenges with virtual and hybrid trials, said Laura Eschleman, a medical liability defense attorney based in Atlanta. Hybrid trials are part virtual and part in person.

Ms. Eschleman has participated in jury selections via Zoom in which jurors lounge in bed during the process and spouses and children waltz into the room as they please, she said.

“With over 36 Zoom boxes of potential jurors, assessing each potential juror was difficult to say the least,” she said. “[Jury selection] has always been an opportunity to introduce the defendant physicians to the jurors as humans; doing it virtually took that away. It is difficult to humanize a box on a screen.”

Regarding one virtual jury selection, Ms. Eschleman said the court had narrowed the pool to a final 12 jurors when one juror’s wife burst into his room and started yelling in front of his computer.

The judge allowed her to speak, and the crying woman begged the judge not to select her husband for the trial because it would disrupt the couple’s child care. After a lengthy exchange, they learned that the child was 16 years old and had his own car. The husband disagreed with his wife and wanted to remain a juror.

“This would have never happened had the twelfth juror been called to an in-person jury selection,” Ms. Eschleman said.

Keeping juries focused while the trial is underway can also be a problem, DeSimone said. He describes the courtroom during malpractice trials as a theater of sorts. Jurors watch intently as witnesses testify, evidence is presented, and the judge gives instructions. During virtual trials, however, watching through a screen doesn’t always yield the same captive audiences, he said.

“During Zoom, it’s much harder to connect with the jury because they won’t be as tuned into it,” he said. “If the jury believes the physician is empathetic, conscientious, caring, and compassionate, they will give the physician the benefit of the doubt, even if something went wrong or a bad outcome occurred. Developing that connection through good eye contact, being a teacher, and showing compassion is the most important thing a physician can do when testifying.”

A related challenge is that medical experts can’t connect as well with jurors, and some may have trouble conveying their message from a screen, said Evan Lyman, a medical malpractice defense attorney based in White Plains, N.Y.

“Some experts like to get out of the witness box and kind of take over the courtroom with a laser pointer or a white board,” he said. “For some, that’s what makes them effective experts. Some experts lose their touch when they can’t do that.”

Technical difficulties during virtual trials can cause further woes, said Kari Adams, vice president of claims for Physicians Insurance – A Mutual Company. She recalled a recent case in which technical problems arose during the defense attorney’s closing arguments.

“It’s hard to see our defense attorneys who are used to using all of their advocacy skills, all of their charisma trying to convey it in a virtual format,” she said. “When it’s disrupted, it can really throw things. A lot of their advocacy and personality can play through, but it’s just a little less in that forum.”
 

Doc fights against virtual trial

When Texas cardiologist Amin Al-Ahmad’s malpractice trial was changed to a virtual format because of COVID-19 concerns, Dr. Al-Ahmad and his attorneys fought the move.

They argued that the malpractice case was too complex for a virtual format and that a video trial would deprive Dr. Al-Ahmad of his rights to due process, including the right to trial by jury.

Dr. Al-Ahmad’s case involved allegations that he had failed to promptly diagnose and treat an atrial esophageal fistula, resulting in a patient’s stroke and ongoing neurologic problems. The trial was expected to last up to 10 days. Nine witnesses were expected to testify, and $1 million in damages were at stake, according to court documents.

“The length of trial anticipated, complexity of the medical issues, the confidential medical information at issue, and the number of anticipated medical records exhibits lead to a real risk of juror ‘Zoom fatigue,’ even if the trial is not interrupted with technology glitches, such as jurors dropping off the link or sound loss,” Dr. Al-Ahmad’s attorneys wrote in a petition to the Texas Supreme Court. “The risks of forcing [the defendants] to trial through the procedure of a remote or virtual jury trial are numerous. Not least of these is the risk that [defendants’] relators will be prevented from presenting an adequate defense or being able to fully preserve error during a virtual trial.”

Another concern regards the lack of uniformity from county to county in conducting a virtual trial, said David A. Wright, an attorney for Dr. Al-Ahmad. Some counties don’t permit them, while others permit parties to opt out of virtual trials, he noted.

“Even those that hold virtual trials seem to have different procedures and rules,” he said. “Travis County, where I have tried my virtual cases, has iPads that they provide to each juror so that they are limited to using just the county iPad for the trial. Others, I have heard, permit jurors to use their own devices. There are simply no uniform rules.”

Despite requests to the trial court and petitions to the appellate and Texas Supreme Court, Dr. Al-Ahmad lost his bid to have his trial delayed until in-person trials resumed. The Texas Supreme Court in late 2021 refused to halt the virtual trial.

Dr. Al-Ahmad, based in Austin, declined to comment through his attorney. Mr. Wright said the court’s denial “was not unexpected.”

Dr. Al-Ahmad’s virtual trial went forward in October 2021, and the jury ruled in his favor.

“We were very pleased with the jury’s verdict,” Mr. Wright said.
 

Are virtual trials ending in higher awards?

In addition to jurors’ not taking their roles as seriously, the casual vibe of virtual trials may also be diminishing how jurors view the verdict’s magnitude.

“Virtual trials don’t have the gravity or the seriousness of a real trial,” Ms. Leedom said. “I don’t think the importance of the jury’s decision weighs on them as much during a Zoom trial as it does an in-person trial.”

Alarmingly, Ms. Leedom said that, in her experience, damages in virtual trials have been higher in comparison with damages awarded during in-person trials.

Ms. Adams agreed with this observation.

“We’ll still win cases, but we’re concerned that, in the cases we lose, the damages can be slightly higher because there hasn’t been that interpersonal connection with the defendant,” she said. “It almost becomes like monopoly money to jurors.”
 

Remember these tips during virtual trials

Physicians undergoing virtual trials may have better experiences if they keep a few tips in mind.

Mr. DeSimone emphasized the importance of eye contact with jurors, which can be tricky during virtual settings. It helps if physicians look at the camera, rather than the screen, while talking.

Physicians should be cognizant of their facial expressions as they watch others speak.

“Don’t roll your eyes like: ‘Oh my gosh, he’s an idiot,’ ” Mr. DeSimone said. “Keep a poker face. Be respectful of what’s going on. Don’t be lulled into letting your guard down.”

Before the virtual trial, practice the cross examination and direct examination with your attorney and record it, Ms. Leedom said. That way, doctors can watch how they present on video and make necessary changes before the real trial. Lighting is also important, she noted. Her firm provides special lamps to clients and witnesses for virtual trials and proceedings.

“The lighting makes a huge difference,” she said.

Its also a good idea for physicians to have a paper copy of the records or exhibits that are going to be used so it’s easy for them to flip through them while on the screen. Physicians should also be mindful of how they come across during video depositions, which are sometimes played during virtual trials, Ms. Adams said.

“If you’re not looking professional during the video deposition – you’re eating, you’re not dressed well – the plaintiff’s attorney will take the most inopportune segment of the deposition and portray the physician as: ‘Look, here’s someone who was careless in the medical care, and look, they don’t even look professional when they’re testifying about this horrifying experience,’ ” she said. “They’ll use the clips to make a very careful provider appear distracted.”
 

Are virtual trials and hearings here to stay?

Whether virtual malpractice trials continue will largely depend on the location in which physicians practice. Some insurance carriers are opting to continue virtual trials, but in some areas, trials are being delayed until in-person proceedings can resume, Ms. Adams said. Some areas never adopted video trials and never ceased in-person trials.

“I think it’s going to be very regionally based,” she said. “Some of the smaller, rural counties just don’t have the capacity or the resources to continue, so they’ll probably just go back to in person.”

Not all virtual proceedings are problematic for physicians, say legal experts. Virtual depositions can be beneficial for doctors because they are less intimidating and confrontational than in-person depositions, Mr. Lyman said.

Additionally, virtual mediations can take much less time than in-person mediations, Ms. Adams said. Video depositions and mediations also save travel costs and reduce time missed from work for physicians.

“But I hope we all go back to in-person trials,” Ms. Leedom said. “Even here in King County, [Washington,] where we’ve done federal and state court trials by Zoom, I’m hopeful that it will go back to in-person trials.”

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

During a recent virtual medical malpractice trial, the judge called a break, and the participants left their screens. When the trial resumed a short time later, one juror was missing. The court called his phone, but there was no answer.

“Everyone had to keep waiting and waiting while the bailiff kept trying to call,” recalled Elizabeth Leedom, a medical malpractice defense attorney based in Seattle. “The juror fell asleep.”

The sleeping juror caused a significant delay in the trial, Ms. Leedom said. Finally, he woke up, and the trial was able to continue.

In another instance, a potential juror showed up drunk to a virtual jury selection. The man was slurring his words as he answered questions, Ms. Leedom said, and when asked if he was okay, he admitted that he had a drinking problem. The judge asked whether he had consumed alcohol, and the man admitted that he’d been drinking that day. He was excused from jury selection.

These alarming incidents are among the mishaps that happen during virtual medical malpractice trials. Since the pandemic started, many courts have moved to virtual settings to slow the spread of COVID-19. Although some courts have now shifted back to in-person trials, some areas continue to mandate virtual malpractice trials, hearings, and depositions.

Such trials can save money and are convenient, but legal experts say virtual trials present serious challenges for physicians and raise concerns about fairness. Some jurors are not taking virtual cases seriously or do not stay focused on the subject matter, according to attorneys.

“Virtual trials are not as fair to physicians as in-person trials,” said Andrew DeSimone, a medical malpractice defense attorney based in Lexington, Ky. “It’s too easy not to pay attention in a virtual setting. And when you are dealing with complex medical topics, juror attention is a paramount issue.”
 

Casual settings, constant interruptions during jury selections

Understanding and reaching the jury have been the greatest challenges with virtual and hybrid trials, said Laura Eschleman, a medical liability defense attorney based in Atlanta. Hybrid trials are part virtual and part in person.

Ms. Eschleman has participated in jury selections via Zoom in which jurors lounge in bed during the process and spouses and children waltz into the room as they please, she said.

“With over 36 Zoom boxes of potential jurors, assessing each potential juror was difficult to say the least,” she said. “[Jury selection] has always been an opportunity to introduce the defendant physicians to the jurors as humans; doing it virtually took that away. It is difficult to humanize a box on a screen.”

Regarding one virtual jury selection, Ms. Eschleman said the court had narrowed the pool to a final 12 jurors when one juror’s wife burst into his room and started yelling in front of his computer.

The judge allowed her to speak, and the crying woman begged the judge not to select her husband for the trial because it would disrupt the couple’s child care. After a lengthy exchange, they learned that the child was 16 years old and had his own car. The husband disagreed with his wife and wanted to remain a juror.

“This would have never happened had the twelfth juror been called to an in-person jury selection,” Ms. Eschleman said.

Keeping juries focused while the trial is underway can also be a problem, DeSimone said. He describes the courtroom during malpractice trials as a theater of sorts. Jurors watch intently as witnesses testify, evidence is presented, and the judge gives instructions. During virtual trials, however, watching through a screen doesn’t always yield the same captive audiences, he said.

“During Zoom, it’s much harder to connect with the jury because they won’t be as tuned into it,” he said. “If the jury believes the physician is empathetic, conscientious, caring, and compassionate, they will give the physician the benefit of the doubt, even if something went wrong or a bad outcome occurred. Developing that connection through good eye contact, being a teacher, and showing compassion is the most important thing a physician can do when testifying.”

A related challenge is that medical experts can’t connect as well with jurors, and some may have trouble conveying their message from a screen, said Evan Lyman, a medical malpractice defense attorney based in White Plains, N.Y.

“Some experts like to get out of the witness box and kind of take over the courtroom with a laser pointer or a white board,” he said. “For some, that’s what makes them effective experts. Some experts lose their touch when they can’t do that.”

Technical difficulties during virtual trials can cause further woes, said Kari Adams, vice president of claims for Physicians Insurance – A Mutual Company. She recalled a recent case in which technical problems arose during the defense attorney’s closing arguments.

“It’s hard to see our defense attorneys who are used to using all of their advocacy skills, all of their charisma trying to convey it in a virtual format,” she said. “When it’s disrupted, it can really throw things. A lot of their advocacy and personality can play through, but it’s just a little less in that forum.”
 

Doc fights against virtual trial

When Texas cardiologist Amin Al-Ahmad’s malpractice trial was changed to a virtual format because of COVID-19 concerns, Dr. Al-Ahmad and his attorneys fought the move.

They argued that the malpractice case was too complex for a virtual format and that a video trial would deprive Dr. Al-Ahmad of his rights to due process, including the right to trial by jury.

Dr. Al-Ahmad’s case involved allegations that he had failed to promptly diagnose and treat an atrial esophageal fistula, resulting in a patient’s stroke and ongoing neurologic problems. The trial was expected to last up to 10 days. Nine witnesses were expected to testify, and $1 million in damages were at stake, according to court documents.

“The length of trial anticipated, complexity of the medical issues, the confidential medical information at issue, and the number of anticipated medical records exhibits lead to a real risk of juror ‘Zoom fatigue,’ even if the trial is not interrupted with technology glitches, such as jurors dropping off the link or sound loss,” Dr. Al-Ahmad’s attorneys wrote in a petition to the Texas Supreme Court. “The risks of forcing [the defendants] to trial through the procedure of a remote or virtual jury trial are numerous. Not least of these is the risk that [defendants’] relators will be prevented from presenting an adequate defense or being able to fully preserve error during a virtual trial.”

Another concern regards the lack of uniformity from county to county in conducting a virtual trial, said David A. Wright, an attorney for Dr. Al-Ahmad. Some counties don’t permit them, while others permit parties to opt out of virtual trials, he noted.

“Even those that hold virtual trials seem to have different procedures and rules,” he said. “Travis County, where I have tried my virtual cases, has iPads that they provide to each juror so that they are limited to using just the county iPad for the trial. Others, I have heard, permit jurors to use their own devices. There are simply no uniform rules.”

Despite requests to the trial court and petitions to the appellate and Texas Supreme Court, Dr. Al-Ahmad lost his bid to have his trial delayed until in-person trials resumed. The Texas Supreme Court in late 2021 refused to halt the virtual trial.

Dr. Al-Ahmad, based in Austin, declined to comment through his attorney. Mr. Wright said the court’s denial “was not unexpected.”

Dr. Al-Ahmad’s virtual trial went forward in October 2021, and the jury ruled in his favor.

“We were very pleased with the jury’s verdict,” Mr. Wright said.
 

Are virtual trials ending in higher awards?

In addition to jurors’ not taking their roles as seriously, the casual vibe of virtual trials may also be diminishing how jurors view the verdict’s magnitude.

“Virtual trials don’t have the gravity or the seriousness of a real trial,” Ms. Leedom said. “I don’t think the importance of the jury’s decision weighs on them as much during a Zoom trial as it does an in-person trial.”

Alarmingly, Ms. Leedom said that, in her experience, damages in virtual trials have been higher in comparison with damages awarded during in-person trials.

Ms. Adams agreed with this observation.

“We’ll still win cases, but we’re concerned that, in the cases we lose, the damages can be slightly higher because there hasn’t been that interpersonal connection with the defendant,” she said. “It almost becomes like monopoly money to jurors.”
 

Remember these tips during virtual trials

Physicians undergoing virtual trials may have better experiences if they keep a few tips in mind.

Mr. DeSimone emphasized the importance of eye contact with jurors, which can be tricky during virtual settings. It helps if physicians look at the camera, rather than the screen, while talking.

Physicians should be cognizant of their facial expressions as they watch others speak.

“Don’t roll your eyes like: ‘Oh my gosh, he’s an idiot,’ ” Mr. DeSimone said. “Keep a poker face. Be respectful of what’s going on. Don’t be lulled into letting your guard down.”

Before the virtual trial, practice the cross examination and direct examination with your attorney and record it, Ms. Leedom said. That way, doctors can watch how they present on video and make necessary changes before the real trial. Lighting is also important, she noted. Her firm provides special lamps to clients and witnesses for virtual trials and proceedings.

“The lighting makes a huge difference,” she said.

Its also a good idea for physicians to have a paper copy of the records or exhibits that are going to be used so it’s easy for them to flip through them while on the screen. Physicians should also be mindful of how they come across during video depositions, which are sometimes played during virtual trials, Ms. Adams said.

“If you’re not looking professional during the video deposition – you’re eating, you’re not dressed well – the plaintiff’s attorney will take the most inopportune segment of the deposition and portray the physician as: ‘Look, here’s someone who was careless in the medical care, and look, they don’t even look professional when they’re testifying about this horrifying experience,’ ” she said. “They’ll use the clips to make a very careful provider appear distracted.”
 

Are virtual trials and hearings here to stay?

Whether virtual malpractice trials continue will largely depend on the location in which physicians practice. Some insurance carriers are opting to continue virtual trials, but in some areas, trials are being delayed until in-person proceedings can resume, Ms. Adams said. Some areas never adopted video trials and never ceased in-person trials.

“I think it’s going to be very regionally based,” she said. “Some of the smaller, rural counties just don’t have the capacity or the resources to continue, so they’ll probably just go back to in person.”

Not all virtual proceedings are problematic for physicians, say legal experts. Virtual depositions can be beneficial for doctors because they are less intimidating and confrontational than in-person depositions, Mr. Lyman said.

Additionally, virtual mediations can take much less time than in-person mediations, Ms. Adams said. Video depositions and mediations also save travel costs and reduce time missed from work for physicians.

“But I hope we all go back to in-person trials,” Ms. Leedom said. “Even here in King County, [Washington,] where we’ve done federal and state court trials by Zoom, I’m hopeful that it will go back to in-person trials.”

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

During a recent virtual medical malpractice trial, the judge called a break, and the participants left their screens. When the trial resumed a short time later, one juror was missing. The court called his phone, but there was no answer.

“Everyone had to keep waiting and waiting while the bailiff kept trying to call,” recalled Elizabeth Leedom, a medical malpractice defense attorney based in Seattle. “The juror fell asleep.”

The sleeping juror caused a significant delay in the trial, Ms. Leedom said. Finally, he woke up, and the trial was able to continue.

In another instance, a potential juror showed up drunk to a virtual jury selection. The man was slurring his words as he answered questions, Ms. Leedom said, and when asked if he was okay, he admitted that he had a drinking problem. The judge asked whether he had consumed alcohol, and the man admitted that he’d been drinking that day. He was excused from jury selection.

These alarming incidents are among the mishaps that happen during virtual medical malpractice trials. Since the pandemic started, many courts have moved to virtual settings to slow the spread of COVID-19. Although some courts have now shifted back to in-person trials, some areas continue to mandate virtual malpractice trials, hearings, and depositions.

Such trials can save money and are convenient, but legal experts say virtual trials present serious challenges for physicians and raise concerns about fairness. Some jurors are not taking virtual cases seriously or do not stay focused on the subject matter, according to attorneys.

“Virtual trials are not as fair to physicians as in-person trials,” said Andrew DeSimone, a medical malpractice defense attorney based in Lexington, Ky. “It’s too easy not to pay attention in a virtual setting. And when you are dealing with complex medical topics, juror attention is a paramount issue.”
 

Casual settings, constant interruptions during jury selections

Understanding and reaching the jury have been the greatest challenges with virtual and hybrid trials, said Laura Eschleman, a medical liability defense attorney based in Atlanta. Hybrid trials are part virtual and part in person.

Ms. Eschleman has participated in jury selections via Zoom in which jurors lounge in bed during the process and spouses and children waltz into the room as they please, she said.

“With over 36 Zoom boxes of potential jurors, assessing each potential juror was difficult to say the least,” she said. “[Jury selection] has always been an opportunity to introduce the defendant physicians to the jurors as humans; doing it virtually took that away. It is difficult to humanize a box on a screen.”

Regarding one virtual jury selection, Ms. Eschleman said the court had narrowed the pool to a final 12 jurors when one juror’s wife burst into his room and started yelling in front of his computer.

The judge allowed her to speak, and the crying woman begged the judge not to select her husband for the trial because it would disrupt the couple’s child care. After a lengthy exchange, they learned that the child was 16 years old and had his own car. The husband disagreed with his wife and wanted to remain a juror.

“This would have never happened had the twelfth juror been called to an in-person jury selection,” Ms. Eschleman said.

Keeping juries focused while the trial is underway can also be a problem, DeSimone said. He describes the courtroom during malpractice trials as a theater of sorts. Jurors watch intently as witnesses testify, evidence is presented, and the judge gives instructions. During virtual trials, however, watching through a screen doesn’t always yield the same captive audiences, he said.

“During Zoom, it’s much harder to connect with the jury because they won’t be as tuned into it,” he said. “If the jury believes the physician is empathetic, conscientious, caring, and compassionate, they will give the physician the benefit of the doubt, even if something went wrong or a bad outcome occurred. Developing that connection through good eye contact, being a teacher, and showing compassion is the most important thing a physician can do when testifying.”

A related challenge is that medical experts can’t connect as well with jurors, and some may have trouble conveying their message from a screen, said Evan Lyman, a medical malpractice defense attorney based in White Plains, N.Y.

“Some experts like to get out of the witness box and kind of take over the courtroom with a laser pointer or a white board,” he said. “For some, that’s what makes them effective experts. Some experts lose their touch when they can’t do that.”

Technical difficulties during virtual trials can cause further woes, said Kari Adams, vice president of claims for Physicians Insurance – A Mutual Company. She recalled a recent case in which technical problems arose during the defense attorney’s closing arguments.

“It’s hard to see our defense attorneys who are used to using all of their advocacy skills, all of their charisma trying to convey it in a virtual format,” she said. “When it’s disrupted, it can really throw things. A lot of their advocacy and personality can play through, but it’s just a little less in that forum.”
 

Doc fights against virtual trial

When Texas cardiologist Amin Al-Ahmad’s malpractice trial was changed to a virtual format because of COVID-19 concerns, Dr. Al-Ahmad and his attorneys fought the move.

They argued that the malpractice case was too complex for a virtual format and that a video trial would deprive Dr. Al-Ahmad of his rights to due process, including the right to trial by jury.

Dr. Al-Ahmad’s case involved allegations that he had failed to promptly diagnose and treat an atrial esophageal fistula, resulting in a patient’s stroke and ongoing neurologic problems. The trial was expected to last up to 10 days. Nine witnesses were expected to testify, and $1 million in damages were at stake, according to court documents.

“The length of trial anticipated, complexity of the medical issues, the confidential medical information at issue, and the number of anticipated medical records exhibits lead to a real risk of juror ‘Zoom fatigue,’ even if the trial is not interrupted with technology glitches, such as jurors dropping off the link or sound loss,” Dr. Al-Ahmad’s attorneys wrote in a petition to the Texas Supreme Court. “The risks of forcing [the defendants] to trial through the procedure of a remote or virtual jury trial are numerous. Not least of these is the risk that [defendants’] relators will be prevented from presenting an adequate defense or being able to fully preserve error during a virtual trial.”

Another concern regards the lack of uniformity from county to county in conducting a virtual trial, said David A. Wright, an attorney for Dr. Al-Ahmad. Some counties don’t permit them, while others permit parties to opt out of virtual trials, he noted.

“Even those that hold virtual trials seem to have different procedures and rules,” he said. “Travis County, where I have tried my virtual cases, has iPads that they provide to each juror so that they are limited to using just the county iPad for the trial. Others, I have heard, permit jurors to use their own devices. There are simply no uniform rules.”

Despite requests to the trial court and petitions to the appellate and Texas Supreme Court, Dr. Al-Ahmad lost his bid to have his trial delayed until in-person trials resumed. The Texas Supreme Court in late 2021 refused to halt the virtual trial.

Dr. Al-Ahmad, based in Austin, declined to comment through his attorney. Mr. Wright said the court’s denial “was not unexpected.”

Dr. Al-Ahmad’s virtual trial went forward in October 2021, and the jury ruled in his favor.

“We were very pleased with the jury’s verdict,” Mr. Wright said.
 

Are virtual trials ending in higher awards?

In addition to jurors’ not taking their roles as seriously, the casual vibe of virtual trials may also be diminishing how jurors view the verdict’s magnitude.

“Virtual trials don’t have the gravity or the seriousness of a real trial,” Ms. Leedom said. “I don’t think the importance of the jury’s decision weighs on them as much during a Zoom trial as it does an in-person trial.”

Alarmingly, Ms. Leedom said that, in her experience, damages in virtual trials have been higher in comparison with damages awarded during in-person trials.

Ms. Adams agreed with this observation.

“We’ll still win cases, but we’re concerned that, in the cases we lose, the damages can be slightly higher because there hasn’t been that interpersonal connection with the defendant,” she said. “It almost becomes like monopoly money to jurors.”
 

Remember these tips during virtual trials

Physicians undergoing virtual trials may have better experiences if they keep a few tips in mind.

Mr. DeSimone emphasized the importance of eye contact with jurors, which can be tricky during virtual settings. It helps if physicians look at the camera, rather than the screen, while talking.

Physicians should be cognizant of their facial expressions as they watch others speak.

“Don’t roll your eyes like: ‘Oh my gosh, he’s an idiot,’ ” Mr. DeSimone said. “Keep a poker face. Be respectful of what’s going on. Don’t be lulled into letting your guard down.”

Before the virtual trial, practice the cross examination and direct examination with your attorney and record it, Ms. Leedom said. That way, doctors can watch how they present on video and make necessary changes before the real trial. Lighting is also important, she noted. Her firm provides special lamps to clients and witnesses for virtual trials and proceedings.

“The lighting makes a huge difference,” she said.

Its also a good idea for physicians to have a paper copy of the records or exhibits that are going to be used so it’s easy for them to flip through them while on the screen. Physicians should also be mindful of how they come across during video depositions, which are sometimes played during virtual trials, Ms. Adams said.

“If you’re not looking professional during the video deposition – you’re eating, you’re not dressed well – the plaintiff’s attorney will take the most inopportune segment of the deposition and portray the physician as: ‘Look, here’s someone who was careless in the medical care, and look, they don’t even look professional when they’re testifying about this horrifying experience,’ ” she said. “They’ll use the clips to make a very careful provider appear distracted.”
 

Are virtual trials and hearings here to stay?

Whether virtual malpractice trials continue will largely depend on the location in which physicians practice. Some insurance carriers are opting to continue virtual trials, but in some areas, trials are being delayed until in-person proceedings can resume, Ms. Adams said. Some areas never adopted video trials and never ceased in-person trials.

“I think it’s going to be very regionally based,” she said. “Some of the smaller, rural counties just don’t have the capacity or the resources to continue, so they’ll probably just go back to in person.”

Not all virtual proceedings are problematic for physicians, say legal experts. Virtual depositions can be beneficial for doctors because they are less intimidating and confrontational than in-person depositions, Mr. Lyman said.

Additionally, virtual mediations can take much less time than in-person mediations, Ms. Adams said. Video depositions and mediations also save travel costs and reduce time missed from work for physicians.

“But I hope we all go back to in-person trials,” Ms. Leedom said. “Even here in King County, [Washington,] where we’ve done federal and state court trials by Zoom, I’m hopeful that it will go back to in-person trials.”

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

Cancer survivors who spend more than 8 hours of the day sitting are five times more likely to die over the ensuing years than their peers who spend less time sitting. Being physically active, on the other hand, lowers the risk of early death, new research shows.

What’s “alarming” is that so many cancer survivors have a sedentary lifestyle, Chao Cao and Lin Yang, PhD, with Alberta Health Services in Calgary, who worked on the study, said in an interview.

The American Cancer Society recommends that cancer survivors follow the same physical activity guidance as the general population. The target is 150-300 minutes of moderate activity or 75-150 minutes of vigorous activity each week (or a combination of these).

“Getting to or exceeding the upper limit of 300 minutes is ideal,” Mr. Cao and Dr. Yang say.

Yet in their study of more than 1,500 cancer survivors, more than half (57%) were inactive, reporting no weekly leisure-time physical activity in the past week.

About 16% were “insufficiently” active, or getting less than 150 minutes per week. Meanwhile, 28% were active, achieving more than 150 minutes of weekly physical activity.

Digging deeper, the researchers found that more than one-third of cancer survivors reported sitting for 6-8 hours each day, and one-quarter reported sitting for more than 8 hours per day.

Over the course of up to 9 years, 293 of the cancer survivors died – 114 from cancer, 41 from heart diseases, and 138 from other causes.

After accounting for things that might influence the results, the risk of dying from any cause or cancer was about 65% lower in cancer survivors who were physically active, relative to their inactive peers.

Sitting for long periods was especially risky, according to the study in JAMA Oncology.

Compared with cancer survivors who sat for less than 4 hours each day, cancer survivors who reported sitting for more than 8 hours a day had nearly twice the risk of dying from any cause and more than twice the risk of dying from cancer.

Cancer survivors who sat for more than 8 hours a day, and were inactive or not active enough, had as much as five times the risk of death from any cause or cancer.

“Be active and sit less, move more, and move frequently,” advise Mr. Cao and Dr. Yang. “Avoiding prolonged sitting is essential for most cancer survivors to reduce excess mortality risks.”

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

Cancer survivors who spend more than 8 hours of the day sitting are five times more likely to die over the ensuing years than their peers who spend less time sitting. Being physically active, on the other hand, lowers the risk of early death, new research shows.

What’s “alarming” is that so many cancer survivors have a sedentary lifestyle, Chao Cao and Lin Yang, PhD, with Alberta Health Services in Calgary, who worked on the study, said in an interview.

The American Cancer Society recommends that cancer survivors follow the same physical activity guidance as the general population. The target is 150-300 minutes of moderate activity or 75-150 minutes of vigorous activity each week (or a combination of these).

“Getting to or exceeding the upper limit of 300 minutes is ideal,” Mr. Cao and Dr. Yang say.

Yet in their study of more than 1,500 cancer survivors, more than half (57%) were inactive, reporting no weekly leisure-time physical activity in the past week.

About 16% were “insufficiently” active, or getting less than 150 minutes per week. Meanwhile, 28% were active, achieving more than 150 minutes of weekly physical activity.

Digging deeper, the researchers found that more than one-third of cancer survivors reported sitting for 6-8 hours each day, and one-quarter reported sitting for more than 8 hours per day.

Over the course of up to 9 years, 293 of the cancer survivors died – 114 from cancer, 41 from heart diseases, and 138 from other causes.

After accounting for things that might influence the results, the risk of dying from any cause or cancer was about 65% lower in cancer survivors who were physically active, relative to their inactive peers.

Sitting for long periods was especially risky, according to the study in JAMA Oncology.

Compared with cancer survivors who sat for less than 4 hours each day, cancer survivors who reported sitting for more than 8 hours a day had nearly twice the risk of dying from any cause and more than twice the risk of dying from cancer.

Cancer survivors who sat for more than 8 hours a day, and were inactive or not active enough, had as much as five times the risk of death from any cause or cancer.

“Be active and sit less, move more, and move frequently,” advise Mr. Cao and Dr. Yang. “Avoiding prolonged sitting is essential for most cancer survivors to reduce excess mortality risks.”

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

Cancer survivors who spend more than 8 hours of the day sitting are five times more likely to die over the ensuing years than their peers who spend less time sitting. Being physically active, on the other hand, lowers the risk of early death, new research shows.

What’s “alarming” is that so many cancer survivors have a sedentary lifestyle, Chao Cao and Lin Yang, PhD, with Alberta Health Services in Calgary, who worked on the study, said in an interview.

The American Cancer Society recommends that cancer survivors follow the same physical activity guidance as the general population. The target is 150-300 minutes of moderate activity or 75-150 minutes of vigorous activity each week (or a combination of these).

“Getting to or exceeding the upper limit of 300 minutes is ideal,” Mr. Cao and Dr. Yang say.

Yet in their study of more than 1,500 cancer survivors, more than half (57%) were inactive, reporting no weekly leisure-time physical activity in the past week.

About 16% were “insufficiently” active, or getting less than 150 minutes per week. Meanwhile, 28% were active, achieving more than 150 minutes of weekly physical activity.

Digging deeper, the researchers found that more than one-third of cancer survivors reported sitting for 6-8 hours each day, and one-quarter reported sitting for more than 8 hours per day.

Over the course of up to 9 years, 293 of the cancer survivors died – 114 from cancer, 41 from heart diseases, and 138 from other causes.

After accounting for things that might influence the results, the risk of dying from any cause or cancer was about 65% lower in cancer survivors who were physically active, relative to their inactive peers.

Sitting for long periods was especially risky, according to the study in JAMA Oncology.

Compared with cancer survivors who sat for less than 4 hours each day, cancer survivors who reported sitting for more than 8 hours a day had nearly twice the risk of dying from any cause and more than twice the risk of dying from cancer.

Cancer survivors who sat for more than 8 hours a day, and were inactive or not active enough, had as much as five times the risk of death from any cause or cancer.

“Be active and sit less, move more, and move frequently,” advise Mr. Cao and Dr. Yang. “Avoiding prolonged sitting is essential for most cancer survivors to reduce excess mortality risks.”

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

The College of American Pathologists (CAP) guidance outperforms the Royal College of Pathologists (RCPath) guidance in predicting recurrence and survival following resection of oral cavity squamous cell carcinoma (OCSCC), according to a retrospective study.

Treatment of OCSCC involves resection of the primary tumor, followed by neck dissection or postoperative radiotherapy when needed, but choice of treatment requires an accurate assessment of resection margins. Previous studies have failed to consistently show a correlation between margin status and clinical outcomes. Tumor size, depth of invasion, and other factors may explain inconsistent findings, but another possibility is the variability in how margin status is defined.

RCPath and CAP are among the most commonly used definitions. RCPath defines a positive margin as invasive tumor within 1 mm of the surgical margin, while CAP defines a positive margin as the presence of primary tumor or high-grade dysplasia at the margin itself. CAP recommends determination of a “final margin status” that also considers separately submitted extra tumor bed margins. Nevertheless, multiple studies have shown that reliance on the main tumor specimen outperformed the combined approach in predicting recurrence and survival.

In a study published online March 7 in Oral Oncology, researchers examined records from 300 patients (33.7% of whom were female) at South Infirmary Victoria University Hospital in Ireland between 2007 and 2020. The researchers found that 28.7% had margins determined by the RCPath definition and 16.7% according to the CAP definition. Forty-nine percent underwent extra tumor bed resections.

The mean follow-up period was 49 months, 64 months for surviving patients. Multivariate analyses accounting for other established prognosticators found that local recurrence was associated with CAP margins (odds ratio [OR], 1.86; 955 confidence interval [CI], 1.02-3.48) and T3/T4 classification (OR, 2.80; 95% CI, 1.53-5.13). CAP margins predicted disease-specific survival (OR, 2.28; 95% CI, 1.53-5.13) and narrowly missed significance in predicting overall survival (OR, 1.65; 95% CI, 0.99-2.75). RCPath margins were not predictive.

The researchers found a significant association between RCPath definition and metastatic nodal disease and extranodal extension, but there was no such relationship between these negative predictors and CAP and final margin status. “This finding may explain the superior independent prognostic ability of CAP margin status over RCPath in our cohort and is consistent with that of previous studies, which concluded that other histological risk factors are more important than margin status in predicting outcome,” the authors wrote.

Studies suggest that margins fewer than 1 mm remain a high-risk group, with worse survival outcomes than those of patients with 1- to 5-mm margins, even if the risk is lower than tumor at margins. “The optimum cut-off between low-risk and high-risk margins in OCSCC remains unresolved,” the authors wrote.

The study was retrospective and relied on data from a single center, and the patients included in the study may not be directly comparable to other OCSCC patients. The study was funded by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital.

The College of American Pathologists (CAP) guidance outperforms the Royal College of Pathologists (RCPath) guidance in predicting recurrence and survival following resection of oral cavity squamous cell carcinoma (OCSCC), according to a retrospective study.

Treatment of OCSCC involves resection of the primary tumor, followed by neck dissection or postoperative radiotherapy when needed, but choice of treatment requires an accurate assessment of resection margins. Previous studies have failed to consistently show a correlation between margin status and clinical outcomes. Tumor size, depth of invasion, and other factors may explain inconsistent findings, but another possibility is the variability in how margin status is defined.

RCPath and CAP are among the most commonly used definitions. RCPath defines a positive margin as invasive tumor within 1 mm of the surgical margin, while CAP defines a positive margin as the presence of primary tumor or high-grade dysplasia at the margin itself. CAP recommends determination of a “final margin status” that also considers separately submitted extra tumor bed margins. Nevertheless, multiple studies have shown that reliance on the main tumor specimen outperformed the combined approach in predicting recurrence and survival.

In a study published online March 7 in Oral Oncology, researchers examined records from 300 patients (33.7% of whom were female) at South Infirmary Victoria University Hospital in Ireland between 2007 and 2020. The researchers found that 28.7% had margins determined by the RCPath definition and 16.7% according to the CAP definition. Forty-nine percent underwent extra tumor bed resections.

The mean follow-up period was 49 months, 64 months for surviving patients. Multivariate analyses accounting for other established prognosticators found that local recurrence was associated with CAP margins (odds ratio [OR], 1.86; 955 confidence interval [CI], 1.02-3.48) and T3/T4 classification (OR, 2.80; 95% CI, 1.53-5.13). CAP margins predicted disease-specific survival (OR, 2.28; 95% CI, 1.53-5.13) and narrowly missed significance in predicting overall survival (OR, 1.65; 95% CI, 0.99-2.75). RCPath margins were not predictive.

The researchers found a significant association between RCPath definition and metastatic nodal disease and extranodal extension, but there was no such relationship between these negative predictors and CAP and final margin status. “This finding may explain the superior independent prognostic ability of CAP margin status over RCPath in our cohort and is consistent with that of previous studies, which concluded that other histological risk factors are more important than margin status in predicting outcome,” the authors wrote.

Studies suggest that margins fewer than 1 mm remain a high-risk group, with worse survival outcomes than those of patients with 1- to 5-mm margins, even if the risk is lower than tumor at margins. “The optimum cut-off between low-risk and high-risk margins in OCSCC remains unresolved,” the authors wrote.

The study was retrospective and relied on data from a single center, and the patients included in the study may not be directly comparable to other OCSCC patients. The study was funded by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital.

The College of American Pathologists (CAP) guidance outperforms the Royal College of Pathologists (RCPath) guidance in predicting recurrence and survival following resection of oral cavity squamous cell carcinoma (OCSCC), according to a retrospective study.

Treatment of OCSCC involves resection of the primary tumor, followed by neck dissection or postoperative radiotherapy when needed, but choice of treatment requires an accurate assessment of resection margins. Previous studies have failed to consistently show a correlation between margin status and clinical outcomes. Tumor size, depth of invasion, and other factors may explain inconsistent findings, but another possibility is the variability in how margin status is defined.

RCPath and CAP are among the most commonly used definitions. RCPath defines a positive margin as invasive tumor within 1 mm of the surgical margin, while CAP defines a positive margin as the presence of primary tumor or high-grade dysplasia at the margin itself. CAP recommends determination of a “final margin status” that also considers separately submitted extra tumor bed margins. Nevertheless, multiple studies have shown that reliance on the main tumor specimen outperformed the combined approach in predicting recurrence and survival.

In a study published online March 7 in Oral Oncology, researchers examined records from 300 patients (33.7% of whom were female) at South Infirmary Victoria University Hospital in Ireland between 2007 and 2020. The researchers found that 28.7% had margins determined by the RCPath definition and 16.7% according to the CAP definition. Forty-nine percent underwent extra tumor bed resections.

The mean follow-up period was 49 months, 64 months for surviving patients. Multivariate analyses accounting for other established prognosticators found that local recurrence was associated with CAP margins (odds ratio [OR], 1.86; 955 confidence interval [CI], 1.02-3.48) and T3/T4 classification (OR, 2.80; 95% CI, 1.53-5.13). CAP margins predicted disease-specific survival (OR, 2.28; 95% CI, 1.53-5.13) and narrowly missed significance in predicting overall survival (OR, 1.65; 95% CI, 0.99-2.75). RCPath margins were not predictive.

The researchers found a significant association between RCPath definition and metastatic nodal disease and extranodal extension, but there was no such relationship between these negative predictors and CAP and final margin status. “This finding may explain the superior independent prognostic ability of CAP margin status over RCPath in our cohort and is consistent with that of previous studies, which concluded that other histological risk factors are more important than margin status in predicting outcome,” the authors wrote.

Studies suggest that margins fewer than 1 mm remain a high-risk group, with worse survival outcomes than those of patients with 1- to 5-mm margins, even if the risk is lower than tumor at margins. “The optimum cut-off between low-risk and high-risk margins in OCSCC remains unresolved,” the authors wrote.

The study was retrospective and relied on data from a single center, and the patients included in the study may not be directly comparable to other OCSCC patients. The study was funded by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital.

People with higher (above the median) consumption of artificial sweeteners – especially aspartame and acesulfame-potassium (acesulfame-K) – had a 13% higher risk of overall cancer over 8 years than those who did not consume these sweeteners.

Higher consumption of aspartame was associated with a 22% increased risk of breast cancer and a 15% increased risk of obesity-related cancer, compared with not consuming any of these sweeteners.*

BigRedCurlyGuy/Thinkstock

These findings from the Nutri-Santé population-based observational study in France were published online March 24, 2022, in PLoS Medicine.

“Our findings do not support the use of artificial sweeteners as safe alternatives for sugar in foods or beverages and provide important and novel information to address the controversies about their potential adverse health effect,” Charlotte Debras, of the French National Institute for Health and Medical Research (Inserm) and Sorbonne Paris Nord University, and colleagues wrote.

“Results from the NutriNet-Santé cohort (n = 102,865) suggest that artificial sweeteners found in many food and beverage brands worldwide may be associated with increased cancer risk, in line with several experimental in vivo/in vitro studies. These findings provide novel information for the re-evaluation of these food additives by health agencies,” they wrote.

Commenting to the U.K. Science Media Center, Duane Mellor, PhD, registered dietitian and senior teaching fellow, Aston (England) University, said: “This study does not prove or even suggest that we should go back to sugar and turn our backs on artificial sweeteners or diet drinks.  

“It does, however, suggest that artificial sweeteners are not a perfect replacement for sugar, they come with their own potential risks, as does sugar. The ideal answer is probably to move away from both, however, that may be unappealing to many who like a little sweetness in their life, so ditching the regular or diet soft drink (soda) for water may not be a well-received health message.”
 

Important analysis, interpret with caution

“I think that this is an important analysis, but the results need to be interpreted with caution,” another expert, John L. Sievenpiper, MD, PhD, associate professor, departments of nutritional sciences and medicine, University of Toronto, said in an interview.

“Large observational studies like this one that assess the exposure to low and no calorie sweeteners with obesity-related chronic diseases are at risk of reverse causality,” he explained. This is “a caveat that is well recognized by investigators in this field ... and guideline and policy makers.”

Reverse causality is a possibility because “it is likely that many high consumers of low- and no-calorie sweeteners (of which aspartame and acesulfame-K are the most common) will be consuming these sweeteners as a weight-loss strategy,” he added, “as opposed to these sweeteners causing obesity and its complications (including cancers).”

His team recently published a Diabetes and Nutrition Study Group–commissioned systematic review and meta-analysis of 17 randomized controlled trials (JAMA Netw Open. 2022;5[3]:e222092). Their findings “suggest that over the moderate term [low- and no-calorie sweetened beverages] are a viable alternative to water as a replacement strategy in adults with overweight or obesity who are at risk for or have diabetes,” states one of two syntheses (the other is in press in Diabetes Care) for the update of the European Association for the Study of Diabetes guidelines coming in the fall of 2022. 

“The bottom line” for the current study, according to Dr. Sievenpiper, “is that it is difficult to disentangle the signals for low- and no-calorie sweeteners from obesity itself and the signals for the sugars and calories that they are replacing/displacing in this analysis. Substitution analyses would be useful to address some of these concerns.”
 

Conflicting results

Recent epidemiologic and animal studies about a possible link between artificial sweeteners and risk of cancer have had conflicting results, and information about specific types of sweeteners and consumption of artificially sweetened foods as well as beverages is lacking, Ms. Debras and colleagues wrote.

They aimed to investigate the associations between intakes of artificial sweeteners (total and the most common ones – aspartame, acesulfame-K, and sucralose) and cancer risk (overall risk and most frequent types – breast, prostate, and obesity-related cancers) in the ongoing NutriNet-Santé study.

“Obesity-related cancers are cancers for which obesity is involved in their etiology as one of the risk (or protective) factors, as recognized by the World Cancer Research Fund (independently of participant BMI [body mass index] status): colorectal, stomach, liver, mouth, pharynx, larynx, esophageal, breast (with opposite associations pre- and post menopause), ovarian, endometrial, and prostate cancers,” the researchers explained.

According to a recent study , “obesity increases the risk of breast cancer in postmenopausal women but, conversely, it appears to be protective in premenopausal women,” Dr. Sievenpiper noted.

The ongoing NutriNet-Santé study was initiated in 2009 to investigate associations between nutrition and health in the French population. Participants aged 18 and older with Internet access enroll voluntarily and self-report medical history and sociodemographic, diet, lifestyle, and health data.

The current cohort included 102,865 adults who enrolled in 2009-2021.

Consumption of artificial sweeteners was determined from repeated 24-hour dietary records that included brand names of processed foods.

At enrollment, participants were an average age of 42 years and 79% were women. They had a mean BMI of 24 kg/m2. On average, they had 5.6 dietary records.

Most participants did not consume artificial sweeteners (63%); those who did were classified as lower consumers (18.5%) or higher consumers (18.5%).

Aspartame was the most common artificial sweetener (58% of intake), followed by acesulfame-K (29%) and sucralose (10%), and these were mostly in soft drinks (53%), table-top sweeteners (29%), and yogurt/cottage cheese (8%). 

During a median 7.7-year follow-up, 3,358 incident cancers – 982 breast, 403 prostate, and 2023 obesity-related cancers – were diagnosed in participants who were a mean age of 60.

Compared with nonconsumers, higher consumers of artificial sweeteners had a higher risk of overall cancer (hazard ratio, 1.13; 95% confidence interval, 1.03-1.25; P-trend = .002), after adjusting for age, sex, education, physical activity, smoking, BMI, height, weight gain during follow-up, diabetes, family history of cancer, number of 24-hour dietary records, baseline caloric intake, and consumption of alcohol, sodium, saturated fatty acids, fiber, sugar, fruit and vegetables, whole-grain foods, and dairy products.

Participants who were higher consumers of aspartame had an increased risk of overall cancer (HR, 1.15; 95% CI, 1.03-1.28; P = .002), as did higher consumers of acesulfame-K (HR, 1.13; 95% CI, 1.01-1.26; P = .007), compared with nonconsumers, after adjusting for the multiple variables. 

Higher consumers of aspartame had a higher risk of breast cancer (HR, 1.22; 95% CI, 1.01-1.48; P = .036) and obesity-related cancers (HR, 1.15; 95% CI, 1.01-1.32; P = .026) than nonconsumers.

Higher consumers of total artificial sweeteners had a higher risk of obesity-related cancers than nonconsumers (HR, 1.13; 95% CI, 1.00-1.28; P = .036).

The researchers acknowledged that study limitations include potential selection bias, residual confounding, and reverse causality, though sensitivity analyses were performed to address these concerns.

The NutriNet-Santé study was supported by several French public institutions. Ms. Debras was supported by a grant from the French National Cancer Institute. This project has received funding from the European Research Council, the French National Cancer Institute, the French Ministry of Health, and the IdEx Université de Paris. Dr. Sievenpiper has reported receiving funding from the Tate and Lyle Nutritional Research Fund at the University of Toronto, the Nutrition Trialists Fund at the University of Toronto, and the International Sweeteners Association.

Correction, 3/31: An earlier version of this article erroneously stated that there was a 22% increased risk of overall cancer, rather than breast cancer. 

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

People with higher (above the median) consumption of artificial sweeteners – especially aspartame and acesulfame-potassium (acesulfame-K) – had a 13% higher risk of overall cancer over 8 years than those who did not consume these sweeteners.

Higher consumption of aspartame was associated with a 22% increased risk of breast cancer and a 15% increased risk of obesity-related cancer, compared with not consuming any of these sweeteners.*

BigRedCurlyGuy/Thinkstock

These findings from the Nutri-Santé population-based observational study in France were published online March 24, 2022, in PLoS Medicine.

“Our findings do not support the use of artificial sweeteners as safe alternatives for sugar in foods or beverages and provide important and novel information to address the controversies about their potential adverse health effect,” Charlotte Debras, of the French National Institute for Health and Medical Research (Inserm) and Sorbonne Paris Nord University, and colleagues wrote.

“Results from the NutriNet-Santé cohort (n = 102,865) suggest that artificial sweeteners found in many food and beverage brands worldwide may be associated with increased cancer risk, in line with several experimental in vivo/in vitro studies. These findings provide novel information for the re-evaluation of these food additives by health agencies,” they wrote.

Commenting to the U.K. Science Media Center, Duane Mellor, PhD, registered dietitian and senior teaching fellow, Aston (England) University, said: “This study does not prove or even suggest that we should go back to sugar and turn our backs on artificial sweeteners or diet drinks.  

“It does, however, suggest that artificial sweeteners are not a perfect replacement for sugar, they come with their own potential risks, as does sugar. The ideal answer is probably to move away from both, however, that may be unappealing to many who like a little sweetness in their life, so ditching the regular or diet soft drink (soda) for water may not be a well-received health message.”
 

Important analysis, interpret with caution

“I think that this is an important analysis, but the results need to be interpreted with caution,” another expert, John L. Sievenpiper, MD, PhD, associate professor, departments of nutritional sciences and medicine, University of Toronto, said in an interview.

“Large observational studies like this one that assess the exposure to low and no calorie sweeteners with obesity-related chronic diseases are at risk of reverse causality,” he explained. This is “a caveat that is well recognized by investigators in this field ... and guideline and policy makers.”

Reverse causality is a possibility because “it is likely that many high consumers of low- and no-calorie sweeteners (of which aspartame and acesulfame-K are the most common) will be consuming these sweeteners as a weight-loss strategy,” he added, “as opposed to these sweeteners causing obesity and its complications (including cancers).”

His team recently published a Diabetes and Nutrition Study Group–commissioned systematic review and meta-analysis of 17 randomized controlled trials (JAMA Netw Open. 2022;5[3]:e222092). Their findings “suggest that over the moderate term [low- and no-calorie sweetened beverages] are a viable alternative to water as a replacement strategy in adults with overweight or obesity who are at risk for or have diabetes,” states one of two syntheses (the other is in press in Diabetes Care) for the update of the European Association for the Study of Diabetes guidelines coming in the fall of 2022. 

“The bottom line” for the current study, according to Dr. Sievenpiper, “is that it is difficult to disentangle the signals for low- and no-calorie sweeteners from obesity itself and the signals for the sugars and calories that they are replacing/displacing in this analysis. Substitution analyses would be useful to address some of these concerns.”
 

Conflicting results

Recent epidemiologic and animal studies about a possible link between artificial sweeteners and risk of cancer have had conflicting results, and information about specific types of sweeteners and consumption of artificially sweetened foods as well as beverages is lacking, Ms. Debras and colleagues wrote.

They aimed to investigate the associations between intakes of artificial sweeteners (total and the most common ones – aspartame, acesulfame-K, and sucralose) and cancer risk (overall risk and most frequent types – breast, prostate, and obesity-related cancers) in the ongoing NutriNet-Santé study.

“Obesity-related cancers are cancers for which obesity is involved in their etiology as one of the risk (or protective) factors, as recognized by the World Cancer Research Fund (independently of participant BMI [body mass index] status): colorectal, stomach, liver, mouth, pharynx, larynx, esophageal, breast (with opposite associations pre- and post menopause), ovarian, endometrial, and prostate cancers,” the researchers explained.

According to a recent study , “obesity increases the risk of breast cancer in postmenopausal women but, conversely, it appears to be protective in premenopausal women,” Dr. Sievenpiper noted.

The ongoing NutriNet-Santé study was initiated in 2009 to investigate associations between nutrition and health in the French population. Participants aged 18 and older with Internet access enroll voluntarily and self-report medical history and sociodemographic, diet, lifestyle, and health data.

The current cohort included 102,865 adults who enrolled in 2009-2021.

Consumption of artificial sweeteners was determined from repeated 24-hour dietary records that included brand names of processed foods.

At enrollment, participants were an average age of 42 years and 79% were women. They had a mean BMI of 24 kg/m2. On average, they had 5.6 dietary records.

Most participants did not consume artificial sweeteners (63%); those who did were classified as lower consumers (18.5%) or higher consumers (18.5%).

Aspartame was the most common artificial sweetener (58% of intake), followed by acesulfame-K (29%) and sucralose (10%), and these were mostly in soft drinks (53%), table-top sweeteners (29%), and yogurt/cottage cheese (8%). 

During a median 7.7-year follow-up, 3,358 incident cancers – 982 breast, 403 prostate, and 2023 obesity-related cancers – were diagnosed in participants who were a mean age of 60.

Compared with nonconsumers, higher consumers of artificial sweeteners had a higher risk of overall cancer (hazard ratio, 1.13; 95% confidence interval, 1.03-1.25; P-trend = .002), after adjusting for age, sex, education, physical activity, smoking, BMI, height, weight gain during follow-up, diabetes, family history of cancer, number of 24-hour dietary records, baseline caloric intake, and consumption of alcohol, sodium, saturated fatty acids, fiber, sugar, fruit and vegetables, whole-grain foods, and dairy products.

Participants who were higher consumers of aspartame had an increased risk of overall cancer (HR, 1.15; 95% CI, 1.03-1.28; P = .002), as did higher consumers of acesulfame-K (HR, 1.13; 95% CI, 1.01-1.26; P = .007), compared with nonconsumers, after adjusting for the multiple variables. 

Higher consumers of aspartame had a higher risk of breast cancer (HR, 1.22; 95% CI, 1.01-1.48; P = .036) and obesity-related cancers (HR, 1.15; 95% CI, 1.01-1.32; P = .026) than nonconsumers.

Higher consumers of total artificial sweeteners had a higher risk of obesity-related cancers than nonconsumers (HR, 1.13; 95% CI, 1.00-1.28; P = .036).

The researchers acknowledged that study limitations include potential selection bias, residual confounding, and reverse causality, though sensitivity analyses were performed to address these concerns.

The NutriNet-Santé study was supported by several French public institutions. Ms. Debras was supported by a grant from the French National Cancer Institute. This project has received funding from the European Research Council, the French National Cancer Institute, the French Ministry of Health, and the IdEx Université de Paris. Dr. Sievenpiper has reported receiving funding from the Tate and Lyle Nutritional Research Fund at the University of Toronto, the Nutrition Trialists Fund at the University of Toronto, and the International Sweeteners Association.

Correction, 3/31: An earlier version of this article erroneously stated that there was a 22% increased risk of overall cancer, rather than breast cancer. 

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

People with higher (above the median) consumption of artificial sweeteners – especially aspartame and acesulfame-potassium (acesulfame-K) – had a 13% higher risk of overall cancer over 8 years than those who did not consume these sweeteners.

Higher consumption of aspartame was associated with a 22% increased risk of breast cancer and a 15% increased risk of obesity-related cancer, compared with not consuming any of these sweeteners.*

BigRedCurlyGuy/Thinkstock

These findings from the Nutri-Santé population-based observational study in France were published online March 24, 2022, in PLoS Medicine.

“Our findings do not support the use of artificial sweeteners as safe alternatives for sugar in foods or beverages and provide important and novel information to address the controversies about their potential adverse health effect,” Charlotte Debras, of the French National Institute for Health and Medical Research (Inserm) and Sorbonne Paris Nord University, and colleagues wrote.

“Results from the NutriNet-Santé cohort (n = 102,865) suggest that artificial sweeteners found in many food and beverage brands worldwide may be associated with increased cancer risk, in line with several experimental in vivo/in vitro studies. These findings provide novel information for the re-evaluation of these food additives by health agencies,” they wrote.

Commenting to the U.K. Science Media Center, Duane Mellor, PhD, registered dietitian and senior teaching fellow, Aston (England) University, said: “This study does not prove or even suggest that we should go back to sugar and turn our backs on artificial sweeteners or diet drinks.  

“It does, however, suggest that artificial sweeteners are not a perfect replacement for sugar, they come with their own potential risks, as does sugar. The ideal answer is probably to move away from both, however, that may be unappealing to many who like a little sweetness in their life, so ditching the regular or diet soft drink (soda) for water may not be a well-received health message.”
 

Important analysis, interpret with caution

“I think that this is an important analysis, but the results need to be interpreted with caution,” another expert, John L. Sievenpiper, MD, PhD, associate professor, departments of nutritional sciences and medicine, University of Toronto, said in an interview.

“Large observational studies like this one that assess the exposure to low and no calorie sweeteners with obesity-related chronic diseases are at risk of reverse causality,” he explained. This is “a caveat that is well recognized by investigators in this field ... and guideline and policy makers.”

Reverse causality is a possibility because “it is likely that many high consumers of low- and no-calorie sweeteners (of which aspartame and acesulfame-K are the most common) will be consuming these sweeteners as a weight-loss strategy,” he added, “as opposed to these sweeteners causing obesity and its complications (including cancers).”

His team recently published a Diabetes and Nutrition Study Group–commissioned systematic review and meta-analysis of 17 randomized controlled trials (JAMA Netw Open. 2022;5[3]:e222092). Their findings “suggest that over the moderate term [low- and no-calorie sweetened beverages] are a viable alternative to water as a replacement strategy in adults with overweight or obesity who are at risk for or have diabetes,” states one of two syntheses (the other is in press in Diabetes Care) for the update of the European Association for the Study of Diabetes guidelines coming in the fall of 2022. 

“The bottom line” for the current study, according to Dr. Sievenpiper, “is that it is difficult to disentangle the signals for low- and no-calorie sweeteners from obesity itself and the signals for the sugars and calories that they are replacing/displacing in this analysis. Substitution analyses would be useful to address some of these concerns.”
 

Conflicting results

Recent epidemiologic and animal studies about a possible link between artificial sweeteners and risk of cancer have had conflicting results, and information about specific types of sweeteners and consumption of artificially sweetened foods as well as beverages is lacking, Ms. Debras and colleagues wrote.

They aimed to investigate the associations between intakes of artificial sweeteners (total and the most common ones – aspartame, acesulfame-K, and sucralose) and cancer risk (overall risk and most frequent types – breast, prostate, and obesity-related cancers) in the ongoing NutriNet-Santé study.

“Obesity-related cancers are cancers for which obesity is involved in their etiology as one of the risk (or protective) factors, as recognized by the World Cancer Research Fund (independently of participant BMI [body mass index] status): colorectal, stomach, liver, mouth, pharynx, larynx, esophageal, breast (with opposite associations pre- and post menopause), ovarian, endometrial, and prostate cancers,” the researchers explained.

According to a recent study , “obesity increases the risk of breast cancer in postmenopausal women but, conversely, it appears to be protective in premenopausal women,” Dr. Sievenpiper noted.

The ongoing NutriNet-Santé study was initiated in 2009 to investigate associations between nutrition and health in the French population. Participants aged 18 and older with Internet access enroll voluntarily and self-report medical history and sociodemographic, diet, lifestyle, and health data.

The current cohort included 102,865 adults who enrolled in 2009-2021.

Consumption of artificial sweeteners was determined from repeated 24-hour dietary records that included brand names of processed foods.

At enrollment, participants were an average age of 42 years and 79% were women. They had a mean BMI of 24 kg/m2. On average, they had 5.6 dietary records.

Most participants did not consume artificial sweeteners (63%); those who did were classified as lower consumers (18.5%) or higher consumers (18.5%).

Aspartame was the most common artificial sweetener (58% of intake), followed by acesulfame-K (29%) and sucralose (10%), and these were mostly in soft drinks (53%), table-top sweeteners (29%), and yogurt/cottage cheese (8%). 

During a median 7.7-year follow-up, 3,358 incident cancers – 982 breast, 403 prostate, and 2023 obesity-related cancers – were diagnosed in participants who were a mean age of 60.

Compared with nonconsumers, higher consumers of artificial sweeteners had a higher risk of overall cancer (hazard ratio, 1.13; 95% confidence interval, 1.03-1.25; P-trend = .002), after adjusting for age, sex, education, physical activity, smoking, BMI, height, weight gain during follow-up, diabetes, family history of cancer, number of 24-hour dietary records, baseline caloric intake, and consumption of alcohol, sodium, saturated fatty acids, fiber, sugar, fruit and vegetables, whole-grain foods, and dairy products.

Participants who were higher consumers of aspartame had an increased risk of overall cancer (HR, 1.15; 95% CI, 1.03-1.28; P = .002), as did higher consumers of acesulfame-K (HR, 1.13; 95% CI, 1.01-1.26; P = .007), compared with nonconsumers, after adjusting for the multiple variables. 

Higher consumers of aspartame had a higher risk of breast cancer (HR, 1.22; 95% CI, 1.01-1.48; P = .036) and obesity-related cancers (HR, 1.15; 95% CI, 1.01-1.32; P = .026) than nonconsumers.

Higher consumers of total artificial sweeteners had a higher risk of obesity-related cancers than nonconsumers (HR, 1.13; 95% CI, 1.00-1.28; P = .036).

The researchers acknowledged that study limitations include potential selection bias, residual confounding, and reverse causality, though sensitivity analyses were performed to address these concerns.

The NutriNet-Santé study was supported by several French public institutions. Ms. Debras was supported by a grant from the French National Cancer Institute. This project has received funding from the European Research Council, the French National Cancer Institute, the French Ministry of Health, and the IdEx Université de Paris. Dr. Sievenpiper has reported receiving funding from the Tate and Lyle Nutritional Research Fund at the University of Toronto, the Nutrition Trialists Fund at the University of Toronto, and the International Sweeteners Association.

Correction, 3/31: An earlier version of this article erroneously stated that there was a 22% increased risk of overall cancer, rather than breast cancer. 

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

Perioperative immunotherapy appears to be safe in the setting of resectable hepatocellular carcinoma (HCC), according to findings from an open-label phase 2 clinical trial published in The Lancet Gastroenterology and Hepatolgy.

The study compared the anti-PD1 antibody nivolumab (Opdivo, Bristol Myers Squibb) alone and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) among patients with resectable disease at a single center in Sweden. The treatments were found to be “safe and feasible in patients with resectable hepatocellular carcinoma,” wrote researchers who were led by Ahmed O. Kaseb, MD, a medical oncologist with MD Anderson Cancer Center, Houston.

The rate of 5-year tumor recurrence following HCC resection can be as high as 70%, and there are no approved neoadjuvant or adjuvant therapies.

Immune checkpoint therapy has not been well studied in early-stage HCC, but it is used in advanced HCC.

The combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab, is currently a first-line treatment for advanced HCC. “Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable, and clinically beneficial against advanced HCC,” according to researchers writing in a Nature Reviews article published in April 2021.

There are other promising immunotherapies under study for HCC, such as additional checkpoint inhibitors, adoptive cell transfer, vaccination, and virotherapy.
 

Small study of 27 patients

The Lancet study included 27 patients (64 years mean age, 19 patients were male). Twenty-three percent of patients on nivolumab alone had a partial pathological response at week 6, while none in the combination group had a response. Among 20 patients who underwent surgery, 3 of 9 (33%) and 3 of 11 (27%) in the combination group experienced a major pathological response. Two patients in the nivolumab and three patients in the combination group achieved a complete pathological response.

Disease progression occurred in 7 of 12 patients who were evaluated in the nivolumab group, and 4 of 13 patients in the combination group. Estimated median time to disease progression in the nivolumab group was 9.4 months (95% confidence interval, 1.47 to not estimable) and 19.53 months (95% CI, 2.33 to not estimable) in the combination group. Two-year progression-free survival was estimated to be 42% (95% CI, 21%-81%) in the nivolumab group and 26% (95% CI, 8%-78%, no significant difference) in the combination group.

Among 20 patients who underwent surgery, 6 patients had experienced a major pathological response. None of the 6 patients had a recurrence after a median follow-up of 26.8 months, versus 7 recurrences among 14 patients without a pathological response (log-rank P = .049).

Seventy-seven percent of patients in the nivolumab group experienced at least one adverse event (23% grade 3-4), as did 86% in the combination group (43% grade 3-4, difference nonsignificant). No patients delayed or canceled surgery because of adverse events.

Patients who had a major pathological response on the combination treatment had higher levels of immune infiltration versus baseline values. Those who had complete pathological responses in the nivolumab group had high infiltration at baseline. Those results imply some optimism for further study. “These data suggest that, with the immune-priming ability of anti–CTLA-4 treatment, nivolumab plus ipilimumab was able to generate a major pathological response even in tumours that had low immune infiltration at baseline,” the authors wrote.

The study was limited by its open-label nature and small sample size, and it was conducted at a single center.

The study was funded by Bristol Myers Squibb and the National Institutes of Health. Dr. Kaseb reports consulting, advisory roles or stock ownership, or both with Bristol-Myers Squibb.
 

Perioperative immunotherapy appears to be safe in the setting of resectable hepatocellular carcinoma (HCC), according to findings from an open-label phase 2 clinical trial published in The Lancet Gastroenterology and Hepatolgy.

The study compared the anti-PD1 antibody nivolumab (Opdivo, Bristol Myers Squibb) alone and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) among patients with resectable disease at a single center in Sweden. The treatments were found to be “safe and feasible in patients with resectable hepatocellular carcinoma,” wrote researchers who were led by Ahmed O. Kaseb, MD, a medical oncologist with MD Anderson Cancer Center, Houston.

The rate of 5-year tumor recurrence following HCC resection can be as high as 70%, and there are no approved neoadjuvant or adjuvant therapies.

Immune checkpoint therapy has not been well studied in early-stage HCC, but it is used in advanced HCC.

The combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab, is currently a first-line treatment for advanced HCC. “Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable, and clinically beneficial against advanced HCC,” according to researchers writing in a Nature Reviews article published in April 2021.

There are other promising immunotherapies under study for HCC, such as additional checkpoint inhibitors, adoptive cell transfer, vaccination, and virotherapy.
 

Small study of 27 patients

The Lancet study included 27 patients (64 years mean age, 19 patients were male). Twenty-three percent of patients on nivolumab alone had a partial pathological response at week 6, while none in the combination group had a response. Among 20 patients who underwent surgery, 3 of 9 (33%) and 3 of 11 (27%) in the combination group experienced a major pathological response. Two patients in the nivolumab and three patients in the combination group achieved a complete pathological response.

Disease progression occurred in 7 of 12 patients who were evaluated in the nivolumab group, and 4 of 13 patients in the combination group. Estimated median time to disease progression in the nivolumab group was 9.4 months (95% confidence interval, 1.47 to not estimable) and 19.53 months (95% CI, 2.33 to not estimable) in the combination group. Two-year progression-free survival was estimated to be 42% (95% CI, 21%-81%) in the nivolumab group and 26% (95% CI, 8%-78%, no significant difference) in the combination group.

Among 20 patients who underwent surgery, 6 patients had experienced a major pathological response. None of the 6 patients had a recurrence after a median follow-up of 26.8 months, versus 7 recurrences among 14 patients without a pathological response (log-rank P = .049).

Seventy-seven percent of patients in the nivolumab group experienced at least one adverse event (23% grade 3-4), as did 86% in the combination group (43% grade 3-4, difference nonsignificant). No patients delayed or canceled surgery because of adverse events.

Patients who had a major pathological response on the combination treatment had higher levels of immune infiltration versus baseline values. Those who had complete pathological responses in the nivolumab group had high infiltration at baseline. Those results imply some optimism for further study. “These data suggest that, with the immune-priming ability of anti–CTLA-4 treatment, nivolumab plus ipilimumab was able to generate a major pathological response even in tumours that had low immune infiltration at baseline,” the authors wrote.

The study was limited by its open-label nature and small sample size, and it was conducted at a single center.

The study was funded by Bristol Myers Squibb and the National Institutes of Health. Dr. Kaseb reports consulting, advisory roles or stock ownership, or both with Bristol-Myers Squibb.
 

Perioperative immunotherapy appears to be safe in the setting of resectable hepatocellular carcinoma (HCC), according to findings from an open-label phase 2 clinical trial published in The Lancet Gastroenterology and Hepatolgy.

The study compared the anti-PD1 antibody nivolumab (Opdivo, Bristol Myers Squibb) alone and nivolumab plus the anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) among patients with resectable disease at a single center in Sweden. The treatments were found to be “safe and feasible in patients with resectable hepatocellular carcinoma,” wrote researchers who were led by Ahmed O. Kaseb, MD, a medical oncologist with MD Anderson Cancer Center, Houston.

The rate of 5-year tumor recurrence following HCC resection can be as high as 70%, and there are no approved neoadjuvant or adjuvant therapies.

Immune checkpoint therapy has not been well studied in early-stage HCC, but it is used in advanced HCC.

The combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab, is currently a first-line treatment for advanced HCC. “Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable, and clinically beneficial against advanced HCC,” according to researchers writing in a Nature Reviews article published in April 2021.

There are other promising immunotherapies under study for HCC, such as additional checkpoint inhibitors, adoptive cell transfer, vaccination, and virotherapy.
 

Small study of 27 patients

The Lancet study included 27 patients (64 years mean age, 19 patients were male). Twenty-three percent of patients on nivolumab alone had a partial pathological response at week 6, while none in the combination group had a response. Among 20 patients who underwent surgery, 3 of 9 (33%) and 3 of 11 (27%) in the combination group experienced a major pathological response. Two patients in the nivolumab and three patients in the combination group achieved a complete pathological response.

Disease progression occurred in 7 of 12 patients who were evaluated in the nivolumab group, and 4 of 13 patients in the combination group. Estimated median time to disease progression in the nivolumab group was 9.4 months (95% confidence interval, 1.47 to not estimable) and 19.53 months (95% CI, 2.33 to not estimable) in the combination group. Two-year progression-free survival was estimated to be 42% (95% CI, 21%-81%) in the nivolumab group and 26% (95% CI, 8%-78%, no significant difference) in the combination group.

Among 20 patients who underwent surgery, 6 patients had experienced a major pathological response. None of the 6 patients had a recurrence after a median follow-up of 26.8 months, versus 7 recurrences among 14 patients without a pathological response (log-rank P = .049).

Seventy-seven percent of patients in the nivolumab group experienced at least one adverse event (23% grade 3-4), as did 86% in the combination group (43% grade 3-4, difference nonsignificant). No patients delayed or canceled surgery because of adverse events.

Patients who had a major pathological response on the combination treatment had higher levels of immune infiltration versus baseline values. Those who had complete pathological responses in the nivolumab group had high infiltration at baseline. Those results imply some optimism for further study. “These data suggest that, with the immune-priming ability of anti–CTLA-4 treatment, nivolumab plus ipilimumab was able to generate a major pathological response even in tumours that had low immune infiltration at baseline,” the authors wrote.

The study was limited by its open-label nature and small sample size, and it was conducted at a single center.

The study was funded by Bristol Myers Squibb and the National Institutes of Health. Dr. Kaseb reports consulting, advisory roles or stock ownership, or both with Bristol-Myers Squibb.