User login
Higher Prostate Cancer Rates Seen in Black Men, but Advanced Cases Similar to White Men
There was a substantial difference in prostate cancer diagnosis across ethnic groups: 25% of Black men with a raised PSA were diagnosed with prostate cancer within 1 year of being tested, compared with 20% of White men and 13% of Asian men, in the analysis of a large primary care cohort in the United Kingdom.
Incidence of advanced prostate cancer for Asian men with a raised PSA result was 4.5%, compared with 7.5% for White men and 7.0% for Black men.
Men included in the study were aged 40 and older and had no prior cancer diagnosis. Their ethnicity and PSA test result were logged in a national dataset between 2010 and 2017.
The study of more than 730,000 men, published in BMC Medicine, didn’t explore reasons for the differences, but experts offer their thoughts on what led to the findings and what these results imply.
Why the Higher Diagnosis Rates but Not More Advanced Disease in Black Men?
Lead author Liz Down, a graduate research assistant at the University of Exeter, Exeter, England, suggests the higher diagnosis rates but not more advanced disease in Black men may be linked to genetic variations.
Her team’s studies have shown that Black men in the United Kingdom and United States have higher levels of PSA. The PSA value is used to identify patients who might benefit from specialist investigation, and current guidelines in the UK and US don’t distinguish between ethnic groups.
As most men have slow-growing prostate cancer, this may lead to a disproportionately higher number of Black men being diagnosed with prostate cancer, she said.
“One possible interpretation,” Ms. Down notes, “is that prostate cancer follows a similar trajectory in Black and White men. What is different, however, is that Black men have higher PSA levels.”
As to why the advanced-cancer incidence is similar in Black and White patients in the study, Daniel George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, says it’s important to understand that the Black men in this study “are not necessarily representative of the Black population at large.”
In this study, “they’re a little bit more healthcare inclined,” Dr. George notes. The study population is actively seeking the PSA test. Their socioeconomic profile might be closer to their White counterparts’, and that may make results more similar, he said.
“It’s possible that because this is a screening and not just men coming in for symptoms or cause, that we’re not seeing as much advanced disease,” he continued.
Amar Kishan, MD, chief of the genitourinary oncology service at University of California Los Angeles (UCLA) Health, says the genomic factors and environmental stressors that lead to elevated PSA counts don’t necessarily translate into aggressiveness of disease.
Why do Different Races have Different Prostate Cancer Risk?
Dr. George points out that the study also highlights that Asian men were significantly less likely to be diagnosed with prostate cancer within 1 year of the test.
The reasons for differences in prostate risk by race are complex, he notes. There are some clues that biologic factors may be at work. For instance, early puberty has a link to prostate cancer as it does to breast cancer, and height is also associated with a greater risk of prostate cancer, Dr. George said.
It’s not necessarily a racial association but there are some biological factors associated with prostate cancer later in life, he explained. “These may be enriched in certain populations, including northern Europeans and patients with African ancestries.”
The study also notes that Black men are more likely to die from prostate cancer than are White men, and Asian men are less likely than White or Black men to die from it.
Ms. Down said the difference in prostate cancer mortality between Black vs White men, in particular, may be related to a number of factors, and age, and lifetime risk of prostate cancer may play a major role, at least in the UK.
Should There Be Different ‘Normal’ PSA Levels for Different Races?
Dr. George says there is likely a need to change the system because a PSA level in one race may not signal the same risk it does in another. So medicine probably needs to standardize what a “normal” PSA is by race, he says, adding that he is a coauthor of an upcoming paper regarding that issue.
The lowest instances of prostate cancer were in Asian patients so this isn’t just a Black and White issue, Dr. George notes. “Being able to establish benchmarks by race and ethnicity is something that is probably needed in the field,” he says.
Dr. Kishan, on the other hand, says data from this study are not enough to support differentiating PSA levels based on race. He noted a limitation of the study is that it was not able to calculate the false-negative rate of PSA tests.
What are the Implications for Treating and Screening for Prostate Cancer
Dr. Kishan says there may be a role for increased intensity of screening, whether at an earlier age or with different intervals, but prostate cancer treatment should not differ by race.
“Our prior study, as well as others,” he says, “have shown that when you balance Black and White patients for every factor that might impact prognosis other than race — such as age, disease aggressiveness, etc. — Black men actually tend to have better outcomes than White men. Thus, it would mean potentially overtreating (i.e., causing unnecessary side effects) to increase treatment intensity purely based on race with the available data.”
According to the paper, prostate cancer incidence in men with higher PSA levels increases with increasing age, even when using age-adjusted thresholds.
Dr. George says we know from this study and other studies as well that Black men are more likely to be diagnosed with prostate at a younger age. “Therefore, we probably need to be thinking about screening Black men starting at a younger age. These are the men who are most likely to benefit from an intervention — patients who have life expectancies of 20 years or more.”
What are the Downsides to Overdiagnosing Prostate Cancer in Men?
“It’s one of the biggest concerns that men have in proactively seeking healthcare,” Dr. George says. “They’re more likely to undergo treatment for this disease if they’re getting screened because (clinicians are) more likely to find it.”
Some of those men, he says, are going to undergo treatment for disease that won’t ultimately kill them, but may cause complications the men shouldn’t have had at all or otherwise may have had later.
“Overtreatment is a real concern. That’s why active surveillance is so important to minimize overtreatment of patients by finding out which cancers are low risk for progression and which are becoming more aggressive,” Dr. George says.
Authors of the study write that “the potential for overdiagnosis and the subsequent psychological and physical impact of diagnosis and treatment is an important consideration.”
All authors of the new paper received financial support from Cancer Research UK, the National Institute for Health and Care Research (NIHR), and the Higgins family for the submitted work.
Dr. George reports no relevant financial relationships.
Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, Janssen, and Boston Scientific; research funding from PointBioPharma, Lantheus, and Janssen; and serving on advisory boards for Lantheus, Janssen and Boston Scientific.
There was a substantial difference in prostate cancer diagnosis across ethnic groups: 25% of Black men with a raised PSA were diagnosed with prostate cancer within 1 year of being tested, compared with 20% of White men and 13% of Asian men, in the analysis of a large primary care cohort in the United Kingdom.
Incidence of advanced prostate cancer for Asian men with a raised PSA result was 4.5%, compared with 7.5% for White men and 7.0% for Black men.
Men included in the study were aged 40 and older and had no prior cancer diagnosis. Their ethnicity and PSA test result were logged in a national dataset between 2010 and 2017.
The study of more than 730,000 men, published in BMC Medicine, didn’t explore reasons for the differences, but experts offer their thoughts on what led to the findings and what these results imply.
Why the Higher Diagnosis Rates but Not More Advanced Disease in Black Men?
Lead author Liz Down, a graduate research assistant at the University of Exeter, Exeter, England, suggests the higher diagnosis rates but not more advanced disease in Black men may be linked to genetic variations.
Her team’s studies have shown that Black men in the United Kingdom and United States have higher levels of PSA. The PSA value is used to identify patients who might benefit from specialist investigation, and current guidelines in the UK and US don’t distinguish between ethnic groups.
As most men have slow-growing prostate cancer, this may lead to a disproportionately higher number of Black men being diagnosed with prostate cancer, she said.
“One possible interpretation,” Ms. Down notes, “is that prostate cancer follows a similar trajectory in Black and White men. What is different, however, is that Black men have higher PSA levels.”
As to why the advanced-cancer incidence is similar in Black and White patients in the study, Daniel George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, says it’s important to understand that the Black men in this study “are not necessarily representative of the Black population at large.”
In this study, “they’re a little bit more healthcare inclined,” Dr. George notes. The study population is actively seeking the PSA test. Their socioeconomic profile might be closer to their White counterparts’, and that may make results more similar, he said.
“It’s possible that because this is a screening and not just men coming in for symptoms or cause, that we’re not seeing as much advanced disease,” he continued.
Amar Kishan, MD, chief of the genitourinary oncology service at University of California Los Angeles (UCLA) Health, says the genomic factors and environmental stressors that lead to elevated PSA counts don’t necessarily translate into aggressiveness of disease.
Why do Different Races have Different Prostate Cancer Risk?
Dr. George points out that the study also highlights that Asian men were significantly less likely to be diagnosed with prostate cancer within 1 year of the test.
The reasons for differences in prostate risk by race are complex, he notes. There are some clues that biologic factors may be at work. For instance, early puberty has a link to prostate cancer as it does to breast cancer, and height is also associated with a greater risk of prostate cancer, Dr. George said.
It’s not necessarily a racial association but there are some biological factors associated with prostate cancer later in life, he explained. “These may be enriched in certain populations, including northern Europeans and patients with African ancestries.”
The study also notes that Black men are more likely to die from prostate cancer than are White men, and Asian men are less likely than White or Black men to die from it.
Ms. Down said the difference in prostate cancer mortality between Black vs White men, in particular, may be related to a number of factors, and age, and lifetime risk of prostate cancer may play a major role, at least in the UK.
Should There Be Different ‘Normal’ PSA Levels for Different Races?
Dr. George says there is likely a need to change the system because a PSA level in one race may not signal the same risk it does in another. So medicine probably needs to standardize what a “normal” PSA is by race, he says, adding that he is a coauthor of an upcoming paper regarding that issue.
The lowest instances of prostate cancer were in Asian patients so this isn’t just a Black and White issue, Dr. George notes. “Being able to establish benchmarks by race and ethnicity is something that is probably needed in the field,” he says.
Dr. Kishan, on the other hand, says data from this study are not enough to support differentiating PSA levels based on race. He noted a limitation of the study is that it was not able to calculate the false-negative rate of PSA tests.
What are the Implications for Treating and Screening for Prostate Cancer
Dr. Kishan says there may be a role for increased intensity of screening, whether at an earlier age or with different intervals, but prostate cancer treatment should not differ by race.
“Our prior study, as well as others,” he says, “have shown that when you balance Black and White patients for every factor that might impact prognosis other than race — such as age, disease aggressiveness, etc. — Black men actually tend to have better outcomes than White men. Thus, it would mean potentially overtreating (i.e., causing unnecessary side effects) to increase treatment intensity purely based on race with the available data.”
According to the paper, prostate cancer incidence in men with higher PSA levels increases with increasing age, even when using age-adjusted thresholds.
Dr. George says we know from this study and other studies as well that Black men are more likely to be diagnosed with prostate at a younger age. “Therefore, we probably need to be thinking about screening Black men starting at a younger age. These are the men who are most likely to benefit from an intervention — patients who have life expectancies of 20 years or more.”
What are the Downsides to Overdiagnosing Prostate Cancer in Men?
“It’s one of the biggest concerns that men have in proactively seeking healthcare,” Dr. George says. “They’re more likely to undergo treatment for this disease if they’re getting screened because (clinicians are) more likely to find it.”
Some of those men, he says, are going to undergo treatment for disease that won’t ultimately kill them, but may cause complications the men shouldn’t have had at all or otherwise may have had later.
“Overtreatment is a real concern. That’s why active surveillance is so important to minimize overtreatment of patients by finding out which cancers are low risk for progression and which are becoming more aggressive,” Dr. George says.
Authors of the study write that “the potential for overdiagnosis and the subsequent psychological and physical impact of diagnosis and treatment is an important consideration.”
All authors of the new paper received financial support from Cancer Research UK, the National Institute for Health and Care Research (NIHR), and the Higgins family for the submitted work.
Dr. George reports no relevant financial relationships.
Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, Janssen, and Boston Scientific; research funding from PointBioPharma, Lantheus, and Janssen; and serving on advisory boards for Lantheus, Janssen and Boston Scientific.
There was a substantial difference in prostate cancer diagnosis across ethnic groups: 25% of Black men with a raised PSA were diagnosed with prostate cancer within 1 year of being tested, compared with 20% of White men and 13% of Asian men, in the analysis of a large primary care cohort in the United Kingdom.
Incidence of advanced prostate cancer for Asian men with a raised PSA result was 4.5%, compared with 7.5% for White men and 7.0% for Black men.
Men included in the study were aged 40 and older and had no prior cancer diagnosis. Their ethnicity and PSA test result were logged in a national dataset between 2010 and 2017.
The study of more than 730,000 men, published in BMC Medicine, didn’t explore reasons for the differences, but experts offer their thoughts on what led to the findings and what these results imply.
Why the Higher Diagnosis Rates but Not More Advanced Disease in Black Men?
Lead author Liz Down, a graduate research assistant at the University of Exeter, Exeter, England, suggests the higher diagnosis rates but not more advanced disease in Black men may be linked to genetic variations.
Her team’s studies have shown that Black men in the United Kingdom and United States have higher levels of PSA. The PSA value is used to identify patients who might benefit from specialist investigation, and current guidelines in the UK and US don’t distinguish between ethnic groups.
As most men have slow-growing prostate cancer, this may lead to a disproportionately higher number of Black men being diagnosed with prostate cancer, she said.
“One possible interpretation,” Ms. Down notes, “is that prostate cancer follows a similar trajectory in Black and White men. What is different, however, is that Black men have higher PSA levels.”
As to why the advanced-cancer incidence is similar in Black and White patients in the study, Daniel George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, says it’s important to understand that the Black men in this study “are not necessarily representative of the Black population at large.”
In this study, “they’re a little bit more healthcare inclined,” Dr. George notes. The study population is actively seeking the PSA test. Their socioeconomic profile might be closer to their White counterparts’, and that may make results more similar, he said.
“It’s possible that because this is a screening and not just men coming in for symptoms or cause, that we’re not seeing as much advanced disease,” he continued.
Amar Kishan, MD, chief of the genitourinary oncology service at University of California Los Angeles (UCLA) Health, says the genomic factors and environmental stressors that lead to elevated PSA counts don’t necessarily translate into aggressiveness of disease.
Why do Different Races have Different Prostate Cancer Risk?
Dr. George points out that the study also highlights that Asian men were significantly less likely to be diagnosed with prostate cancer within 1 year of the test.
The reasons for differences in prostate risk by race are complex, he notes. There are some clues that biologic factors may be at work. For instance, early puberty has a link to prostate cancer as it does to breast cancer, and height is also associated with a greater risk of prostate cancer, Dr. George said.
It’s not necessarily a racial association but there are some biological factors associated with prostate cancer later in life, he explained. “These may be enriched in certain populations, including northern Europeans and patients with African ancestries.”
The study also notes that Black men are more likely to die from prostate cancer than are White men, and Asian men are less likely than White or Black men to die from it.
Ms. Down said the difference in prostate cancer mortality between Black vs White men, in particular, may be related to a number of factors, and age, and lifetime risk of prostate cancer may play a major role, at least in the UK.
Should There Be Different ‘Normal’ PSA Levels for Different Races?
Dr. George says there is likely a need to change the system because a PSA level in one race may not signal the same risk it does in another. So medicine probably needs to standardize what a “normal” PSA is by race, he says, adding that he is a coauthor of an upcoming paper regarding that issue.
The lowest instances of prostate cancer were in Asian patients so this isn’t just a Black and White issue, Dr. George notes. “Being able to establish benchmarks by race and ethnicity is something that is probably needed in the field,” he says.
Dr. Kishan, on the other hand, says data from this study are not enough to support differentiating PSA levels based on race. He noted a limitation of the study is that it was not able to calculate the false-negative rate of PSA tests.
What are the Implications for Treating and Screening for Prostate Cancer
Dr. Kishan says there may be a role for increased intensity of screening, whether at an earlier age or with different intervals, but prostate cancer treatment should not differ by race.
“Our prior study, as well as others,” he says, “have shown that when you balance Black and White patients for every factor that might impact prognosis other than race — such as age, disease aggressiveness, etc. — Black men actually tend to have better outcomes than White men. Thus, it would mean potentially overtreating (i.e., causing unnecessary side effects) to increase treatment intensity purely based on race with the available data.”
According to the paper, prostate cancer incidence in men with higher PSA levels increases with increasing age, even when using age-adjusted thresholds.
Dr. George says we know from this study and other studies as well that Black men are more likely to be diagnosed with prostate at a younger age. “Therefore, we probably need to be thinking about screening Black men starting at a younger age. These are the men who are most likely to benefit from an intervention — patients who have life expectancies of 20 years or more.”
What are the Downsides to Overdiagnosing Prostate Cancer in Men?
“It’s one of the biggest concerns that men have in proactively seeking healthcare,” Dr. George says. “They’re more likely to undergo treatment for this disease if they’re getting screened because (clinicians are) more likely to find it.”
Some of those men, he says, are going to undergo treatment for disease that won’t ultimately kill them, but may cause complications the men shouldn’t have had at all or otherwise may have had later.
“Overtreatment is a real concern. That’s why active surveillance is so important to minimize overtreatment of patients by finding out which cancers are low risk for progression and which are becoming more aggressive,” Dr. George says.
Authors of the study write that “the potential for overdiagnosis and the subsequent psychological and physical impact of diagnosis and treatment is an important consideration.”
All authors of the new paper received financial support from Cancer Research UK, the National Institute for Health and Care Research (NIHR), and the Higgins family for the submitted work.
Dr. George reports no relevant financial relationships.
Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, Janssen, and Boston Scientific; research funding from PointBioPharma, Lantheus, and Janssen; and serving on advisory boards for Lantheus, Janssen and Boston Scientific.
FROM BMC MEDICINE
Study Characterizes Pathologic B-Cell Maturation in Crohn’s Disease
, according to investigators.
These findings begin to address a knowledge gap in Crohn’s disease that has been more thoroughly explored in ulcerative colitis, reported lead author Sonja Kappel-Latif, MD, PhD, of Medical University of Vienna, Vienna, Austria, and colleagues.
“Recent studies have investigated the role of B-cell responses in ulcerative colitis, which exclusively affects the colon, whereas data in CD, which mainly affects the terminal ileum, are insufficient,” the investigators wrote in wrote in Cellular and Molecular Gastroenterology and Hepatology. “Granuloma formation within the thickened, inflamed mesentery of patients with CD, however, is associated with significantly worse outcome, and microstructural analysis has suggested increased numbers of B cells in CD mesentery.”
Previous studies have shown that abnormal B-cell development in patients with CD leads to development of IgG targeting commensal — instead of pathogenic — gut bacteria. Yet B-cell receptor sequencing in CD has only been conducted on peripheral blood, despite awareness that anticommensal IgG antibodies can be transported across mucosal barriers in patients with ulcerative colitis, sustaining intestinal inflammation.
To better characterize local B-cell responses in CD, the investigators evaluated paired samples of draining mesenteric lymph nodes (MLNs) from both healthy and adjacently affected intestinal tissue, yielding a range of findings.
First, the investigators noted that CD19+ B cells and CD45+ leukocytes were expanded in affected MLNs, while T cells were reduced. A closer look showed that IgD-CD27- B cells were more abundant among CD19+CD45+ B cells in affected MLNs. Within this CD45+CD19+CD27+IgD- B-cell fraction, CD38- memory B cells were reduced.
The above findings suggest “ongoing antigenic stimulation within affected MLNs,” the investigators wrote.
Further comparison of paired samples showed that germinal centers (within which B cells mature) were significantly larger in affected MLNs, and contained dark and light zones. In contrast, healthy MLNs had smaller, more immature germinal centers.
Due to T-cell dependence during B-cell isotype switching within these germinal centers, the investigators next conducted immunohistochemistry staining for Bcl6, a “master regulator” of T-follicular helper cells expressed in class-switching B cells, and Ki67, which indicates cell proliferation. These analyses shows that both markers were “highly positive” within the germinal centers of affected MLNs.
Next, Dr. Kappel-Latif and colleagues conducted B-cell receptor (BCR) sequencing to characterize differences in class switching. Compared with healthy MLNs, affected MLNs showed decreased use of IGHA and IGHE alongside a significant uptick in IGHG1/2.
Further analyses showed that somatic hypermutation (SHM) frequency was significantly higher in IGHM and IGHA B cells, which was driven by mutations in complementary determining regions (CDRs) and framework regions of IGHA B cells, and mutations in the CDRs of IGHM B cells.
BCR diversity increased in the IGHG1/2 B cells, but remained unchanged in the IGHM or IGHA B cells.
“Overall, our results indicate ongoing class switching within draining MLNs of affected intestinal segments, with a shift toward IGHG1/2 BCRs,” the investigators concluded. “The lack of high SHM rates within IGHG1/2 BCRs, the difference between IGHA and IGHG1/2 BCRs in single MLNs, and increased diversity in IGHG1/2 BCRs suggests that many antigens do not result in long-lasting immunologic stimulation, and IGHA and IGHG1/2 responses may target different pathogens/commensals.”
The study was supported by the Austrian Science Fund and the Major of Vienna. The investigators disclosed no conflicts of interest.
The pathophysiology of inflammatory bowel disease (IBD) is complex and involves multiple mechanisms. Among these mechanisms, dysfunction and overactivation of the intestinal immune system are widely implicated. Dysfunctions in both the innate and adaptive immune systems have been demonstrated. However, mucosal immunology research related to IBD has long been particularly focused on T lymphocytes due to the failure of the rituximab clinical trial (anti-CD20) in ulcerative colitis (UC). Recent data have indicated modifications in the landscape of B lymphocyte subpopulations within the inflamed mucosa of patients with UC or ileal Crohn’s disease (CD).
Similarly, to what was previously shown in the inflamed colonic and ileal mucosa of IBD patients, isotype usage showed a skewing from IgA to IgG1. Further analysis of the B cell receptor (BCR) showed a very diverse repertoire of B cells, reflecting a large panel of antigenic stimulation. As we know, IBD are complex diseases that may not be explained by a single or a limited set of antigenic drivers.
Whether these changes in the B-cell compartment are a triggering event of inflammation or a bystander, reflecting the increased intestinal permeability and exposure to microbiota antigens during inflammation, remains to be explored and further studied.
Mathieu Uzzan, MD, PhD, is based in the gastroenterology department, Hopital Henri Mondor, APHP, Créteil, France. He has no relevant disclosures.
The pathophysiology of inflammatory bowel disease (IBD) is complex and involves multiple mechanisms. Among these mechanisms, dysfunction and overactivation of the intestinal immune system are widely implicated. Dysfunctions in both the innate and adaptive immune systems have been demonstrated. However, mucosal immunology research related to IBD has long been particularly focused on T lymphocytes due to the failure of the rituximab clinical trial (anti-CD20) in ulcerative colitis (UC). Recent data have indicated modifications in the landscape of B lymphocyte subpopulations within the inflamed mucosa of patients with UC or ileal Crohn’s disease (CD).
Similarly, to what was previously shown in the inflamed colonic and ileal mucosa of IBD patients, isotype usage showed a skewing from IgA to IgG1. Further analysis of the B cell receptor (BCR) showed a very diverse repertoire of B cells, reflecting a large panel of antigenic stimulation. As we know, IBD are complex diseases that may not be explained by a single or a limited set of antigenic drivers.
Whether these changes in the B-cell compartment are a triggering event of inflammation or a bystander, reflecting the increased intestinal permeability and exposure to microbiota antigens during inflammation, remains to be explored and further studied.
Mathieu Uzzan, MD, PhD, is based in the gastroenterology department, Hopital Henri Mondor, APHP, Créteil, France. He has no relevant disclosures.
The pathophysiology of inflammatory bowel disease (IBD) is complex and involves multiple mechanisms. Among these mechanisms, dysfunction and overactivation of the intestinal immune system are widely implicated. Dysfunctions in both the innate and adaptive immune systems have been demonstrated. However, mucosal immunology research related to IBD has long been particularly focused on T lymphocytes due to the failure of the rituximab clinical trial (anti-CD20) in ulcerative colitis (UC). Recent data have indicated modifications in the landscape of B lymphocyte subpopulations within the inflamed mucosa of patients with UC or ileal Crohn’s disease (CD).
Similarly, to what was previously shown in the inflamed colonic and ileal mucosa of IBD patients, isotype usage showed a skewing from IgA to IgG1. Further analysis of the B cell receptor (BCR) showed a very diverse repertoire of B cells, reflecting a large panel of antigenic stimulation. As we know, IBD are complex diseases that may not be explained by a single or a limited set of antigenic drivers.
Whether these changes in the B-cell compartment are a triggering event of inflammation or a bystander, reflecting the increased intestinal permeability and exposure to microbiota antigens during inflammation, remains to be explored and further studied.
Mathieu Uzzan, MD, PhD, is based in the gastroenterology department, Hopital Henri Mondor, APHP, Créteil, France. He has no relevant disclosures.
, according to investigators.
These findings begin to address a knowledge gap in Crohn’s disease that has been more thoroughly explored in ulcerative colitis, reported lead author Sonja Kappel-Latif, MD, PhD, of Medical University of Vienna, Vienna, Austria, and colleagues.
“Recent studies have investigated the role of B-cell responses in ulcerative colitis, which exclusively affects the colon, whereas data in CD, which mainly affects the terminal ileum, are insufficient,” the investigators wrote in wrote in Cellular and Molecular Gastroenterology and Hepatology. “Granuloma formation within the thickened, inflamed mesentery of patients with CD, however, is associated with significantly worse outcome, and microstructural analysis has suggested increased numbers of B cells in CD mesentery.”
Previous studies have shown that abnormal B-cell development in patients with CD leads to development of IgG targeting commensal — instead of pathogenic — gut bacteria. Yet B-cell receptor sequencing in CD has only been conducted on peripheral blood, despite awareness that anticommensal IgG antibodies can be transported across mucosal barriers in patients with ulcerative colitis, sustaining intestinal inflammation.
To better characterize local B-cell responses in CD, the investigators evaluated paired samples of draining mesenteric lymph nodes (MLNs) from both healthy and adjacently affected intestinal tissue, yielding a range of findings.
First, the investigators noted that CD19+ B cells and CD45+ leukocytes were expanded in affected MLNs, while T cells were reduced. A closer look showed that IgD-CD27- B cells were more abundant among CD19+CD45+ B cells in affected MLNs. Within this CD45+CD19+CD27+IgD- B-cell fraction, CD38- memory B cells were reduced.
The above findings suggest “ongoing antigenic stimulation within affected MLNs,” the investigators wrote.
Further comparison of paired samples showed that germinal centers (within which B cells mature) were significantly larger in affected MLNs, and contained dark and light zones. In contrast, healthy MLNs had smaller, more immature germinal centers.
Due to T-cell dependence during B-cell isotype switching within these germinal centers, the investigators next conducted immunohistochemistry staining for Bcl6, a “master regulator” of T-follicular helper cells expressed in class-switching B cells, and Ki67, which indicates cell proliferation. These analyses shows that both markers were “highly positive” within the germinal centers of affected MLNs.
Next, Dr. Kappel-Latif and colleagues conducted B-cell receptor (BCR) sequencing to characterize differences in class switching. Compared with healthy MLNs, affected MLNs showed decreased use of IGHA and IGHE alongside a significant uptick in IGHG1/2.
Further analyses showed that somatic hypermutation (SHM) frequency was significantly higher in IGHM and IGHA B cells, which was driven by mutations in complementary determining regions (CDRs) and framework regions of IGHA B cells, and mutations in the CDRs of IGHM B cells.
BCR diversity increased in the IGHG1/2 B cells, but remained unchanged in the IGHM or IGHA B cells.
“Overall, our results indicate ongoing class switching within draining MLNs of affected intestinal segments, with a shift toward IGHG1/2 BCRs,” the investigators concluded. “The lack of high SHM rates within IGHG1/2 BCRs, the difference between IGHA and IGHG1/2 BCRs in single MLNs, and increased diversity in IGHG1/2 BCRs suggests that many antigens do not result in long-lasting immunologic stimulation, and IGHA and IGHG1/2 responses may target different pathogens/commensals.”
The study was supported by the Austrian Science Fund and the Major of Vienna. The investigators disclosed no conflicts of interest.
, according to investigators.
These findings begin to address a knowledge gap in Crohn’s disease that has been more thoroughly explored in ulcerative colitis, reported lead author Sonja Kappel-Latif, MD, PhD, of Medical University of Vienna, Vienna, Austria, and colleagues.
“Recent studies have investigated the role of B-cell responses in ulcerative colitis, which exclusively affects the colon, whereas data in CD, which mainly affects the terminal ileum, are insufficient,” the investigators wrote in wrote in Cellular and Molecular Gastroenterology and Hepatology. “Granuloma formation within the thickened, inflamed mesentery of patients with CD, however, is associated with significantly worse outcome, and microstructural analysis has suggested increased numbers of B cells in CD mesentery.”
Previous studies have shown that abnormal B-cell development in patients with CD leads to development of IgG targeting commensal — instead of pathogenic — gut bacteria. Yet B-cell receptor sequencing in CD has only been conducted on peripheral blood, despite awareness that anticommensal IgG antibodies can be transported across mucosal barriers in patients with ulcerative colitis, sustaining intestinal inflammation.
To better characterize local B-cell responses in CD, the investigators evaluated paired samples of draining mesenteric lymph nodes (MLNs) from both healthy and adjacently affected intestinal tissue, yielding a range of findings.
First, the investigators noted that CD19+ B cells and CD45+ leukocytes were expanded in affected MLNs, while T cells were reduced. A closer look showed that IgD-CD27- B cells were more abundant among CD19+CD45+ B cells in affected MLNs. Within this CD45+CD19+CD27+IgD- B-cell fraction, CD38- memory B cells were reduced.
The above findings suggest “ongoing antigenic stimulation within affected MLNs,” the investigators wrote.
Further comparison of paired samples showed that germinal centers (within which B cells mature) were significantly larger in affected MLNs, and contained dark and light zones. In contrast, healthy MLNs had smaller, more immature germinal centers.
Due to T-cell dependence during B-cell isotype switching within these germinal centers, the investigators next conducted immunohistochemistry staining for Bcl6, a “master regulator” of T-follicular helper cells expressed in class-switching B cells, and Ki67, which indicates cell proliferation. These analyses shows that both markers were “highly positive” within the germinal centers of affected MLNs.
Next, Dr. Kappel-Latif and colleagues conducted B-cell receptor (BCR) sequencing to characterize differences in class switching. Compared with healthy MLNs, affected MLNs showed decreased use of IGHA and IGHE alongside a significant uptick in IGHG1/2.
Further analyses showed that somatic hypermutation (SHM) frequency was significantly higher in IGHM and IGHA B cells, which was driven by mutations in complementary determining regions (CDRs) and framework regions of IGHA B cells, and mutations in the CDRs of IGHM B cells.
BCR diversity increased in the IGHG1/2 B cells, but remained unchanged in the IGHM or IGHA B cells.
“Overall, our results indicate ongoing class switching within draining MLNs of affected intestinal segments, with a shift toward IGHG1/2 BCRs,” the investigators concluded. “The lack of high SHM rates within IGHG1/2 BCRs, the difference between IGHA and IGHG1/2 BCRs in single MLNs, and increased diversity in IGHG1/2 BCRs suggests that many antigens do not result in long-lasting immunologic stimulation, and IGHA and IGHG1/2 responses may target different pathogens/commensals.”
The study was supported by the Austrian Science Fund and the Major of Vienna. The investigators disclosed no conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Latest NCCN Melanoma Guidelines Capture Dynamic of Constantly Evolving Best Practice
SAN DIEGO — that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.
Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.
Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time.
Next AAD Guidelines More Than 1 Year Away
The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago.
Many of the changes in the 2024 NCCN guidelines capture incremental advances rather than a radical departure from previous practice. One example involves shave biopsies. According to a new recommendation, residual pigment or tumor found at the base of a shave procedure, whether for tumor removal or biopsy, should prompt a deeper punch or elliptical biopsy.
The additional biopsy “should be performed immediately and submitted in a separate container to the pathologist,” Dr. Swetter said.
Further, the biopsy should be accompanied with a note to the pathologist that the shave specimen was transected. She added that the Breslow thickness (the measurement of the depth of the melanoma from the top of the granular layer down to the deepest point of the tumor) can accompany each of the two tissue specimens submitted to the pathologist.
This update — like most of the NCCN guidelines — is a category 2A recommendation. Category 1 recommendations signal a high level of evidence, such as a multicenter randomized trial. A 2A recommendation is based on nondefinitive evidence, but it does represent near uniform (≥ 85% agreement) expert consensus.
More Than 50% Consensus Generally Required
The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.
Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website.
Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.
Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.
There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
Best Margins for MIS Undefined
So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.
The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.
Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.
Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.
“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.
This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.
Dr. Swetter and Dr. Kim report no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO — that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.
Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.
Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time.
Next AAD Guidelines More Than 1 Year Away
The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago.
Many of the changes in the 2024 NCCN guidelines capture incremental advances rather than a radical departure from previous practice. One example involves shave biopsies. According to a new recommendation, residual pigment or tumor found at the base of a shave procedure, whether for tumor removal or biopsy, should prompt a deeper punch or elliptical biopsy.
The additional biopsy “should be performed immediately and submitted in a separate container to the pathologist,” Dr. Swetter said.
Further, the biopsy should be accompanied with a note to the pathologist that the shave specimen was transected. She added that the Breslow thickness (the measurement of the depth of the melanoma from the top of the granular layer down to the deepest point of the tumor) can accompany each of the two tissue specimens submitted to the pathologist.
This update — like most of the NCCN guidelines — is a category 2A recommendation. Category 1 recommendations signal a high level of evidence, such as a multicenter randomized trial. A 2A recommendation is based on nondefinitive evidence, but it does represent near uniform (≥ 85% agreement) expert consensus.
More Than 50% Consensus Generally Required
The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.
Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website.
Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.
Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.
There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
Best Margins for MIS Undefined
So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.
The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.
Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.
Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.
“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.
This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.
Dr. Swetter and Dr. Kim report no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO — that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.
Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.
Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time.
Next AAD Guidelines More Than 1 Year Away
The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago.
Many of the changes in the 2024 NCCN guidelines capture incremental advances rather than a radical departure from previous practice. One example involves shave biopsies. According to a new recommendation, residual pigment or tumor found at the base of a shave procedure, whether for tumor removal or biopsy, should prompt a deeper punch or elliptical biopsy.
The additional biopsy “should be performed immediately and submitted in a separate container to the pathologist,” Dr. Swetter said.
Further, the biopsy should be accompanied with a note to the pathologist that the shave specimen was transected. She added that the Breslow thickness (the measurement of the depth of the melanoma from the top of the granular layer down to the deepest point of the tumor) can accompany each of the two tissue specimens submitted to the pathologist.
This update — like most of the NCCN guidelines — is a category 2A recommendation. Category 1 recommendations signal a high level of evidence, such as a multicenter randomized trial. A 2A recommendation is based on nondefinitive evidence, but it does represent near uniform (≥ 85% agreement) expert consensus.
More Than 50% Consensus Generally Required
The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.
Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website.
Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.
Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.
There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
Best Margins for MIS Undefined
So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.
The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.
Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.
Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.
“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.
This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.
Dr. Swetter and Dr. Kim report no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM AAD 2024
AGA Supports Fecal Microbiota Therapies for CDI but Not IBD or IBS
Addressing Clostridium difficile infection (CDI), Crohn’s disease (CD) ulcerative colitis (UC), pouchitis, and irritable bowel syndrome (IBS), the guidance supports FMT for the prevention of recurrent CDI but not for inflammatory bowel disease (IBD) or IBS — outside of clinical trials.
The AGA’s recommendations were published in Gastroenterology.
“Fecal microbiota–based therapies are effective therapy to prevent recurrent C. difficile in select patients,” the AGA guideline states. “Conventional fecal microbiota transplant is an adjuvant treatment for select adults hospitalized with severe or fulminant C. difficile infection not responding to standard of care antibiotics. Fecal microbiota transplant cannot yet be recommended in other gastrointestinal conditions.”
“We thought it was important to write this guideline because of the growing number of trials of FMT in IBD and IBS populations. It was also important with the new FDA-approved treatments on the market,” the guideline’s first author, Anne F. Peery, MD, MSCR, AGAF, told this news organization, noting that the recently approved products did not yield better results than those of conventional rectal FMT. “The guidelines will help clinicians understand the available therapies and how to use these treatments,” added Dr. Peery, associate professor in the Division of Gastroenterology and Hepatology at the University of North Carolina School of Medicine in Chapel Hill.
Although the existing evidence is of low or very low certainty, Dr. Peery acknowledged, gastroenterologists “should be comfortable with conventional FMT and also the new FDA-approved products. We spent a considerable amount of time developing implementation considerations, which is practical advice to help clinicians use the guideline recommendations.”
Designed to counteract intestinal dysbiosis and restore protective gut flora, the FMT approach includes conventional, colonoscopically delivered donor stool transplants as well as two newly approved options: rectally given fecal microbiota (live-jslm/ Rebyota) and most recently, orally delivered fecal microbiota spores (live-brpk/ Vowst).
The AGA urges careful pretreatment consideration for patients who require frequent antibiotics or long-term antibiotic prophylaxis since ongoing antibiotics may diminish the efficacy of FMT.
The guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis, followed by the Evidence-to-Decision framework to develop recommendations for these therapies and algorithms for their implementation into clinical practice.
Recommendations
The eight-member panel suggested the following practices on behalf of the AGA Clinical Guidelines Committee:
- In immunocompetent adults with recurrent CDI, select use of FMT can be used after completion of standard-of-care antibiotics to prevent recurrence. It can be considered after the second recurrence (episode 3) of CDI or in select patients at high risk for either recurrent CDI or a morbid CDI recurrence. Recurrent CDI is defined as clinically significant diarrhea ≥ 3 unformed stools in 24 hours with a confirmatory positive test within 8 weeks of completing antibiotics. Select use includes patients who have recovered from severe, fulminant, or particularly treatment-refractory CDI and patients with significant comorbidities. Severe CDI involves a leukocyte count of ≥15 × 109 cells/L and/or creatinine ≥1.5 mg/dL, while fulminant CDI involves shock, ileus, or megacolon and can be fatal.
- In mildly or moderately immunocompromised adults with recurrent CDI, the guidance recommends select use of conventional fecal microbiota transplant.
- In severely immunocompromised adults or those undergoing cytotoxic treatment, the AGA advises against the use of any fecal microbiota-based therapies to prevent recurrent CDI.
- Conventional FMT is not advised in patients who have bowel perforation or obstruction or are severely immunocompromised.
- For CDI patients not interested in FMT, reasonable alternatives to prevent recurrence are a vancomycin taper, tapered-pulsed fidaxomicin, or bezlotoxumab.
- In adults hospitalized with severe or fulminant CDI not responding to standard-of-care antibiotics, the AGA recommends select use of conventional FM transplant.
- In the current absence of evidence, the guidance advises against the use of conventional fecal microbiota transplant as treatment for IBD or IBS except in the context of clinical trials.
“We felt the data for using FMT in the treatment of UC was promising, but there is still a lot more work to be done in IBD and IBS,” Dr. Peery said. For each disease section the guideline outlined directions for future research. It will be updated in 3-5 years as more evidence becomes available.
This guideline was fully funded by the AGA Institute. Dr. Peery and fellow panel member Dr. Benjamin Lebwohl are supported by grants the National Institute of Diabetes and Digestive and Kidney Diseases. Panel member Colleen R. Kelly, MD, is supported by the National Institute of Allergy and Infectious Diseases.
None of the panel members had any conflicts of interest to report.
Addressing Clostridium difficile infection (CDI), Crohn’s disease (CD) ulcerative colitis (UC), pouchitis, and irritable bowel syndrome (IBS), the guidance supports FMT for the prevention of recurrent CDI but not for inflammatory bowel disease (IBD) or IBS — outside of clinical trials.
The AGA’s recommendations were published in Gastroenterology.
“Fecal microbiota–based therapies are effective therapy to prevent recurrent C. difficile in select patients,” the AGA guideline states. “Conventional fecal microbiota transplant is an adjuvant treatment for select adults hospitalized with severe or fulminant C. difficile infection not responding to standard of care antibiotics. Fecal microbiota transplant cannot yet be recommended in other gastrointestinal conditions.”
“We thought it was important to write this guideline because of the growing number of trials of FMT in IBD and IBS populations. It was also important with the new FDA-approved treatments on the market,” the guideline’s first author, Anne F. Peery, MD, MSCR, AGAF, told this news organization, noting that the recently approved products did not yield better results than those of conventional rectal FMT. “The guidelines will help clinicians understand the available therapies and how to use these treatments,” added Dr. Peery, associate professor in the Division of Gastroenterology and Hepatology at the University of North Carolina School of Medicine in Chapel Hill.
Although the existing evidence is of low or very low certainty, Dr. Peery acknowledged, gastroenterologists “should be comfortable with conventional FMT and also the new FDA-approved products. We spent a considerable amount of time developing implementation considerations, which is practical advice to help clinicians use the guideline recommendations.”
Designed to counteract intestinal dysbiosis and restore protective gut flora, the FMT approach includes conventional, colonoscopically delivered donor stool transplants as well as two newly approved options: rectally given fecal microbiota (live-jslm/ Rebyota) and most recently, orally delivered fecal microbiota spores (live-brpk/ Vowst).
The AGA urges careful pretreatment consideration for patients who require frequent antibiotics or long-term antibiotic prophylaxis since ongoing antibiotics may diminish the efficacy of FMT.
The guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis, followed by the Evidence-to-Decision framework to develop recommendations for these therapies and algorithms for their implementation into clinical practice.
Recommendations
The eight-member panel suggested the following practices on behalf of the AGA Clinical Guidelines Committee:
- In immunocompetent adults with recurrent CDI, select use of FMT can be used after completion of standard-of-care antibiotics to prevent recurrence. It can be considered after the second recurrence (episode 3) of CDI or in select patients at high risk for either recurrent CDI or a morbid CDI recurrence. Recurrent CDI is defined as clinically significant diarrhea ≥ 3 unformed stools in 24 hours with a confirmatory positive test within 8 weeks of completing antibiotics. Select use includes patients who have recovered from severe, fulminant, or particularly treatment-refractory CDI and patients with significant comorbidities. Severe CDI involves a leukocyte count of ≥15 × 109 cells/L and/or creatinine ≥1.5 mg/dL, while fulminant CDI involves shock, ileus, or megacolon and can be fatal.
- In mildly or moderately immunocompromised adults with recurrent CDI, the guidance recommends select use of conventional fecal microbiota transplant.
- In severely immunocompromised adults or those undergoing cytotoxic treatment, the AGA advises against the use of any fecal microbiota-based therapies to prevent recurrent CDI.
- Conventional FMT is not advised in patients who have bowel perforation or obstruction or are severely immunocompromised.
- For CDI patients not interested in FMT, reasonable alternatives to prevent recurrence are a vancomycin taper, tapered-pulsed fidaxomicin, or bezlotoxumab.
- In adults hospitalized with severe or fulminant CDI not responding to standard-of-care antibiotics, the AGA recommends select use of conventional FM transplant.
- In the current absence of evidence, the guidance advises against the use of conventional fecal microbiota transplant as treatment for IBD or IBS except in the context of clinical trials.
“We felt the data for using FMT in the treatment of UC was promising, but there is still a lot more work to be done in IBD and IBS,” Dr. Peery said. For each disease section the guideline outlined directions for future research. It will be updated in 3-5 years as more evidence becomes available.
This guideline was fully funded by the AGA Institute. Dr. Peery and fellow panel member Dr. Benjamin Lebwohl are supported by grants the National Institute of Diabetes and Digestive and Kidney Diseases. Panel member Colleen R. Kelly, MD, is supported by the National Institute of Allergy and Infectious Diseases.
None of the panel members had any conflicts of interest to report.
Addressing Clostridium difficile infection (CDI), Crohn’s disease (CD) ulcerative colitis (UC), pouchitis, and irritable bowel syndrome (IBS), the guidance supports FMT for the prevention of recurrent CDI but not for inflammatory bowel disease (IBD) or IBS — outside of clinical trials.
The AGA’s recommendations were published in Gastroenterology.
“Fecal microbiota–based therapies are effective therapy to prevent recurrent C. difficile in select patients,” the AGA guideline states. “Conventional fecal microbiota transplant is an adjuvant treatment for select adults hospitalized with severe or fulminant C. difficile infection not responding to standard of care antibiotics. Fecal microbiota transplant cannot yet be recommended in other gastrointestinal conditions.”
“We thought it was important to write this guideline because of the growing number of trials of FMT in IBD and IBS populations. It was also important with the new FDA-approved treatments on the market,” the guideline’s first author, Anne F. Peery, MD, MSCR, AGAF, told this news organization, noting that the recently approved products did not yield better results than those of conventional rectal FMT. “The guidelines will help clinicians understand the available therapies and how to use these treatments,” added Dr. Peery, associate professor in the Division of Gastroenterology and Hepatology at the University of North Carolina School of Medicine in Chapel Hill.
Although the existing evidence is of low or very low certainty, Dr. Peery acknowledged, gastroenterologists “should be comfortable with conventional FMT and also the new FDA-approved products. We spent a considerable amount of time developing implementation considerations, which is practical advice to help clinicians use the guideline recommendations.”
Designed to counteract intestinal dysbiosis and restore protective gut flora, the FMT approach includes conventional, colonoscopically delivered donor stool transplants as well as two newly approved options: rectally given fecal microbiota (live-jslm/ Rebyota) and most recently, orally delivered fecal microbiota spores (live-brpk/ Vowst).
The AGA urges careful pretreatment consideration for patients who require frequent antibiotics or long-term antibiotic prophylaxis since ongoing antibiotics may diminish the efficacy of FMT.
The guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis, followed by the Evidence-to-Decision framework to develop recommendations for these therapies and algorithms for their implementation into clinical practice.
Recommendations
The eight-member panel suggested the following practices on behalf of the AGA Clinical Guidelines Committee:
- In immunocompetent adults with recurrent CDI, select use of FMT can be used after completion of standard-of-care antibiotics to prevent recurrence. It can be considered after the second recurrence (episode 3) of CDI or in select patients at high risk for either recurrent CDI or a morbid CDI recurrence. Recurrent CDI is defined as clinically significant diarrhea ≥ 3 unformed stools in 24 hours with a confirmatory positive test within 8 weeks of completing antibiotics. Select use includes patients who have recovered from severe, fulminant, or particularly treatment-refractory CDI and patients with significant comorbidities. Severe CDI involves a leukocyte count of ≥15 × 109 cells/L and/or creatinine ≥1.5 mg/dL, while fulminant CDI involves shock, ileus, or megacolon and can be fatal.
- In mildly or moderately immunocompromised adults with recurrent CDI, the guidance recommends select use of conventional fecal microbiota transplant.
- In severely immunocompromised adults or those undergoing cytotoxic treatment, the AGA advises against the use of any fecal microbiota-based therapies to prevent recurrent CDI.
- Conventional FMT is not advised in patients who have bowel perforation or obstruction or are severely immunocompromised.
- For CDI patients not interested in FMT, reasonable alternatives to prevent recurrence are a vancomycin taper, tapered-pulsed fidaxomicin, or bezlotoxumab.
- In adults hospitalized with severe or fulminant CDI not responding to standard-of-care antibiotics, the AGA recommends select use of conventional FM transplant.
- In the current absence of evidence, the guidance advises against the use of conventional fecal microbiota transplant as treatment for IBD or IBS except in the context of clinical trials.
“We felt the data for using FMT in the treatment of UC was promising, but there is still a lot more work to be done in IBD and IBS,” Dr. Peery said. For each disease section the guideline outlined directions for future research. It will be updated in 3-5 years as more evidence becomes available.
This guideline was fully funded by the AGA Institute. Dr. Peery and fellow panel member Dr. Benjamin Lebwohl are supported by grants the National Institute of Diabetes and Digestive and Kidney Diseases. Panel member Colleen R. Kelly, MD, is supported by the National Institute of Allergy and Infectious Diseases.
None of the panel members had any conflicts of interest to report.
FROM GASTROENTEROLOGY
Global Meta-Analysis: 1 in 12 Adults May Have Fecal Incontinence
FI is more common among individuals 60 years and older, yet a considerable portion of younger people — almost 5% — may also suffer from FI, reported Isabelle Mack, PhD, of University Medical Hospital, Tübingen, Germany, and colleagues.
“Clinicians’ understanding of the prevalence and risk factors for FI have evolved with time,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Initially, FI was regarded as a symptom that predominantly affected older people, especially nursing home residents. Its prevalence among community-dwelling adults was underrecognized, possibly because persons with FI were hesitant to even disclose that they were symptomatic. Now, we recognize that FI is common in the community.”
The only previous meta-analysis of FI, published in 2006, included both community and noncommunity studies, and reported an FI prevalence of 4.3%. Two subsequent reviews put the median prevalence at 7.7%, yet neither offered geographic insights.
To address this knowledge gap, Dr. Mack and colleagues conducted a meta-analysis of 80 studies involving 548,316 community-dwelling teenagers and adults. The median response rate across the studies was 66%.
Evaluating these data revealed a pooled global prevalence of FI was 8.0%, with a lower rate of 5.4% when FI was confined to Rome criteria.
“Placed in perspective, the 8.0% prevalence of FI is lower than or similar to the global prevalence of IBS, as assessed by a meta-regression (11.2%) and by a systematic review (8.8%) using pre–Rome IV criteria, and it is twofold greater than the IBS prevalence assessed with Rome IV criteria,” the investigators wrote.
Among individuals aged 60 years and older, the FI prevalence was 9.3%, compared with 4.9% for younger people (odds ratio [OR], 1.75; 95% CI, 1.39-2.20).
“These differences are at least partly explained by age-associated declines in anorectal function (e.g., lower anal resting pressure and rectal distensibility, denervation of the external anal sphincter),” the investigators wrote.
FI was also significantly more common among women than men (9.1% vs 7.4%; OR, 1.17; 95% CI, 1.06-1.28).
“Although these differences in FI prevalence between men and women seem relatively small, most patients with FI who seek medical attention are women (unpublished data),” the investigators wrote. “We suspect that men less commonly seek medical attention for FI because they may be secretly resigned to having FI, because FI may have less of an emotional impact on men, and because health literacy with regard to FI is lower for men.”
Geographically, prevalence of FI was highest in Australia and Oceania, followed by North America, Asia, and Europe. Data were insufficient to estimates rates in the Middle East and Africa.
Dr. Mack and colleagues concluded by noting how bothersome FI is for so many individuals worldwide, which should warrant closer attention from the medical community.
“Because nearly one in four community-dwelling women with FI report that the symptom has a moderate or severe impact on one or more domains of quality of life, more resources should be devoted to research in this area,” they wrote. “Future epidemiologic studies of FI should also assess the severity of FI, risk factors for FI, and the impact of FI on quality of life. In addition, because some patients are reluctant to acknowledge or discuss FI during an in-person interview, written or internet-based surveys may be preferable.”
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The investigators disclosed no conflicts of interest.
Fecal incontinence (FI) is the GI disease that remains invisible to many except its sufferers. Even in the seemingly safe confines of a physician’s office, many patients won’t admit to providers that they suffer from this socially isolating condition. This systematic review and meta-analysis by Mack et al. — like other prevalence studies before it — serves as a useful reminder just how common this hidden disease remains. While FI is common in institutionalized persons, this study importantly found that 1 in 12 community-dwelling individuals worldwide suffer from FI as well.
What should the practicing clinician take away from this study? Simply put, when it comes to FI, you need to ask: how often, how much, how urgent (or passive), and what type (solid or liquid). This disease is far too common to remain in the shadows, yet most GI fellows do not receive sufficient training on a condition that is so widespread.
Kyle Staller, MD, MPH, is director, GI Motility Laboratory at Massachusetts General Hospital and Harvard Medical School, both in Boston. He has served as a consultant for Anji, Ardelyx, GI Supply, Mahana, and Restalsis, and received research support from Ardelyx.
Fecal incontinence (FI) is the GI disease that remains invisible to many except its sufferers. Even in the seemingly safe confines of a physician’s office, many patients won’t admit to providers that they suffer from this socially isolating condition. This systematic review and meta-analysis by Mack et al. — like other prevalence studies before it — serves as a useful reminder just how common this hidden disease remains. While FI is common in institutionalized persons, this study importantly found that 1 in 12 community-dwelling individuals worldwide suffer from FI as well.
What should the practicing clinician take away from this study? Simply put, when it comes to FI, you need to ask: how often, how much, how urgent (or passive), and what type (solid or liquid). This disease is far too common to remain in the shadows, yet most GI fellows do not receive sufficient training on a condition that is so widespread.
Kyle Staller, MD, MPH, is director, GI Motility Laboratory at Massachusetts General Hospital and Harvard Medical School, both in Boston. He has served as a consultant for Anji, Ardelyx, GI Supply, Mahana, and Restalsis, and received research support from Ardelyx.
Fecal incontinence (FI) is the GI disease that remains invisible to many except its sufferers. Even in the seemingly safe confines of a physician’s office, many patients won’t admit to providers that they suffer from this socially isolating condition. This systematic review and meta-analysis by Mack et al. — like other prevalence studies before it — serves as a useful reminder just how common this hidden disease remains. While FI is common in institutionalized persons, this study importantly found that 1 in 12 community-dwelling individuals worldwide suffer from FI as well.
What should the practicing clinician take away from this study? Simply put, when it comes to FI, you need to ask: how often, how much, how urgent (or passive), and what type (solid or liquid). This disease is far too common to remain in the shadows, yet most GI fellows do not receive sufficient training on a condition that is so widespread.
Kyle Staller, MD, MPH, is director, GI Motility Laboratory at Massachusetts General Hospital and Harvard Medical School, both in Boston. He has served as a consultant for Anji, Ardelyx, GI Supply, Mahana, and Restalsis, and received research support from Ardelyx.
FI is more common among individuals 60 years and older, yet a considerable portion of younger people — almost 5% — may also suffer from FI, reported Isabelle Mack, PhD, of University Medical Hospital, Tübingen, Germany, and colleagues.
“Clinicians’ understanding of the prevalence and risk factors for FI have evolved with time,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Initially, FI was regarded as a symptom that predominantly affected older people, especially nursing home residents. Its prevalence among community-dwelling adults was underrecognized, possibly because persons with FI were hesitant to even disclose that they were symptomatic. Now, we recognize that FI is common in the community.”
The only previous meta-analysis of FI, published in 2006, included both community and noncommunity studies, and reported an FI prevalence of 4.3%. Two subsequent reviews put the median prevalence at 7.7%, yet neither offered geographic insights.
To address this knowledge gap, Dr. Mack and colleagues conducted a meta-analysis of 80 studies involving 548,316 community-dwelling teenagers and adults. The median response rate across the studies was 66%.
Evaluating these data revealed a pooled global prevalence of FI was 8.0%, with a lower rate of 5.4% when FI was confined to Rome criteria.
“Placed in perspective, the 8.0% prevalence of FI is lower than or similar to the global prevalence of IBS, as assessed by a meta-regression (11.2%) and by a systematic review (8.8%) using pre–Rome IV criteria, and it is twofold greater than the IBS prevalence assessed with Rome IV criteria,” the investigators wrote.
Among individuals aged 60 years and older, the FI prevalence was 9.3%, compared with 4.9% for younger people (odds ratio [OR], 1.75; 95% CI, 1.39-2.20).
“These differences are at least partly explained by age-associated declines in anorectal function (e.g., lower anal resting pressure and rectal distensibility, denervation of the external anal sphincter),” the investigators wrote.
FI was also significantly more common among women than men (9.1% vs 7.4%; OR, 1.17; 95% CI, 1.06-1.28).
“Although these differences in FI prevalence between men and women seem relatively small, most patients with FI who seek medical attention are women (unpublished data),” the investigators wrote. “We suspect that men less commonly seek medical attention for FI because they may be secretly resigned to having FI, because FI may have less of an emotional impact on men, and because health literacy with regard to FI is lower for men.”
Geographically, prevalence of FI was highest in Australia and Oceania, followed by North America, Asia, and Europe. Data were insufficient to estimates rates in the Middle East and Africa.
Dr. Mack and colleagues concluded by noting how bothersome FI is for so many individuals worldwide, which should warrant closer attention from the medical community.
“Because nearly one in four community-dwelling women with FI report that the symptom has a moderate or severe impact on one or more domains of quality of life, more resources should be devoted to research in this area,” they wrote. “Future epidemiologic studies of FI should also assess the severity of FI, risk factors for FI, and the impact of FI on quality of life. In addition, because some patients are reluctant to acknowledge or discuss FI during an in-person interview, written or internet-based surveys may be preferable.”
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The investigators disclosed no conflicts of interest.
FI is more common among individuals 60 years and older, yet a considerable portion of younger people — almost 5% — may also suffer from FI, reported Isabelle Mack, PhD, of University Medical Hospital, Tübingen, Germany, and colleagues.
“Clinicians’ understanding of the prevalence and risk factors for FI have evolved with time,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Initially, FI was regarded as a symptom that predominantly affected older people, especially nursing home residents. Its prevalence among community-dwelling adults was underrecognized, possibly because persons with FI were hesitant to even disclose that they were symptomatic. Now, we recognize that FI is common in the community.”
The only previous meta-analysis of FI, published in 2006, included both community and noncommunity studies, and reported an FI prevalence of 4.3%. Two subsequent reviews put the median prevalence at 7.7%, yet neither offered geographic insights.
To address this knowledge gap, Dr. Mack and colleagues conducted a meta-analysis of 80 studies involving 548,316 community-dwelling teenagers and adults. The median response rate across the studies was 66%.
Evaluating these data revealed a pooled global prevalence of FI was 8.0%, with a lower rate of 5.4% when FI was confined to Rome criteria.
“Placed in perspective, the 8.0% prevalence of FI is lower than or similar to the global prevalence of IBS, as assessed by a meta-regression (11.2%) and by a systematic review (8.8%) using pre–Rome IV criteria, and it is twofold greater than the IBS prevalence assessed with Rome IV criteria,” the investigators wrote.
Among individuals aged 60 years and older, the FI prevalence was 9.3%, compared with 4.9% for younger people (odds ratio [OR], 1.75; 95% CI, 1.39-2.20).
“These differences are at least partly explained by age-associated declines in anorectal function (e.g., lower anal resting pressure and rectal distensibility, denervation of the external anal sphincter),” the investigators wrote.
FI was also significantly more common among women than men (9.1% vs 7.4%; OR, 1.17; 95% CI, 1.06-1.28).
“Although these differences in FI prevalence between men and women seem relatively small, most patients with FI who seek medical attention are women (unpublished data),” the investigators wrote. “We suspect that men less commonly seek medical attention for FI because they may be secretly resigned to having FI, because FI may have less of an emotional impact on men, and because health literacy with regard to FI is lower for men.”
Geographically, prevalence of FI was highest in Australia and Oceania, followed by North America, Asia, and Europe. Data were insufficient to estimates rates in the Middle East and Africa.
Dr. Mack and colleagues concluded by noting how bothersome FI is for so many individuals worldwide, which should warrant closer attention from the medical community.
“Because nearly one in four community-dwelling women with FI report that the symptom has a moderate or severe impact on one or more domains of quality of life, more resources should be devoted to research in this area,” they wrote. “Future epidemiologic studies of FI should also assess the severity of FI, risk factors for FI, and the impact of FI on quality of life. In addition, because some patients are reluctant to acknowledge or discuss FI during an in-person interview, written or internet-based surveys may be preferable.”
This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The investigators disclosed no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Dupilumab for Eosinophilic Esophagitis: How Is it Improving Treatment?
The US Food and Drug Administration approvals of dupilumab (Dupixent, Regeneron/Sanofi) for adults and children with eosinophilic esophagitis (EoE) affirmed the safety and efficacy of the drug, which is the first product indicated specifically for treatment of this disease.
The recent expanded approval for its use in kids aged 1 year and older imply that clinicians can prescribe it for just about any patient with the immune disorder.
But is dupilumab right for everyone?
What the Trials Said
Dupilumab, given by injection, is a recombinant human immunoglobulin-G4 monoclonal antibody that inhibits interleukin 4 (IL-4) and IL-13 signaling.
The first approval for EoE, on May 22, 2022, for adults and children aged 12 years and older weighing at least 40 kg, was based on data from 321 participants in the first two parts of a three-part phase 3 trial involving patients with EoE despite 8 weeks of high-dose proton pump inhibitor (PPI) therapy and with substantial symptom burden.
At 24 weeks, histologic remission occurred in 60% of patients in Part A of the trial and 59% in Part B who received a weekly 300-mg dose of dupilumab compared with 5% and 6% taking placebo. Additionally, Part A and B participants taking the drug weekly experienced a 69% and 64% reduction in disease symptoms, respectively, vs 32% and 41% for placebo. The drug also outperformed placebo in reducing patients’ esophageal eosinophilic counts and abnormal endoscopic findings.
The second approval, on January 25, 2024, for children aged 1 year and older weighing at least 15 kg, was based on data from a two-part, placebo-controlled trial involving 102 children, ages 1-11 years, with EoE. The study involved a 16-week treatment period and a 36-week extended period during which eligible children from the dupilumab group continued to receive their weight-based dose level and those who were on placebo switched to active treatment. The trial showed that a greater proportion of children taking the drug achieved histological remission.
A Major Advance but Temper Expectations
,” Philip Katz, MD, AGAF, professor of medicine in the gastroenterology division at Weill Cornell Medicine, New York City, said in an interview. “I’ve been using it since The New England Journal of Medicine paper was published about a year and a half ago , and as a slow adopter, I like it.”
Dr. Katz and his colleagues have been prescribing dupilumab mainly for patients who haven’t responded to other medications, mainly PPIs and steroids.
“We start people on it without stopping anything else,” Dr. Katz said. “Then, as symptoms evolve and people have a positive response, we stop the other medications. For example, in one patient who did very well on the drug, we stopped his steroids and now, we’re weaning him off his PPI. It’s a process. This is not a disease where you can rush people.”
The tempered approach is in part because of payer issues, he noted.
“It’s very difficult to get it reimbursed in the US if you haven’t tried something else first,” Dr. Katz said. “And because it’s still relatively new in this field, standard treatment is still used frequently.”
Although Dr. Katz has had “incredible success” with dupilumab so far, “nothing should be considered a miracle drug,” he said. “A couple of people have had injection reactions, and one person couldn’t tolerate the drug. So, while it seems to have an excellent response rate, it’s not 100%. Like any new drug, it will have to find its true success rate.”
Taking a Step-Up Approach
Like Dr. Katz, Evan Dellon, MD, MPH, AGAF, director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina at Chapel Hill, North Carolina, is enthusiastic about dupilumab.
“It’s a boon to the field, and now, some real-world data are coming out and looking very much like the clinical trial data, which are reassuring,” said Dr. Dellon, a coauthor of The New England Journal of Medicine paper.
It’s been a “game changer,” particularly for people who weren’t doing well with their current treatments, he said. “In my practice, I’ve been seeing a lowish response rate for PPIs, and about 30%-40% not responding to topical steroids, since we don’t have a standard formulation for that. The diet elimination therapy is effective if people can do it well and adhere to it. But there’s a group of people who don’t respond, and probably, a larger group who can’t really do that treatment long term. So, the drug has been fantastic for those patients.”
Although the drug is approved for patients aged 1 year and older with no caveats, “it’s not the right medicine for every patient,” he said. “Patients in the clinical trials had EoE for 5 years, many of them were treatment refractory, and just under half had dilations and strictures,” he said. “They represent a certain group of patients.”
Dr. Dellon is taking a “step-up approach” to EoE treatment, first trying the standard interventions — PPIs, steroids, and an elimination diet — that many patients do respond to.
For new patients who choose medication therapy, he prescribes PPIs and then topical steroids and then steps up to dupilumab for patients who aren’t responding or who have a strong preference for starting the drug early.
In addition to EoE, the drug is approved for certain patients with atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis. As such, Dr. Dellon said that he will try dupilumab early on in patients with multiple atopic conditions, such as asthma, eczema, or nasal disease.
“Even if their EoE is not that severe, those patients can still benefit from a more streamlined systemic therapy,” he said.
Challenges and Questions Still Remain
Not surprisingly, both Dr. Katz and Dr. Dellon pointed to dupilumab’s cost and the related challenge of convincing insurance companies to cover the drug as major challenges to more widespread use. The lack of long-term data also poses a challenge.
Side effects, which often stand in the way of the use of a new drug, are not an issue, for the most part, at least in the short term, according to Dr. Dellon. The most common side effects are discomfort, redness at the injection site, and pain related to the injection.
“Keeping the medication out of the refrigerator for a bit to bring it up to room temperature can help, as can doing the injection in the lower abdomen,” he said. “Otherwise, it’s well tolerated, with no side effects that are unique to EoE.”
Data from the third part of the clinical trial, which followed patients from weeks 24-52 of treatment, indicated that improvements in histological, symptomatic, endoscopic, and molecular features of EoE among patients taking weekly dupilumab continued or improved.
In my practice, “my observations have been that people are maintaining their responses,” said Dr. Dellon, a coauthor of the paper on the study’s third part.
However, one critical question is whether the dose intensity and/or frequency can be decreased over time without reducing the response rate.
“Hopefully, we’ll start getting data on that in the next year or two,” Dr. Dellon said. “It’s hard to do that yet because the drug has only been out for a year or year and a half, and people are just getting to that year of the initial dosing.”
Another question is how to use the drug in people who are different from the clinical trial population, such as those who have been responding to other therapies but want to switch, and people who are newly diagnosed but who have severe disease. Can the drug be used earlier in these populations?
Dr. Dellon would like to see a study that utilizes the new EoE index of severity metric to focus specifically on dupilumab use in patients with severe disease.
Early findings from his recent real-world study of 46 patients with severe disease who would not have qualified for the clinical trials found histologic, endoscopic, and symptom improvement in 91% of patients with refractory and fibrostenotic EoE after 6 months of dupilumab treatment.
While women tend to be well represented in the clinical trial, the drug needs to be tested in a more diverse population, Dr. Dellon noted. Research is underway looking at dupilumab effectiveness in people with different race/ethnicities.
EoE is more common among White people but that may be the result of a “detection issue,” he said. “When clinicians see a Black or Hispanic patient with dysphagia, for example, they may not be thinking of EoE. And there are also some data suggesting that EoE presents slightly differently in non-White populations, which again could decrease the suspicion for it. This is an area we need to learn more about.”
Don’t ‘Abandon’ Current Interventions
“We’ve got an exciting drug that is going to help a lot of people with a complex disease,” Dr. Katz said. “But we should not forget that there are other interventions that have been successful, and quite frankly, they don’t need to be abandoned.”
“Learn about the drug if you’ve never used it,” he advised. “Read the studies so you understand who the patients were as a baseline for where you’re going to use it. Be prepared to do the appropriate paperwork requirements to get approvals from insurers. And look for more literature because it’s coming.”
“Overall, dupilumab has really changed care in people with moderate to severe disease who are not responding or are intolerant to the other treatments,” Dr. Dellon said. “That’s the natural place for the medication to go at this point.”
Dr. Katz is a consultant to Phathom Pharma, Sebela Pharma, Medpace (not active), and Medtronic.
Dr. Dellon received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda. He served as a consultant to Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio. He also received educational grants from Allakos, Aqilion, Holoclara, and Invea.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration approvals of dupilumab (Dupixent, Regeneron/Sanofi) for adults and children with eosinophilic esophagitis (EoE) affirmed the safety and efficacy of the drug, which is the first product indicated specifically for treatment of this disease.
The recent expanded approval for its use in kids aged 1 year and older imply that clinicians can prescribe it for just about any patient with the immune disorder.
But is dupilumab right for everyone?
What the Trials Said
Dupilumab, given by injection, is a recombinant human immunoglobulin-G4 monoclonal antibody that inhibits interleukin 4 (IL-4) and IL-13 signaling.
The first approval for EoE, on May 22, 2022, for adults and children aged 12 years and older weighing at least 40 kg, was based on data from 321 participants in the first two parts of a three-part phase 3 trial involving patients with EoE despite 8 weeks of high-dose proton pump inhibitor (PPI) therapy and with substantial symptom burden.
At 24 weeks, histologic remission occurred in 60% of patients in Part A of the trial and 59% in Part B who received a weekly 300-mg dose of dupilumab compared with 5% and 6% taking placebo. Additionally, Part A and B participants taking the drug weekly experienced a 69% and 64% reduction in disease symptoms, respectively, vs 32% and 41% for placebo. The drug also outperformed placebo in reducing patients’ esophageal eosinophilic counts and abnormal endoscopic findings.
The second approval, on January 25, 2024, for children aged 1 year and older weighing at least 15 kg, was based on data from a two-part, placebo-controlled trial involving 102 children, ages 1-11 years, with EoE. The study involved a 16-week treatment period and a 36-week extended period during which eligible children from the dupilumab group continued to receive their weight-based dose level and those who were on placebo switched to active treatment. The trial showed that a greater proportion of children taking the drug achieved histological remission.
A Major Advance but Temper Expectations
,” Philip Katz, MD, AGAF, professor of medicine in the gastroenterology division at Weill Cornell Medicine, New York City, said in an interview. “I’ve been using it since The New England Journal of Medicine paper was published about a year and a half ago , and as a slow adopter, I like it.”
Dr. Katz and his colleagues have been prescribing dupilumab mainly for patients who haven’t responded to other medications, mainly PPIs and steroids.
“We start people on it without stopping anything else,” Dr. Katz said. “Then, as symptoms evolve and people have a positive response, we stop the other medications. For example, in one patient who did very well on the drug, we stopped his steroids and now, we’re weaning him off his PPI. It’s a process. This is not a disease where you can rush people.”
The tempered approach is in part because of payer issues, he noted.
“It’s very difficult to get it reimbursed in the US if you haven’t tried something else first,” Dr. Katz said. “And because it’s still relatively new in this field, standard treatment is still used frequently.”
Although Dr. Katz has had “incredible success” with dupilumab so far, “nothing should be considered a miracle drug,” he said. “A couple of people have had injection reactions, and one person couldn’t tolerate the drug. So, while it seems to have an excellent response rate, it’s not 100%. Like any new drug, it will have to find its true success rate.”
Taking a Step-Up Approach
Like Dr. Katz, Evan Dellon, MD, MPH, AGAF, director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina at Chapel Hill, North Carolina, is enthusiastic about dupilumab.
“It’s a boon to the field, and now, some real-world data are coming out and looking very much like the clinical trial data, which are reassuring,” said Dr. Dellon, a coauthor of The New England Journal of Medicine paper.
It’s been a “game changer,” particularly for people who weren’t doing well with their current treatments, he said. “In my practice, I’ve been seeing a lowish response rate for PPIs, and about 30%-40% not responding to topical steroids, since we don’t have a standard formulation for that. The diet elimination therapy is effective if people can do it well and adhere to it. But there’s a group of people who don’t respond, and probably, a larger group who can’t really do that treatment long term. So, the drug has been fantastic for those patients.”
Although the drug is approved for patients aged 1 year and older with no caveats, “it’s not the right medicine for every patient,” he said. “Patients in the clinical trials had EoE for 5 years, many of them were treatment refractory, and just under half had dilations and strictures,” he said. “They represent a certain group of patients.”
Dr. Dellon is taking a “step-up approach” to EoE treatment, first trying the standard interventions — PPIs, steroids, and an elimination diet — that many patients do respond to.
For new patients who choose medication therapy, he prescribes PPIs and then topical steroids and then steps up to dupilumab for patients who aren’t responding or who have a strong preference for starting the drug early.
In addition to EoE, the drug is approved for certain patients with atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis. As such, Dr. Dellon said that he will try dupilumab early on in patients with multiple atopic conditions, such as asthma, eczema, or nasal disease.
“Even if their EoE is not that severe, those patients can still benefit from a more streamlined systemic therapy,” he said.
Challenges and Questions Still Remain
Not surprisingly, both Dr. Katz and Dr. Dellon pointed to dupilumab’s cost and the related challenge of convincing insurance companies to cover the drug as major challenges to more widespread use. The lack of long-term data also poses a challenge.
Side effects, which often stand in the way of the use of a new drug, are not an issue, for the most part, at least in the short term, according to Dr. Dellon. The most common side effects are discomfort, redness at the injection site, and pain related to the injection.
“Keeping the medication out of the refrigerator for a bit to bring it up to room temperature can help, as can doing the injection in the lower abdomen,” he said. “Otherwise, it’s well tolerated, with no side effects that are unique to EoE.”
Data from the third part of the clinical trial, which followed patients from weeks 24-52 of treatment, indicated that improvements in histological, symptomatic, endoscopic, and molecular features of EoE among patients taking weekly dupilumab continued or improved.
In my practice, “my observations have been that people are maintaining their responses,” said Dr. Dellon, a coauthor of the paper on the study’s third part.
However, one critical question is whether the dose intensity and/or frequency can be decreased over time without reducing the response rate.
“Hopefully, we’ll start getting data on that in the next year or two,” Dr. Dellon said. “It’s hard to do that yet because the drug has only been out for a year or year and a half, and people are just getting to that year of the initial dosing.”
Another question is how to use the drug in people who are different from the clinical trial population, such as those who have been responding to other therapies but want to switch, and people who are newly diagnosed but who have severe disease. Can the drug be used earlier in these populations?
Dr. Dellon would like to see a study that utilizes the new EoE index of severity metric to focus specifically on dupilumab use in patients with severe disease.
Early findings from his recent real-world study of 46 patients with severe disease who would not have qualified for the clinical trials found histologic, endoscopic, and symptom improvement in 91% of patients with refractory and fibrostenotic EoE after 6 months of dupilumab treatment.
While women tend to be well represented in the clinical trial, the drug needs to be tested in a more diverse population, Dr. Dellon noted. Research is underway looking at dupilumab effectiveness in people with different race/ethnicities.
EoE is more common among White people but that may be the result of a “detection issue,” he said. “When clinicians see a Black or Hispanic patient with dysphagia, for example, they may not be thinking of EoE. And there are also some data suggesting that EoE presents slightly differently in non-White populations, which again could decrease the suspicion for it. This is an area we need to learn more about.”
Don’t ‘Abandon’ Current Interventions
“We’ve got an exciting drug that is going to help a lot of people with a complex disease,” Dr. Katz said. “But we should not forget that there are other interventions that have been successful, and quite frankly, they don’t need to be abandoned.”
“Learn about the drug if you’ve never used it,” he advised. “Read the studies so you understand who the patients were as a baseline for where you’re going to use it. Be prepared to do the appropriate paperwork requirements to get approvals from insurers. And look for more literature because it’s coming.”
“Overall, dupilumab has really changed care in people with moderate to severe disease who are not responding or are intolerant to the other treatments,” Dr. Dellon said. “That’s the natural place for the medication to go at this point.”
Dr. Katz is a consultant to Phathom Pharma, Sebela Pharma, Medpace (not active), and Medtronic.
Dr. Dellon received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda. He served as a consultant to Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio. He also received educational grants from Allakos, Aqilion, Holoclara, and Invea.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration approvals of dupilumab (Dupixent, Regeneron/Sanofi) for adults and children with eosinophilic esophagitis (EoE) affirmed the safety and efficacy of the drug, which is the first product indicated specifically for treatment of this disease.
The recent expanded approval for its use in kids aged 1 year and older imply that clinicians can prescribe it for just about any patient with the immune disorder.
But is dupilumab right for everyone?
What the Trials Said
Dupilumab, given by injection, is a recombinant human immunoglobulin-G4 monoclonal antibody that inhibits interleukin 4 (IL-4) and IL-13 signaling.
The first approval for EoE, on May 22, 2022, for adults and children aged 12 years and older weighing at least 40 kg, was based on data from 321 participants in the first two parts of a three-part phase 3 trial involving patients with EoE despite 8 weeks of high-dose proton pump inhibitor (PPI) therapy and with substantial symptom burden.
At 24 weeks, histologic remission occurred in 60% of patients in Part A of the trial and 59% in Part B who received a weekly 300-mg dose of dupilumab compared with 5% and 6% taking placebo. Additionally, Part A and B participants taking the drug weekly experienced a 69% and 64% reduction in disease symptoms, respectively, vs 32% and 41% for placebo. The drug also outperformed placebo in reducing patients’ esophageal eosinophilic counts and abnormal endoscopic findings.
The second approval, on January 25, 2024, for children aged 1 year and older weighing at least 15 kg, was based on data from a two-part, placebo-controlled trial involving 102 children, ages 1-11 years, with EoE. The study involved a 16-week treatment period and a 36-week extended period during which eligible children from the dupilumab group continued to receive their weight-based dose level and those who were on placebo switched to active treatment. The trial showed that a greater proportion of children taking the drug achieved histological remission.
A Major Advance but Temper Expectations
,” Philip Katz, MD, AGAF, professor of medicine in the gastroenterology division at Weill Cornell Medicine, New York City, said in an interview. “I’ve been using it since The New England Journal of Medicine paper was published about a year and a half ago , and as a slow adopter, I like it.”
Dr. Katz and his colleagues have been prescribing dupilumab mainly for patients who haven’t responded to other medications, mainly PPIs and steroids.
“We start people on it without stopping anything else,” Dr. Katz said. “Then, as symptoms evolve and people have a positive response, we stop the other medications. For example, in one patient who did very well on the drug, we stopped his steroids and now, we’re weaning him off his PPI. It’s a process. This is not a disease where you can rush people.”
The tempered approach is in part because of payer issues, he noted.
“It’s very difficult to get it reimbursed in the US if you haven’t tried something else first,” Dr. Katz said. “And because it’s still relatively new in this field, standard treatment is still used frequently.”
Although Dr. Katz has had “incredible success” with dupilumab so far, “nothing should be considered a miracle drug,” he said. “A couple of people have had injection reactions, and one person couldn’t tolerate the drug. So, while it seems to have an excellent response rate, it’s not 100%. Like any new drug, it will have to find its true success rate.”
Taking a Step-Up Approach
Like Dr. Katz, Evan Dellon, MD, MPH, AGAF, director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina at Chapel Hill, North Carolina, is enthusiastic about dupilumab.
“It’s a boon to the field, and now, some real-world data are coming out and looking very much like the clinical trial data, which are reassuring,” said Dr. Dellon, a coauthor of The New England Journal of Medicine paper.
It’s been a “game changer,” particularly for people who weren’t doing well with their current treatments, he said. “In my practice, I’ve been seeing a lowish response rate for PPIs, and about 30%-40% not responding to topical steroids, since we don’t have a standard formulation for that. The diet elimination therapy is effective if people can do it well and adhere to it. But there’s a group of people who don’t respond, and probably, a larger group who can’t really do that treatment long term. So, the drug has been fantastic for those patients.”
Although the drug is approved for patients aged 1 year and older with no caveats, “it’s not the right medicine for every patient,” he said. “Patients in the clinical trials had EoE for 5 years, many of them were treatment refractory, and just under half had dilations and strictures,” he said. “They represent a certain group of patients.”
Dr. Dellon is taking a “step-up approach” to EoE treatment, first trying the standard interventions — PPIs, steroids, and an elimination diet — that many patients do respond to.
For new patients who choose medication therapy, he prescribes PPIs and then topical steroids and then steps up to dupilumab for patients who aren’t responding or who have a strong preference for starting the drug early.
In addition to EoE, the drug is approved for certain patients with atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis. As such, Dr. Dellon said that he will try dupilumab early on in patients with multiple atopic conditions, such as asthma, eczema, or nasal disease.
“Even if their EoE is not that severe, those patients can still benefit from a more streamlined systemic therapy,” he said.
Challenges and Questions Still Remain
Not surprisingly, both Dr. Katz and Dr. Dellon pointed to dupilumab’s cost and the related challenge of convincing insurance companies to cover the drug as major challenges to more widespread use. The lack of long-term data also poses a challenge.
Side effects, which often stand in the way of the use of a new drug, are not an issue, for the most part, at least in the short term, according to Dr. Dellon. The most common side effects are discomfort, redness at the injection site, and pain related to the injection.
“Keeping the medication out of the refrigerator for a bit to bring it up to room temperature can help, as can doing the injection in the lower abdomen,” he said. “Otherwise, it’s well tolerated, with no side effects that are unique to EoE.”
Data from the third part of the clinical trial, which followed patients from weeks 24-52 of treatment, indicated that improvements in histological, symptomatic, endoscopic, and molecular features of EoE among patients taking weekly dupilumab continued or improved.
In my practice, “my observations have been that people are maintaining their responses,” said Dr. Dellon, a coauthor of the paper on the study’s third part.
However, one critical question is whether the dose intensity and/or frequency can be decreased over time without reducing the response rate.
“Hopefully, we’ll start getting data on that in the next year or two,” Dr. Dellon said. “It’s hard to do that yet because the drug has only been out for a year or year and a half, and people are just getting to that year of the initial dosing.”
Another question is how to use the drug in people who are different from the clinical trial population, such as those who have been responding to other therapies but want to switch, and people who are newly diagnosed but who have severe disease. Can the drug be used earlier in these populations?
Dr. Dellon would like to see a study that utilizes the new EoE index of severity metric to focus specifically on dupilumab use in patients with severe disease.
Early findings from his recent real-world study of 46 patients with severe disease who would not have qualified for the clinical trials found histologic, endoscopic, and symptom improvement in 91% of patients with refractory and fibrostenotic EoE after 6 months of dupilumab treatment.
While women tend to be well represented in the clinical trial, the drug needs to be tested in a more diverse population, Dr. Dellon noted. Research is underway looking at dupilumab effectiveness in people with different race/ethnicities.
EoE is more common among White people but that may be the result of a “detection issue,” he said. “When clinicians see a Black or Hispanic patient with dysphagia, for example, they may not be thinking of EoE. And there are also some data suggesting that EoE presents slightly differently in non-White populations, which again could decrease the suspicion for it. This is an area we need to learn more about.”
Don’t ‘Abandon’ Current Interventions
“We’ve got an exciting drug that is going to help a lot of people with a complex disease,” Dr. Katz said. “But we should not forget that there are other interventions that have been successful, and quite frankly, they don’t need to be abandoned.”
“Learn about the drug if you’ve never used it,” he advised. “Read the studies so you understand who the patients were as a baseline for where you’re going to use it. Be prepared to do the appropriate paperwork requirements to get approvals from insurers. And look for more literature because it’s coming.”
“Overall, dupilumab has really changed care in people with moderate to severe disease who are not responding or are intolerant to the other treatments,” Dr. Dellon said. “That’s the natural place for the medication to go at this point.”
Dr. Katz is a consultant to Phathom Pharma, Sebela Pharma, Medpace (not active), and Medtronic.
Dr. Dellon received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda. He served as a consultant to Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio. He also received educational grants from Allakos, Aqilion, Holoclara, and Invea.
A version of this article appeared on Medscape.com.
The Paradox of Achalasia Symptoms
In contrast to most diseases, as achalasia progresses, the symptoms improve. Specifically, reduction of symptoms of dysphagia lulls the gastroenterologist into thinking their patients are doing well.
This improvement in dysphagia is likely due to two mechanisms. The first is that as the esophagus dilates, there is a greater capacity for food accumulation before sensation occurs. Whether this is completely a volume issue or whether there is a contribution from increased esophageal body distensibility is unclear. Similarly, as achalasia results from inflammation and destruction of the motor neurons of the myenteric plexus, sensory neurons are also damaged. As a result, the patient’s ability to sense food retention lessens. To some degree, this explains the phenomenon of patients presenting with megaesophagus; after years of initially diminishing or stable symptoms managed with patient accommodation, patients present with end-stage disease manifested by a food-impacted esophagus, nocturnal aspiration, and weight loss.
This aspect of the natural history of achalasia has led esophagologists to follow patients with achalasia after treatment at regular intervals with objective examinations such as timed esophagography to mitigate against this worsening yet symptomatically stable course.
Dr. Katzka is based in the Division of Digestive and Liver Diseases, Columbia University Medical Center, New York. He receives research support from Medtronic and is an associate editor for GI & Hepatology News. Previously published in Gastro Hep Advances. 2024 Jan 19. doi: 10.1016/j.gastha.2024.01.006.
In contrast to most diseases, as achalasia progresses, the symptoms improve. Specifically, reduction of symptoms of dysphagia lulls the gastroenterologist into thinking their patients are doing well.
This improvement in dysphagia is likely due to two mechanisms. The first is that as the esophagus dilates, there is a greater capacity for food accumulation before sensation occurs. Whether this is completely a volume issue or whether there is a contribution from increased esophageal body distensibility is unclear. Similarly, as achalasia results from inflammation and destruction of the motor neurons of the myenteric plexus, sensory neurons are also damaged. As a result, the patient’s ability to sense food retention lessens. To some degree, this explains the phenomenon of patients presenting with megaesophagus; after years of initially diminishing or stable symptoms managed with patient accommodation, patients present with end-stage disease manifested by a food-impacted esophagus, nocturnal aspiration, and weight loss.
This aspect of the natural history of achalasia has led esophagologists to follow patients with achalasia after treatment at regular intervals with objective examinations such as timed esophagography to mitigate against this worsening yet symptomatically stable course.
Dr. Katzka is based in the Division of Digestive and Liver Diseases, Columbia University Medical Center, New York. He receives research support from Medtronic and is an associate editor for GI & Hepatology News. Previously published in Gastro Hep Advances. 2024 Jan 19. doi: 10.1016/j.gastha.2024.01.006.
In contrast to most diseases, as achalasia progresses, the symptoms improve. Specifically, reduction of symptoms of dysphagia lulls the gastroenterologist into thinking their patients are doing well.
This improvement in dysphagia is likely due to two mechanisms. The first is that as the esophagus dilates, there is a greater capacity for food accumulation before sensation occurs. Whether this is completely a volume issue or whether there is a contribution from increased esophageal body distensibility is unclear. Similarly, as achalasia results from inflammation and destruction of the motor neurons of the myenteric plexus, sensory neurons are also damaged. As a result, the patient’s ability to sense food retention lessens. To some degree, this explains the phenomenon of patients presenting with megaesophagus; after years of initially diminishing or stable symptoms managed with patient accommodation, patients present with end-stage disease manifested by a food-impacted esophagus, nocturnal aspiration, and weight loss.
This aspect of the natural history of achalasia has led esophagologists to follow patients with achalasia after treatment at regular intervals with objective examinations such as timed esophagography to mitigate against this worsening yet symptomatically stable course.
Dr. Katzka is based in the Division of Digestive and Liver Diseases, Columbia University Medical Center, New York. He receives research support from Medtronic and is an associate editor for GI & Hepatology News. Previously published in Gastro Hep Advances. 2024 Jan 19. doi: 10.1016/j.gastha.2024.01.006.
New Cancer Surgical Tech Gets Positive Vote, But Some Cite Safety Concerns
A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.
LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.
Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.
“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.
However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.
In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.
“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”
The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.
On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.
“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”
Is the Technology Safe?
Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.
After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.
If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.
In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.
Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.
Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.
“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”
During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.
Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.
David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.
“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.
Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.
She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.
MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.
Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.
“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”
During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.
“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
Committee Expresses Support
During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.
Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.
Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.
“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”
Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.
“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”
Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.
The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.
If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.
Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.
The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.
A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.
LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.
Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.
“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.
However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.
In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.
“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”
The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.
On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.
“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”
Is the Technology Safe?
Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.
After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.
If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.
In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.
Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.
Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.
“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”
During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.
Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.
David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.
“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.
Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.
She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.
MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.
Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.
“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”
During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.
“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
Committee Expresses Support
During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.
Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.
Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.
“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”
Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.
“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”
Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.
The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.
If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.
Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.
The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.
A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.
LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.
Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.
“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.
However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.
In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.
“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”
The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.
On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.
“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”
Is the Technology Safe?
Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.
After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.
If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.
In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.
Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.
Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.
“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”
During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.
Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.
David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.
“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.
Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.
She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.
MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.
Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.
“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”
During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.
“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
Committee Expresses Support
During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.
Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.
Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.
“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”
Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.
“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”
Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.
The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.
If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.
Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.
The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.
New Data on Mild COVID’s Risk for Neurologic, Psychiatric Disorders
While severe COVID-19 is associated with a significantly higher risk for psychiatric and neurologic disorders a year after infection, mild does not carry the same risk, a new study shows.
However, less severe COVID-19 was not linked to a higher incidence of psychiatric diagnoses and was associated with only a slightly higher risk for neurologic disorders.
The new research challenges previous findings of long-term risk for psychiatric and neurologic disorders associated with SARS-CoV-2 in patients who had not been hospitalized for the condition.
“Our study does not support previous findings of substantial post-acute neurologic and psychiatric morbidities among the general population of SARS-CoV-2-infected individuals but does corroborate an elevated risk among the most severe cases with COVID-19,” the authors wrote.
The study was published online on February 21 in Neurology.
‘Alarming’ Findings
Previous studies have reported nervous system symptoms in patients who have experienced COVID-19, which may persist for several weeks or months after the acute phase, even in milder cases.
But these findings haven’t been consistent across all studies, and few studies have addressed the potential effect of different viral variants and vaccination status on post-acute psychiatric and neurologic morbidities.
“Our study was partly motivated by our strong research interest in the associations between infectious disease and later chronic disease and partly by international studies, such as those conducted in the US Veterans Health databases, that have suggested substantial risks of psychiatric and neurological conditions associated with infection,” senior author Anders Hviid, MSc, DrMedSci, head of the department and professor of pharmacoepidemiology, Statens Serum Institut, Copenhagen, Denmark, told this news organization.
Investigators drew on data from the Danish National Patient Registry to compare the risk for neurologic and psychiatric disorders during the 12 months after acute COVID-19 infection to risk among people who never tested positive.
They examined data on all recorded hospital contacts between January 2005 and January 2023 for a discharge diagnosis of at least one of 11 psychiatric illnesses or at least one of 30 neurologic disorders.
The researchers compared the incidence of each disorder within 1-12 months after infection with those of COVID-naive individuals and stratified analyses according to time since infection, vaccination status, variant period, age, sex, and infection severity.
The final study cohort included 1.8 million individuals who tested positive during the study period and 1.5 who didn’t. Three quarters of those who tested positive were infected primarily with the Omicron variant.
Hospitalized vs Nonhospitalized
Overall, individuals who tested positive had a 24% lower risk for psychiatric disorders during the post-acute period (incident rate ratio [IRR], 0.76; 95% CI, 0.74-0.78) compared with the control group, but a 5% higher risk for any neurologic disorder (IRR, 1.05; 95% CI, 1.04-1.07).
Age, sex, and variant had less influence on risk than infection severity, where the differences between hospitalized and nonhospitalized patients were significant.
Compared with COVID-negative individuals, the risk for any psychiatric disorder was double for hospitalized patients (IRR, 2.05; 95% CI, 1.78-2.37) but was 25% lower among nonhospitalized patients (IRR, 0.75; 95% CI, 0.73-0.77).
For neurologic disorders, the IRR for hospitalized patients was 2.44 (95% CI, 2.29-2.60) compared with COVID-negative individuals vs an IRR of only 1.02 (95% CI, 1.01-1.04) among nonhospitalized patients.
“In a general population, there was little support for clinically relevant post-acute risk increases of psychiatric and neurologic disorders associated with SARS-CoV-2 infection without hospitalization. This was particularly true for vaccinated individuals and for the more recent variants,” the authors wrote, adding that the only exception was for change in sense and smell.
‘Flaws’ in Previous Studies?
The findings in hospitalized patients were in line with previous findings, but those in nonhospitalized patients stand out, they added.
Previous studies were done predominantly in older males with comorbidities and those who were more socioeconomically disadvantaged, which could lead to a bias, Dr. Hviid said.
Those other studies “had a number of fundamental flaws that we do not believe our study has,” Dr. Hviid said. “Our study was conducted in the general population, with free and universal testing and healthcare.”
Researchers stress that sequelae after infection are predominantly associated with severe illness.
“Today, a healthy vaccinated adult having an asymptomatic or mild bout of COVID-19 with the current variants shouldn’t fear developing serious psychiatric or neurologic disorders in the months or years after infection.”
One limitation is that only hospital contacts were included, omitting possible diagnoses given outside hospital settings.
‘Extreme Caution’ Required
The link between COVID-19 and brain health is “complex,” and the new findings should be viewed cautiously, said Maxime Taquet, MRCPsych, PhD, National Institute for Health and Care Research clinical lecturer and specialty registrar in Psychiatry, Oxford Health NHS Foundation Trust, England, who commented on the findings.
Previous research by Dr. Taquet, who was not involved in the current study, found an increased risk for neurologic and psychiatric diagnoses during the first 6 months after COVID-19 diagnosis.
The current study “contributes to better understanding this link by providing data from another country with a different organization of healthcare provision than the US, where most of the existing data come from,” Dr. Taquet said.
However, “some observations — for example, that COVID-19 is associated with a 50% reduction in the risk of autism, a condition present from very early in life — call for extreme caution in the interpretation of the findings, as they suggest that residual bias has not been accounted for,” Dr. Taquet continued.
Authors of an accompanying editorial, Eric Chow, MD, MS, MPH, of the Division of Allergy and Infectious Diseases, University of Washington, School of Public Health, and Anita Chopra, MD, of the post-COVID Clinic, University of Washington, Seattle, called the study a “critical contribution to the published literature.”
The association of neurologic and psychiatric diagnoses with severe disease “is a reminder of the importance of risk reduction by combining vaccinations with improved indoor ventilation and masking,” they concluded.
The study was supported by a grant from the Independent Research Fund Denmark. Dr. Hviid and coauthors, Dr. Chopra, and Dr. Taquet reported no relevant financial relationships. Dr. Chow received a travel award from the Infectious Diseases Society of America to attend ID Week 2022.
A version of this article appeared on Medscape.com.
While severe COVID-19 is associated with a significantly higher risk for psychiatric and neurologic disorders a year after infection, mild does not carry the same risk, a new study shows.
However, less severe COVID-19 was not linked to a higher incidence of psychiatric diagnoses and was associated with only a slightly higher risk for neurologic disorders.
The new research challenges previous findings of long-term risk for psychiatric and neurologic disorders associated with SARS-CoV-2 in patients who had not been hospitalized for the condition.
“Our study does not support previous findings of substantial post-acute neurologic and psychiatric morbidities among the general population of SARS-CoV-2-infected individuals but does corroborate an elevated risk among the most severe cases with COVID-19,” the authors wrote.
The study was published online on February 21 in Neurology.
‘Alarming’ Findings
Previous studies have reported nervous system symptoms in patients who have experienced COVID-19, which may persist for several weeks or months after the acute phase, even in milder cases.
But these findings haven’t been consistent across all studies, and few studies have addressed the potential effect of different viral variants and vaccination status on post-acute psychiatric and neurologic morbidities.
“Our study was partly motivated by our strong research interest in the associations between infectious disease and later chronic disease and partly by international studies, such as those conducted in the US Veterans Health databases, that have suggested substantial risks of psychiatric and neurological conditions associated with infection,” senior author Anders Hviid, MSc, DrMedSci, head of the department and professor of pharmacoepidemiology, Statens Serum Institut, Copenhagen, Denmark, told this news organization.
Investigators drew on data from the Danish National Patient Registry to compare the risk for neurologic and psychiatric disorders during the 12 months after acute COVID-19 infection to risk among people who never tested positive.
They examined data on all recorded hospital contacts between January 2005 and January 2023 for a discharge diagnosis of at least one of 11 psychiatric illnesses or at least one of 30 neurologic disorders.
The researchers compared the incidence of each disorder within 1-12 months after infection with those of COVID-naive individuals and stratified analyses according to time since infection, vaccination status, variant period, age, sex, and infection severity.
The final study cohort included 1.8 million individuals who tested positive during the study period and 1.5 who didn’t. Three quarters of those who tested positive were infected primarily with the Omicron variant.
Hospitalized vs Nonhospitalized
Overall, individuals who tested positive had a 24% lower risk for psychiatric disorders during the post-acute period (incident rate ratio [IRR], 0.76; 95% CI, 0.74-0.78) compared with the control group, but a 5% higher risk for any neurologic disorder (IRR, 1.05; 95% CI, 1.04-1.07).
Age, sex, and variant had less influence on risk than infection severity, where the differences between hospitalized and nonhospitalized patients were significant.
Compared with COVID-negative individuals, the risk for any psychiatric disorder was double for hospitalized patients (IRR, 2.05; 95% CI, 1.78-2.37) but was 25% lower among nonhospitalized patients (IRR, 0.75; 95% CI, 0.73-0.77).
For neurologic disorders, the IRR for hospitalized patients was 2.44 (95% CI, 2.29-2.60) compared with COVID-negative individuals vs an IRR of only 1.02 (95% CI, 1.01-1.04) among nonhospitalized patients.
“In a general population, there was little support for clinically relevant post-acute risk increases of psychiatric and neurologic disorders associated with SARS-CoV-2 infection without hospitalization. This was particularly true for vaccinated individuals and for the more recent variants,” the authors wrote, adding that the only exception was for change in sense and smell.
‘Flaws’ in Previous Studies?
The findings in hospitalized patients were in line with previous findings, but those in nonhospitalized patients stand out, they added.
Previous studies were done predominantly in older males with comorbidities and those who were more socioeconomically disadvantaged, which could lead to a bias, Dr. Hviid said.
Those other studies “had a number of fundamental flaws that we do not believe our study has,” Dr. Hviid said. “Our study was conducted in the general population, with free and universal testing and healthcare.”
Researchers stress that sequelae after infection are predominantly associated with severe illness.
“Today, a healthy vaccinated adult having an asymptomatic or mild bout of COVID-19 with the current variants shouldn’t fear developing serious psychiatric or neurologic disorders in the months or years after infection.”
One limitation is that only hospital contacts were included, omitting possible diagnoses given outside hospital settings.
‘Extreme Caution’ Required
The link between COVID-19 and brain health is “complex,” and the new findings should be viewed cautiously, said Maxime Taquet, MRCPsych, PhD, National Institute for Health and Care Research clinical lecturer and specialty registrar in Psychiatry, Oxford Health NHS Foundation Trust, England, who commented on the findings.
Previous research by Dr. Taquet, who was not involved in the current study, found an increased risk for neurologic and psychiatric diagnoses during the first 6 months after COVID-19 diagnosis.
The current study “contributes to better understanding this link by providing data from another country with a different organization of healthcare provision than the US, where most of the existing data come from,” Dr. Taquet said.
However, “some observations — for example, that COVID-19 is associated with a 50% reduction in the risk of autism, a condition present from very early in life — call for extreme caution in the interpretation of the findings, as they suggest that residual bias has not been accounted for,” Dr. Taquet continued.
Authors of an accompanying editorial, Eric Chow, MD, MS, MPH, of the Division of Allergy and Infectious Diseases, University of Washington, School of Public Health, and Anita Chopra, MD, of the post-COVID Clinic, University of Washington, Seattle, called the study a “critical contribution to the published literature.”
The association of neurologic and psychiatric diagnoses with severe disease “is a reminder of the importance of risk reduction by combining vaccinations with improved indoor ventilation and masking,” they concluded.
The study was supported by a grant from the Independent Research Fund Denmark. Dr. Hviid and coauthors, Dr. Chopra, and Dr. Taquet reported no relevant financial relationships. Dr. Chow received a travel award from the Infectious Diseases Society of America to attend ID Week 2022.
A version of this article appeared on Medscape.com.
While severe COVID-19 is associated with a significantly higher risk for psychiatric and neurologic disorders a year after infection, mild does not carry the same risk, a new study shows.
However, less severe COVID-19 was not linked to a higher incidence of psychiatric diagnoses and was associated with only a slightly higher risk for neurologic disorders.
The new research challenges previous findings of long-term risk for psychiatric and neurologic disorders associated with SARS-CoV-2 in patients who had not been hospitalized for the condition.
“Our study does not support previous findings of substantial post-acute neurologic and psychiatric morbidities among the general population of SARS-CoV-2-infected individuals but does corroborate an elevated risk among the most severe cases with COVID-19,” the authors wrote.
The study was published online on February 21 in Neurology.
‘Alarming’ Findings
Previous studies have reported nervous system symptoms in patients who have experienced COVID-19, which may persist for several weeks or months after the acute phase, even in milder cases.
But these findings haven’t been consistent across all studies, and few studies have addressed the potential effect of different viral variants and vaccination status on post-acute psychiatric and neurologic morbidities.
“Our study was partly motivated by our strong research interest in the associations between infectious disease and later chronic disease and partly by international studies, such as those conducted in the US Veterans Health databases, that have suggested substantial risks of psychiatric and neurological conditions associated with infection,” senior author Anders Hviid, MSc, DrMedSci, head of the department and professor of pharmacoepidemiology, Statens Serum Institut, Copenhagen, Denmark, told this news organization.
Investigators drew on data from the Danish National Patient Registry to compare the risk for neurologic and psychiatric disorders during the 12 months after acute COVID-19 infection to risk among people who never tested positive.
They examined data on all recorded hospital contacts between January 2005 and January 2023 for a discharge diagnosis of at least one of 11 psychiatric illnesses or at least one of 30 neurologic disorders.
The researchers compared the incidence of each disorder within 1-12 months after infection with those of COVID-naive individuals and stratified analyses according to time since infection, vaccination status, variant period, age, sex, and infection severity.
The final study cohort included 1.8 million individuals who tested positive during the study period and 1.5 who didn’t. Three quarters of those who tested positive were infected primarily with the Omicron variant.
Hospitalized vs Nonhospitalized
Overall, individuals who tested positive had a 24% lower risk for psychiatric disorders during the post-acute period (incident rate ratio [IRR], 0.76; 95% CI, 0.74-0.78) compared with the control group, but a 5% higher risk for any neurologic disorder (IRR, 1.05; 95% CI, 1.04-1.07).
Age, sex, and variant had less influence on risk than infection severity, where the differences between hospitalized and nonhospitalized patients were significant.
Compared with COVID-negative individuals, the risk for any psychiatric disorder was double for hospitalized patients (IRR, 2.05; 95% CI, 1.78-2.37) but was 25% lower among nonhospitalized patients (IRR, 0.75; 95% CI, 0.73-0.77).
For neurologic disorders, the IRR for hospitalized patients was 2.44 (95% CI, 2.29-2.60) compared with COVID-negative individuals vs an IRR of only 1.02 (95% CI, 1.01-1.04) among nonhospitalized patients.
“In a general population, there was little support for clinically relevant post-acute risk increases of psychiatric and neurologic disorders associated with SARS-CoV-2 infection without hospitalization. This was particularly true for vaccinated individuals and for the more recent variants,” the authors wrote, adding that the only exception was for change in sense and smell.
‘Flaws’ in Previous Studies?
The findings in hospitalized patients were in line with previous findings, but those in nonhospitalized patients stand out, they added.
Previous studies were done predominantly in older males with comorbidities and those who were more socioeconomically disadvantaged, which could lead to a bias, Dr. Hviid said.
Those other studies “had a number of fundamental flaws that we do not believe our study has,” Dr. Hviid said. “Our study was conducted in the general population, with free and universal testing and healthcare.”
Researchers stress that sequelae after infection are predominantly associated with severe illness.
“Today, a healthy vaccinated adult having an asymptomatic or mild bout of COVID-19 with the current variants shouldn’t fear developing serious psychiatric or neurologic disorders in the months or years after infection.”
One limitation is that only hospital contacts were included, omitting possible diagnoses given outside hospital settings.
‘Extreme Caution’ Required
The link between COVID-19 and brain health is “complex,” and the new findings should be viewed cautiously, said Maxime Taquet, MRCPsych, PhD, National Institute for Health and Care Research clinical lecturer and specialty registrar in Psychiatry, Oxford Health NHS Foundation Trust, England, who commented on the findings.
Previous research by Dr. Taquet, who was not involved in the current study, found an increased risk for neurologic and psychiatric diagnoses during the first 6 months after COVID-19 diagnosis.
The current study “contributes to better understanding this link by providing data from another country with a different organization of healthcare provision than the US, where most of the existing data come from,” Dr. Taquet said.
However, “some observations — for example, that COVID-19 is associated with a 50% reduction in the risk of autism, a condition present from very early in life — call for extreme caution in the interpretation of the findings, as they suggest that residual bias has not been accounted for,” Dr. Taquet continued.
Authors of an accompanying editorial, Eric Chow, MD, MS, MPH, of the Division of Allergy and Infectious Diseases, University of Washington, School of Public Health, and Anita Chopra, MD, of the post-COVID Clinic, University of Washington, Seattle, called the study a “critical contribution to the published literature.”
The association of neurologic and psychiatric diagnoses with severe disease “is a reminder of the importance of risk reduction by combining vaccinations with improved indoor ventilation and masking,” they concluded.
The study was supported by a grant from the Independent Research Fund Denmark. Dr. Hviid and coauthors, Dr. Chopra, and Dr. Taquet reported no relevant financial relationships. Dr. Chow received a travel award from the Infectious Diseases Society of America to attend ID Week 2022.
A version of this article appeared on Medscape.com.
Does Exercise Reduce Cancer Risk? It’s Just Not That Simple
“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.
Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.
The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.
What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?
Here’s an overview of the state of the evidence.
Exercise and Cancer Types: A Mixed Bag
When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.
For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.
The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.
The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”
Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations.
“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.
That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.
“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”
And it’s challenging to put all the evidence together, Dr. Jones added.
The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.
Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.
In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.
The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.
Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).
What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.
Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).
The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.
But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.
How Big Is the Effect?
Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.
But how much of a difference can exercise make?
Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.
These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.
“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.
“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.
The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.
Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.
For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).
But there may be an exercise sweet spot that maximizes the cancer risk benefit.
Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.
The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.
Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.
Why Exercise May Lower Cancer Risk
Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.
Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.
The why remains unclear, though some studies offer clues.
“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.
That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.
A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.
Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.
Defining an Exercise ‘Prescription’
Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.
The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.
But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.
Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.
Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.
But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.
“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.
Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.
There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.
“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.
Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.
“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”
A version of this article appeared on Medscape.com.
“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.
Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.
The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.
What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?
Here’s an overview of the state of the evidence.
Exercise and Cancer Types: A Mixed Bag
When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.
For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.
The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.
The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”
Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations.
“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.
That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.
“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”
And it’s challenging to put all the evidence together, Dr. Jones added.
The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.
Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.
In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.
The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.
Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).
What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.
Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).
The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.
But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.
How Big Is the Effect?
Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.
But how much of a difference can exercise make?
Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.
These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.
“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.
“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.
The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.
Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.
For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).
But there may be an exercise sweet spot that maximizes the cancer risk benefit.
Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.
The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.
Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.
Why Exercise May Lower Cancer Risk
Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.
Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.
The why remains unclear, though some studies offer clues.
“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.
That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.
A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.
Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.
Defining an Exercise ‘Prescription’
Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.
The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.
But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.
Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.
Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.
But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.
“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.
Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.
There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.
“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.
Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.
“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”
A version of this article appeared on Medscape.com.
“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.
Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.
The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.
What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?
Here’s an overview of the state of the evidence.
Exercise and Cancer Types: A Mixed Bag
When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.
For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.
The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.
The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”
Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations.
“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.
That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.
“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”
And it’s challenging to put all the evidence together, Dr. Jones added.
The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.
Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.
In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.
The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.
Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).
What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.
Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).
The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.
But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.
How Big Is the Effect?
Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.
But how much of a difference can exercise make?
Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.
These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.
“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.
“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.
The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.
Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.
For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).
But there may be an exercise sweet spot that maximizes the cancer risk benefit.
Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.
The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.
Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.
Why Exercise May Lower Cancer Risk
Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.
Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.
The why remains unclear, though some studies offer clues.
“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.
That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.
A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.
Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.
Defining an Exercise ‘Prescription’
Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.
The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.
But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.
Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.
Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.
But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.
“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.
Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.
There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.
“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.
Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.
“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”
A version of this article appeared on Medscape.com.