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Best strategy to prevent schizophrenia relapse yields unexpected results
A large meta-analysis sheds light on the best antipsychotic maintenance strategy to prevent relapse in clinically stable schizophrenia – with some unexpected results that have potential implications for changes to current guidelines.
Consistent with the researchers’ hypothesis, continuing antipsychotic treatment at the standard dose, switching to another antipsychotic, and reducing the dose were all significantly more effective than stopping antipsychotic treatment in preventing relapse.
However, contrary to the researchers’ hypothesis, which was based on current literature, switching to another antipsychotic was just as effective as continuing an antipsychotic at the standard dose.
Switching to another antipsychotic “does not increase the risk of relapse. This result was not expected, as previous literature suggested otherwise,” Giovanni Ostuzzi, MD, PhD, with University of Verona (Italy) said in an interview.
“On the other hand, reducing the dose below the standard range used in the acute phase carries a tangible risk of relapse, and should be limited to selected cases, for example those where the risk of withdrawing the treatment altogether is particularly high,” Dr. Ostuzzi said.
“These results should inform evidence-based guidelines, considering that clinical practices for relapse prevention are still heterogeneous and too often guided by clinical common sense only,” he added.
The study was published online in Lancet Psychiatry.
Guideline update warranted
The researchers evaluated the effect of different antipsychotic treatment strategies on risk for relapse in a network meta-analysis of 98 randomized controlled trials (RCTs) involving nearly 14,000 patients.
Compared to stopping the antipsychotic, all continuation strategies were effective in preventing relapse.
The risk for relapse was largely (and similarly) reduced when continuing the antipsychotic at the standard dose or switching to a different antipsychotic (relative risk, 0.37 and RR, 0.44, respectively), the researchers found.
Both strategies outperformed the strategy of reducing the antipsychotic dose below the standard (RR, 0.68), which was inferior to the other two strategies.
For every three patients continuing an antipsychotic at standard doses, one additional patient will avoid relapse, compared with patients stopping an antipsychotic, “which can be regarded as a large-effect magnitude according to commonly used thresholds and results from RCTs in acute schizophrenia,” the researchers write.
The number needed to treat (NNT) slightly increased to about 3.5 for patients who switched antipsychotic treatment – “still regarded as a large-effect magnitude,” they note.
“Currently, most psychiatrists are aware of the benefits of continuing antipsychotics in clinically stable individuals. However, they might face the necessity of changing the ongoing treatment strategy, generally because of burdening side effects, poor adherence, or both,” said Dr. Ostuzzi.
the investigators write.
More to the story
In an accompanying editorial, Marieke J.H. Begemann, PhD, University Medical Center Groningen (the Netherlands) and colleagues note the large number of patients included in the analysis provide “great credibility” to the findings, which are “trustworthy and important, yet only tell part of the story.”
They note that, while tapering information was often missing, antipsychotic discontinuation was probably abrupt for about two-thirds of the included studies.
“The issue of slow versus swift tapering is not yet settled, as there is a scarcity of RCTs that provide very gradual tapering over several months,” the editorialists write.
To fill this gap, several randomized trials are now in progress to specifically address the effects of gradual tapering or discontinuation vs. antipsychotic maintenance treatment in clinically stable schizophrenia.
“Time is pressing, as patients, their families, and clinicians need evidence-based data to weigh up the risks and benefits of maintaining, switching, or reducing medication with respect to a range of outcomes that are important to them, including social functioning, cognition, physical health, sexual health, and quality of life, thus going well beyond relapse prevention,” the editorialists note.
“Schizophrenia-spectrum disorders are heterogeneous with a largely unpredictable course, and we have known for a long time that a substantial proportion of patients who experienced a first psychosis can manage without antipsychotic medication. The challenge for future research is therefore to identify this subgroup on the basis of individual characteristics and guide them in tapering medication safely,” they add.
The study had no funding source. Dr. Ostuzzi reports no relevant financial relationships. A complete list of author disclosures is available with the original article. The editorialists have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A large meta-analysis sheds light on the best antipsychotic maintenance strategy to prevent relapse in clinically stable schizophrenia – with some unexpected results that have potential implications for changes to current guidelines.
Consistent with the researchers’ hypothesis, continuing antipsychotic treatment at the standard dose, switching to another antipsychotic, and reducing the dose were all significantly more effective than stopping antipsychotic treatment in preventing relapse.
However, contrary to the researchers’ hypothesis, which was based on current literature, switching to another antipsychotic was just as effective as continuing an antipsychotic at the standard dose.
Switching to another antipsychotic “does not increase the risk of relapse. This result was not expected, as previous literature suggested otherwise,” Giovanni Ostuzzi, MD, PhD, with University of Verona (Italy) said in an interview.
“On the other hand, reducing the dose below the standard range used in the acute phase carries a tangible risk of relapse, and should be limited to selected cases, for example those where the risk of withdrawing the treatment altogether is particularly high,” Dr. Ostuzzi said.
“These results should inform evidence-based guidelines, considering that clinical practices for relapse prevention are still heterogeneous and too often guided by clinical common sense only,” he added.
The study was published online in Lancet Psychiatry.
Guideline update warranted
The researchers evaluated the effect of different antipsychotic treatment strategies on risk for relapse in a network meta-analysis of 98 randomized controlled trials (RCTs) involving nearly 14,000 patients.
Compared to stopping the antipsychotic, all continuation strategies were effective in preventing relapse.
The risk for relapse was largely (and similarly) reduced when continuing the antipsychotic at the standard dose or switching to a different antipsychotic (relative risk, 0.37 and RR, 0.44, respectively), the researchers found.
Both strategies outperformed the strategy of reducing the antipsychotic dose below the standard (RR, 0.68), which was inferior to the other two strategies.
For every three patients continuing an antipsychotic at standard doses, one additional patient will avoid relapse, compared with patients stopping an antipsychotic, “which can be regarded as a large-effect magnitude according to commonly used thresholds and results from RCTs in acute schizophrenia,” the researchers write.
The number needed to treat (NNT) slightly increased to about 3.5 for patients who switched antipsychotic treatment – “still regarded as a large-effect magnitude,” they note.
“Currently, most psychiatrists are aware of the benefits of continuing antipsychotics in clinically stable individuals. However, they might face the necessity of changing the ongoing treatment strategy, generally because of burdening side effects, poor adherence, or both,” said Dr. Ostuzzi.
the investigators write.
More to the story
In an accompanying editorial, Marieke J.H. Begemann, PhD, University Medical Center Groningen (the Netherlands) and colleagues note the large number of patients included in the analysis provide “great credibility” to the findings, which are “trustworthy and important, yet only tell part of the story.”
They note that, while tapering information was often missing, antipsychotic discontinuation was probably abrupt for about two-thirds of the included studies.
“The issue of slow versus swift tapering is not yet settled, as there is a scarcity of RCTs that provide very gradual tapering over several months,” the editorialists write.
To fill this gap, several randomized trials are now in progress to specifically address the effects of gradual tapering or discontinuation vs. antipsychotic maintenance treatment in clinically stable schizophrenia.
“Time is pressing, as patients, their families, and clinicians need evidence-based data to weigh up the risks and benefits of maintaining, switching, or reducing medication with respect to a range of outcomes that are important to them, including social functioning, cognition, physical health, sexual health, and quality of life, thus going well beyond relapse prevention,” the editorialists note.
“Schizophrenia-spectrum disorders are heterogeneous with a largely unpredictable course, and we have known for a long time that a substantial proportion of patients who experienced a first psychosis can manage without antipsychotic medication. The challenge for future research is therefore to identify this subgroup on the basis of individual characteristics and guide them in tapering medication safely,” they add.
The study had no funding source. Dr. Ostuzzi reports no relevant financial relationships. A complete list of author disclosures is available with the original article. The editorialists have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A large meta-analysis sheds light on the best antipsychotic maintenance strategy to prevent relapse in clinically stable schizophrenia – with some unexpected results that have potential implications for changes to current guidelines.
Consistent with the researchers’ hypothesis, continuing antipsychotic treatment at the standard dose, switching to another antipsychotic, and reducing the dose were all significantly more effective than stopping antipsychotic treatment in preventing relapse.
However, contrary to the researchers’ hypothesis, which was based on current literature, switching to another antipsychotic was just as effective as continuing an antipsychotic at the standard dose.
Switching to another antipsychotic “does not increase the risk of relapse. This result was not expected, as previous literature suggested otherwise,” Giovanni Ostuzzi, MD, PhD, with University of Verona (Italy) said in an interview.
“On the other hand, reducing the dose below the standard range used in the acute phase carries a tangible risk of relapse, and should be limited to selected cases, for example those where the risk of withdrawing the treatment altogether is particularly high,” Dr. Ostuzzi said.
“These results should inform evidence-based guidelines, considering that clinical practices for relapse prevention are still heterogeneous and too often guided by clinical common sense only,” he added.
The study was published online in Lancet Psychiatry.
Guideline update warranted
The researchers evaluated the effect of different antipsychotic treatment strategies on risk for relapse in a network meta-analysis of 98 randomized controlled trials (RCTs) involving nearly 14,000 patients.
Compared to stopping the antipsychotic, all continuation strategies were effective in preventing relapse.
The risk for relapse was largely (and similarly) reduced when continuing the antipsychotic at the standard dose or switching to a different antipsychotic (relative risk, 0.37 and RR, 0.44, respectively), the researchers found.
Both strategies outperformed the strategy of reducing the antipsychotic dose below the standard (RR, 0.68), which was inferior to the other two strategies.
For every three patients continuing an antipsychotic at standard doses, one additional patient will avoid relapse, compared with patients stopping an antipsychotic, “which can be regarded as a large-effect magnitude according to commonly used thresholds and results from RCTs in acute schizophrenia,” the researchers write.
The number needed to treat (NNT) slightly increased to about 3.5 for patients who switched antipsychotic treatment – “still regarded as a large-effect magnitude,” they note.
“Currently, most psychiatrists are aware of the benefits of continuing antipsychotics in clinically stable individuals. However, they might face the necessity of changing the ongoing treatment strategy, generally because of burdening side effects, poor adherence, or both,” said Dr. Ostuzzi.
the investigators write.
More to the story
In an accompanying editorial, Marieke J.H. Begemann, PhD, University Medical Center Groningen (the Netherlands) and colleagues note the large number of patients included in the analysis provide “great credibility” to the findings, which are “trustworthy and important, yet only tell part of the story.”
They note that, while tapering information was often missing, antipsychotic discontinuation was probably abrupt for about two-thirds of the included studies.
“The issue of slow versus swift tapering is not yet settled, as there is a scarcity of RCTs that provide very gradual tapering over several months,” the editorialists write.
To fill this gap, several randomized trials are now in progress to specifically address the effects of gradual tapering or discontinuation vs. antipsychotic maintenance treatment in clinically stable schizophrenia.
“Time is pressing, as patients, their families, and clinicians need evidence-based data to weigh up the risks and benefits of maintaining, switching, or reducing medication with respect to a range of outcomes that are important to them, including social functioning, cognition, physical health, sexual health, and quality of life, thus going well beyond relapse prevention,” the editorialists note.
“Schizophrenia-spectrum disorders are heterogeneous with a largely unpredictable course, and we have known for a long time that a substantial proportion of patients who experienced a first psychosis can manage without antipsychotic medication. The challenge for future research is therefore to identify this subgroup on the basis of individual characteristics and guide them in tapering medication safely,” they add.
The study had no funding source. Dr. Ostuzzi reports no relevant financial relationships. A complete list of author disclosures is available with the original article. The editorialists have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE LANCET PSYCHIATRY
Lifestyle medicine eases anxiety symptoms
Despite the availability of effective treatment strategies, including pharmacotherapy, psychotherapy, and combination therapy, the prevalence of anxiety continues to increase, especially in low-income and conflict-ridden countries, Vincent Wing-Hei Wong, a PhD student at The Chinese University of Hong Kong, and colleagues wrote.
Previous studies have shown that lifestyle factors including diet, sleep, and sedentary behavior are involved in the development of anxiety symptoms, but the impact of lifestyle medicine (LM) as a treatment for anxiety has not been well studied, they wrote.
In a meta-analysis published in the Journal of Affective Disorders, the researchers identified 53 randomized, controlled trials with a total of 18,894 participants. Anxiety symptoms were measured using self-report questionnaires including the Hospital Anxiety and Depression Scale, the Depression Anxiety and Stress Scale, and the General Anxiety Disorder–7. Random-effects models were used to assess the effect of the intervention at immediate post treatment, short-term follow-up (1-3 months post treatment), medium follow-up (4-6 months), and long-term follow-up (7 months or more).
The studies included various combinations of LM intervention involving exercise, stress management, and sleep management. The interventions ranged from 1 month to 4 years, with an average duration of 6.3 months.
Overall, patients randomized to multicomponent LM interventions showed significantly improved symptoms compared to controls immediately after treatment and at short-term follow-up (P < .001 for both).
However, no significant differences were noted between the multicomponent LM intervention and control groups at medium-term follow-up, the researchers said. Only one study included data on long-term effects, so these effects were not evaluated in a meta-analysis, and more research is needed.
In a subgroup analysis, the effect was greatest for individuals with moderate anxiety symptoms at baseline (P < .05). “Our results could perhaps be explained by the occurrence of floor effect; those with higher baseline anxiety symptoms have greater room for improvement relative to those with fewer symptoms,” the researchers wrote.
The study findings were limited by several factors including the risk of overall bias and publication bias for the selected studies, as well as the limited degree of improvement because most patients had minimal anxiety symptoms at baseline, the researchers noted. Other limitations included the small number of studies for subgroup comparisons and the use of self-reports.
However, the results were strengthened by the use of broad search terms to capture multiple lifestyle determinants, and the diverse study populations and backgrounds from individuals in 19 countries.
The results support findings from previous studies, and support the value of multicomponent LM interventions for patients with anxiety in the short-term and immediately after treatment, the researchers emphasized.
“The LM approach, which leverages a range of universal lifestyle measures to manage anxiety and other common mental disorders such as depression, may be a viable solution to address the huge mental health burden through empowering individuals to practice self-management,” they concluded.
However, the researchers acknowledged the need for more randomized, controlled trials targeting patients with higher baseline anxiety levels or anxiety disorders, and using technology to improve treatment adherence.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Despite the availability of effective treatment strategies, including pharmacotherapy, psychotherapy, and combination therapy, the prevalence of anxiety continues to increase, especially in low-income and conflict-ridden countries, Vincent Wing-Hei Wong, a PhD student at The Chinese University of Hong Kong, and colleagues wrote.
Previous studies have shown that lifestyle factors including diet, sleep, and sedentary behavior are involved in the development of anxiety symptoms, but the impact of lifestyle medicine (LM) as a treatment for anxiety has not been well studied, they wrote.
In a meta-analysis published in the Journal of Affective Disorders, the researchers identified 53 randomized, controlled trials with a total of 18,894 participants. Anxiety symptoms were measured using self-report questionnaires including the Hospital Anxiety and Depression Scale, the Depression Anxiety and Stress Scale, and the General Anxiety Disorder–7. Random-effects models were used to assess the effect of the intervention at immediate post treatment, short-term follow-up (1-3 months post treatment), medium follow-up (4-6 months), and long-term follow-up (7 months or more).
The studies included various combinations of LM intervention involving exercise, stress management, and sleep management. The interventions ranged from 1 month to 4 years, with an average duration of 6.3 months.
Overall, patients randomized to multicomponent LM interventions showed significantly improved symptoms compared to controls immediately after treatment and at short-term follow-up (P < .001 for both).
However, no significant differences were noted between the multicomponent LM intervention and control groups at medium-term follow-up, the researchers said. Only one study included data on long-term effects, so these effects were not evaluated in a meta-analysis, and more research is needed.
In a subgroup analysis, the effect was greatest for individuals with moderate anxiety symptoms at baseline (P < .05). “Our results could perhaps be explained by the occurrence of floor effect; those with higher baseline anxiety symptoms have greater room for improvement relative to those with fewer symptoms,” the researchers wrote.
The study findings were limited by several factors including the risk of overall bias and publication bias for the selected studies, as well as the limited degree of improvement because most patients had minimal anxiety symptoms at baseline, the researchers noted. Other limitations included the small number of studies for subgroup comparisons and the use of self-reports.
However, the results were strengthened by the use of broad search terms to capture multiple lifestyle determinants, and the diverse study populations and backgrounds from individuals in 19 countries.
The results support findings from previous studies, and support the value of multicomponent LM interventions for patients with anxiety in the short-term and immediately after treatment, the researchers emphasized.
“The LM approach, which leverages a range of universal lifestyle measures to manage anxiety and other common mental disorders such as depression, may be a viable solution to address the huge mental health burden through empowering individuals to practice self-management,” they concluded.
However, the researchers acknowledged the need for more randomized, controlled trials targeting patients with higher baseline anxiety levels or anxiety disorders, and using technology to improve treatment adherence.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Despite the availability of effective treatment strategies, including pharmacotherapy, psychotherapy, and combination therapy, the prevalence of anxiety continues to increase, especially in low-income and conflict-ridden countries, Vincent Wing-Hei Wong, a PhD student at The Chinese University of Hong Kong, and colleagues wrote.
Previous studies have shown that lifestyle factors including diet, sleep, and sedentary behavior are involved in the development of anxiety symptoms, but the impact of lifestyle medicine (LM) as a treatment for anxiety has not been well studied, they wrote.
In a meta-analysis published in the Journal of Affective Disorders, the researchers identified 53 randomized, controlled trials with a total of 18,894 participants. Anxiety symptoms were measured using self-report questionnaires including the Hospital Anxiety and Depression Scale, the Depression Anxiety and Stress Scale, and the General Anxiety Disorder–7. Random-effects models were used to assess the effect of the intervention at immediate post treatment, short-term follow-up (1-3 months post treatment), medium follow-up (4-6 months), and long-term follow-up (7 months or more).
The studies included various combinations of LM intervention involving exercise, stress management, and sleep management. The interventions ranged from 1 month to 4 years, with an average duration of 6.3 months.
Overall, patients randomized to multicomponent LM interventions showed significantly improved symptoms compared to controls immediately after treatment and at short-term follow-up (P < .001 for both).
However, no significant differences were noted between the multicomponent LM intervention and control groups at medium-term follow-up, the researchers said. Only one study included data on long-term effects, so these effects were not evaluated in a meta-analysis, and more research is needed.
In a subgroup analysis, the effect was greatest for individuals with moderate anxiety symptoms at baseline (P < .05). “Our results could perhaps be explained by the occurrence of floor effect; those with higher baseline anxiety symptoms have greater room for improvement relative to those with fewer symptoms,” the researchers wrote.
The study findings were limited by several factors including the risk of overall bias and publication bias for the selected studies, as well as the limited degree of improvement because most patients had minimal anxiety symptoms at baseline, the researchers noted. Other limitations included the small number of studies for subgroup comparisons and the use of self-reports.
However, the results were strengthened by the use of broad search terms to capture multiple lifestyle determinants, and the diverse study populations and backgrounds from individuals in 19 countries.
The results support findings from previous studies, and support the value of multicomponent LM interventions for patients with anxiety in the short-term and immediately after treatment, the researchers emphasized.
“The LM approach, which leverages a range of universal lifestyle measures to manage anxiety and other common mental disorders such as depression, may be a viable solution to address the huge mental health burden through empowering individuals to practice self-management,” they concluded.
However, the researchers acknowledged the need for more randomized, controlled trials targeting patients with higher baseline anxiety levels or anxiety disorders, and using technology to improve treatment adherence.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM THE JOURNAL OF AFFECTIVE DISORDERS
Fertility rates lower in disadvantaged neighborhoods
A new study ties the odds of conception to the advantages of the neighborhood a woman lives in.
In a cohort of more than 6,000 women who were trying to get pregnant without fertility treatments, the probability of conception was reduced 21%-23% per menstrual cycle when comparing the most disadvantaged neighborhoods with the least disadvantaged.
“When disadvantaged neighborhood status was categorized within each state (as opposed to nationally), the results were slightly larger in magnitude,” wrote authors of the study published online in JAMA Network Open.
Among 6,356 participants, 3,725 pregnancies were observed for 27,427 menstrual cycles of follow-up. Average age was 30, and most participants were non-Hispanic White (5,297 [83.3%]) and had not previously given birth (4,179 [65.7%]).
When the researchers compared the top and bottom deciles of disadvantaged neighborhood status, adjusted fecundability ratios (the per-cycle probability of conception) were 0.79 (95% confidence interval [CI], 0.66-0.96) for national-level area deprivation index (ADI) rankings and 0.77 (95% CI, 0.65-0.92) for within-state ADI rankings. ADI score includes population indicators related to educational attainment, housing, employment, and poverty.
“These findings suggest that investments in disadvantaged neighborhoods may yield positive cobenefits for fertility,” the authors wrote.
The researchers used the Pregnancy Study Online, for which baseline data were collected from women in the United States from June 19, 2013, through April 12, 2019.
In the United States, 10%-15% of reproductive-aged couples experience infertility, defined as the inability to conceive after a year of unprotected intercourse.
Reason behind the numbers unclear
Mark Hornstein, MD, director in the reproductive endocrinology division of Brigham and Women’s Hospital and professor at Harvard Medical School, both in Boston, said in an interview that this study gives the “what” but the “why” is harder to pinpoint.
What is not known, he said, is what kind of access the women had to fertility counseling or treatment.
The association between fertility and neighborhood advantage status is very plausible given the well-established links between disadvantaged regions and poorer health outcomes, he said, adding that the authors make a good case for their conclusions in the paper.
The authors ruled out many potential confounders, such as age of the women, reproductive history, multivitamin use, education level, household income, and frequency of intercourse, and still there was a difference between disadvantaged and advantaged neighborhoods, he noted.
Dr. Hornstein said his own research team has found that lack of knowledge about insurance coverage regarding infertility services may keep women from seeking the services.
“One of the things I worry about it access,” he said. “[The study authors] didn’t really look at that. They just looked at what the chances were that they got pregnant. But they didn’t say how many of those women had a workup, an evaluation, for why they were having difficulty, if they were, or had treatment. So I don’t know if some or all or none of that difference that they saw from the highest neighborhood health score to the most disadvantaged – if that was from inherent problems in the area, access to the best health care, or some combination.”
Discussions have focused on changing personal behaviors
Discussions on improving fertility often center on changing personal behaviors, the authors noted. “However, structural, political, and environmental factors may also play a substantial role,” they wrote.
The findings are in line with previous research on the effect of stress on in vitro outcomes, they pointed out. “Perceived stress has been associated with poorer in vitro fertilization outcomes and reduced fecundability among couples attempting spontaneous conception,” the authors noted.
Studies also have shown that living in a disadvantaged neighborhood is linked with comorbidities during pregnancy, such as increased risks of gestational hypertension (risk ratio for lowest vs. highest quartile: 1.24 [95% CI, 1.14-1.35]) and poor gestational weight gain (relative risk for lowest vs. highest quartile: 1.1 [95% CI, 1.1-1.2]).
In addition, policies such as those that support civil rights, protect the environment, and invest in underresourced communities have been shown to improve health markers such as life expectancy.
Policy decisions can also perpetuate a cycle of stress, they wrote. Disadvantaged communities may have more air pollution, which has been shown to have negative effects on fertility. Unemployment has been linked with decreased population-level fertility rates. Lack of green space may result in fewer areas to reduce stress.
A study coauthor reported grants from the National Institutes of Health during the conduct of the study; nonfinancial support from Swiss Precision Diagnostics GmbH, Labcorp, Kindara.com, and FertilityFriend.com; and consulting for AbbVie outside the submitted work. No other author disclosures were reported. Dr. Hornstein reported no relevant financial relationships.
A new study ties the odds of conception to the advantages of the neighborhood a woman lives in.
In a cohort of more than 6,000 women who were trying to get pregnant without fertility treatments, the probability of conception was reduced 21%-23% per menstrual cycle when comparing the most disadvantaged neighborhoods with the least disadvantaged.
“When disadvantaged neighborhood status was categorized within each state (as opposed to nationally), the results were slightly larger in magnitude,” wrote authors of the study published online in JAMA Network Open.
Among 6,356 participants, 3,725 pregnancies were observed for 27,427 menstrual cycles of follow-up. Average age was 30, and most participants were non-Hispanic White (5,297 [83.3%]) and had not previously given birth (4,179 [65.7%]).
When the researchers compared the top and bottom deciles of disadvantaged neighborhood status, adjusted fecundability ratios (the per-cycle probability of conception) were 0.79 (95% confidence interval [CI], 0.66-0.96) for national-level area deprivation index (ADI) rankings and 0.77 (95% CI, 0.65-0.92) for within-state ADI rankings. ADI score includes population indicators related to educational attainment, housing, employment, and poverty.
“These findings suggest that investments in disadvantaged neighborhoods may yield positive cobenefits for fertility,” the authors wrote.
The researchers used the Pregnancy Study Online, for which baseline data were collected from women in the United States from June 19, 2013, through April 12, 2019.
In the United States, 10%-15% of reproductive-aged couples experience infertility, defined as the inability to conceive after a year of unprotected intercourse.
Reason behind the numbers unclear
Mark Hornstein, MD, director in the reproductive endocrinology division of Brigham and Women’s Hospital and professor at Harvard Medical School, both in Boston, said in an interview that this study gives the “what” but the “why” is harder to pinpoint.
What is not known, he said, is what kind of access the women had to fertility counseling or treatment.
The association between fertility and neighborhood advantage status is very plausible given the well-established links between disadvantaged regions and poorer health outcomes, he said, adding that the authors make a good case for their conclusions in the paper.
The authors ruled out many potential confounders, such as age of the women, reproductive history, multivitamin use, education level, household income, and frequency of intercourse, and still there was a difference between disadvantaged and advantaged neighborhoods, he noted.
Dr. Hornstein said his own research team has found that lack of knowledge about insurance coverage regarding infertility services may keep women from seeking the services.
“One of the things I worry about it access,” he said. “[The study authors] didn’t really look at that. They just looked at what the chances were that they got pregnant. But they didn’t say how many of those women had a workup, an evaluation, for why they were having difficulty, if they were, or had treatment. So I don’t know if some or all or none of that difference that they saw from the highest neighborhood health score to the most disadvantaged – if that was from inherent problems in the area, access to the best health care, or some combination.”
Discussions have focused on changing personal behaviors
Discussions on improving fertility often center on changing personal behaviors, the authors noted. “However, structural, political, and environmental factors may also play a substantial role,” they wrote.
The findings are in line with previous research on the effect of stress on in vitro outcomes, they pointed out. “Perceived stress has been associated with poorer in vitro fertilization outcomes and reduced fecundability among couples attempting spontaneous conception,” the authors noted.
Studies also have shown that living in a disadvantaged neighborhood is linked with comorbidities during pregnancy, such as increased risks of gestational hypertension (risk ratio for lowest vs. highest quartile: 1.24 [95% CI, 1.14-1.35]) and poor gestational weight gain (relative risk for lowest vs. highest quartile: 1.1 [95% CI, 1.1-1.2]).
In addition, policies such as those that support civil rights, protect the environment, and invest in underresourced communities have been shown to improve health markers such as life expectancy.
Policy decisions can also perpetuate a cycle of stress, they wrote. Disadvantaged communities may have more air pollution, which has been shown to have negative effects on fertility. Unemployment has been linked with decreased population-level fertility rates. Lack of green space may result in fewer areas to reduce stress.
A study coauthor reported grants from the National Institutes of Health during the conduct of the study; nonfinancial support from Swiss Precision Diagnostics GmbH, Labcorp, Kindara.com, and FertilityFriend.com; and consulting for AbbVie outside the submitted work. No other author disclosures were reported. Dr. Hornstein reported no relevant financial relationships.
A new study ties the odds of conception to the advantages of the neighborhood a woman lives in.
In a cohort of more than 6,000 women who were trying to get pregnant without fertility treatments, the probability of conception was reduced 21%-23% per menstrual cycle when comparing the most disadvantaged neighborhoods with the least disadvantaged.
“When disadvantaged neighborhood status was categorized within each state (as opposed to nationally), the results were slightly larger in magnitude,” wrote authors of the study published online in JAMA Network Open.
Among 6,356 participants, 3,725 pregnancies were observed for 27,427 menstrual cycles of follow-up. Average age was 30, and most participants were non-Hispanic White (5,297 [83.3%]) and had not previously given birth (4,179 [65.7%]).
When the researchers compared the top and bottom deciles of disadvantaged neighborhood status, adjusted fecundability ratios (the per-cycle probability of conception) were 0.79 (95% confidence interval [CI], 0.66-0.96) for national-level area deprivation index (ADI) rankings and 0.77 (95% CI, 0.65-0.92) for within-state ADI rankings. ADI score includes population indicators related to educational attainment, housing, employment, and poverty.
“These findings suggest that investments in disadvantaged neighborhoods may yield positive cobenefits for fertility,” the authors wrote.
The researchers used the Pregnancy Study Online, for which baseline data were collected from women in the United States from June 19, 2013, through April 12, 2019.
In the United States, 10%-15% of reproductive-aged couples experience infertility, defined as the inability to conceive after a year of unprotected intercourse.
Reason behind the numbers unclear
Mark Hornstein, MD, director in the reproductive endocrinology division of Brigham and Women’s Hospital and professor at Harvard Medical School, both in Boston, said in an interview that this study gives the “what” but the “why” is harder to pinpoint.
What is not known, he said, is what kind of access the women had to fertility counseling or treatment.
The association between fertility and neighborhood advantage status is very plausible given the well-established links between disadvantaged regions and poorer health outcomes, he said, adding that the authors make a good case for their conclusions in the paper.
The authors ruled out many potential confounders, such as age of the women, reproductive history, multivitamin use, education level, household income, and frequency of intercourse, and still there was a difference between disadvantaged and advantaged neighborhoods, he noted.
Dr. Hornstein said his own research team has found that lack of knowledge about insurance coverage regarding infertility services may keep women from seeking the services.
“One of the things I worry about it access,” he said. “[The study authors] didn’t really look at that. They just looked at what the chances were that they got pregnant. But they didn’t say how many of those women had a workup, an evaluation, for why they were having difficulty, if they were, or had treatment. So I don’t know if some or all or none of that difference that they saw from the highest neighborhood health score to the most disadvantaged – if that was from inherent problems in the area, access to the best health care, or some combination.”
Discussions have focused on changing personal behaviors
Discussions on improving fertility often center on changing personal behaviors, the authors noted. “However, structural, political, and environmental factors may also play a substantial role,” they wrote.
The findings are in line with previous research on the effect of stress on in vitro outcomes, they pointed out. “Perceived stress has been associated with poorer in vitro fertilization outcomes and reduced fecundability among couples attempting spontaneous conception,” the authors noted.
Studies also have shown that living in a disadvantaged neighborhood is linked with comorbidities during pregnancy, such as increased risks of gestational hypertension (risk ratio for lowest vs. highest quartile: 1.24 [95% CI, 1.14-1.35]) and poor gestational weight gain (relative risk for lowest vs. highest quartile: 1.1 [95% CI, 1.1-1.2]).
In addition, policies such as those that support civil rights, protect the environment, and invest in underresourced communities have been shown to improve health markers such as life expectancy.
Policy decisions can also perpetuate a cycle of stress, they wrote. Disadvantaged communities may have more air pollution, which has been shown to have negative effects on fertility. Unemployment has been linked with decreased population-level fertility rates. Lack of green space may result in fewer areas to reduce stress.
A study coauthor reported grants from the National Institutes of Health during the conduct of the study; nonfinancial support from Swiss Precision Diagnostics GmbH, Labcorp, Kindara.com, and FertilityFriend.com; and consulting for AbbVie outside the submitted work. No other author disclosures were reported. Dr. Hornstein reported no relevant financial relationships.
Will ESD replace EMR for large colorectal polyps?
Dear colleagues,
Resection of polyps is the bread and butter of endoscopy. Advances in technology have enabled us to tackle larger and more complex lesions throughout the gastrointestinal tract, especially through endoscopic mucosal resection (EMR). Endoscopic submucosal dissection (ESD) is another technique that offers much promise for complex colorectal polyps and is being rapidly adopted in the West. But do its benefits outweigh the costs in time, money and additional training needed for successful ESD? How can we justify higher recurrence rates with EMR when ESD is available? Will reimbursement continue to favor EMR? In this issue of Perspectives, Dr. Alexis Bayudan and Dr. Craig A. Munroe make the case for adopting ESD, while Dr. Sumeet Tewani highlights all the benefits of EMR. I invite you to a great debate and look forward to hearing your own thoughts on Twitter @AGA_GIHN and by email at ginews@gastro.org.
Gyanprakash A. Ketwaroo, MD, MSc, is assistant professor of medicine at Baylor College of Medicine, Houston. He is an associate editor for GI & Hepatology News.
The future standard of care
BY ALEXIS BAYUDAN, MD, AND CRAIG A. MUNROE, MD
Endoscopic submucosal dissection (ESD) is a minimally invasive, organ-sparing, flexible endoscopic technique used to treat advanced neoplasia of the digestive tract, with the goal of en bloc resection for accurate histologic assessment. ESD was introduced over 25 years ago in Japan by a small group of innovative endoscopists.1 After its initial adoption and success with removing gastric lesions, ESD later evolved as a technique used for complete resection of lesions throughout the gastrointestinal tract.
The intent of ESD is to achieve clear pathologic evaluation of deep and lateral margins, which is generally lost when piecemeal EMR (pEMR) is performed on lesions larger than 2 cm. With growing global experience, the evidence is clear that ESD is advantageous when compared to pEMR in the resection of large colorectal lesions en bloc, leading to improved curative resection rates and less local recurrence.
From our own experience, and from the results of many studies, we know that although procedure time in ESD can be longer, the rate of complete resection is far superior. ESD was previously cited as having a 10% risk of perforation in the 1990s and early 2000s, but current rates are closer to 4.5%, as noted by Nimii et al., with nearly complete successful treatment with endoscopic closure.1 In a 2021 meta-analysis reviewing a total of 21 studies, Lim et. al demonstrate that, although there is an increased risk of perforation with ESD compared to EMR (risk ratio, 7.597; 95% confidence interval, 4.281-13.479; P < .001), there is no significant difference in bleeding risk between the two techniques (RR, 7.597; 95% CI, 4.281-13.479; P < .001).2
Since its inception, many refinements of the ESD technique have occurred through technology, and better understanding of anatomy and disease states. These include, but are not limited to, improvements in hemostatic and closure techniques, electrosurgical equipment, resection and traction devices, the use of carbon dioxide, the ability to perform full-thickness endoscopic surgery, and submucosal lifting.1 The realm of endoscopic innovation is moving at a rapid pace within commercial and noncommercial entities, and advancements in ESD devices will allow for further improvements in procedure times and decreased procedural complications. Conversely, there have been few advancements in EMR technique in decades.
Further developments in ESD will continue to democratize this intervention, so that it can be practiced in all medical centers, not just expert centers. However, for ESD to become standard of care in the Western world, it will require more exposure and training. ESD has rapidly spread throughout Japan because of the master-mentor relationship that fosters safe learning, in addition to an abundance of highly skilled EMR-experienced physicians who went on to acquire their skills under the supervision of ESD experts. Current methods of teaching ESD, such as using pig models to practice specific steps of the procedure, can be implemented in Western gastroenterology training programs and through GI and surgical society training programs to learn safe operation in the third space. Mentorship and proctorship are also mandatory. The incorporation of ESD into standard practice over pEMR is very akin to laparoscopic cholecystectomy revolutionizing gallbladder surgery, even though open cholecystectomy was known to be effective.
A major limitation in the adoption of ESD in the West is reimbursement. Despite mounting evidence of the superiority of ESD in well-trained hands, and the additional training needed to safely perform these procedures, there had not been a pathway forward for payment for the increased requirements needed to perform these procedures safely.3 This leads to more endoscopists performing pEMR in the West which is anti-innovative. In October 2021, the Centers for Medicare and Medicaid Services expanded the reimbursement for ESD (Healthcare Common Procedure Coding System C9779). The availability of billing codes paves the way for increasing patient access to these therapies. Hopefully, additional codes will follow.
With the mounting evidence demonstrating ESD is superior to pEMR in terms of curative resection and recurrence rates, we think it is time for ESD to be incorporated widely into Western practice. ESD is still evolving and improving; ESD will become both safer and more effective. ESD has revolutionized endoscopic resection, and we are just beginning to see the possibilities and value of these techniques.
Dr. Baydan is a second-year fellow, and Dr. Munroe is an associate professor, both at the University of California, San Francisco. They have no relevant conflicts of interest.
References
1. Ferreira J et al. Clin Colon Rectal Surg. 2015 Sep; 28(3):146-151.
2. Lim X et al. World J Gastroenterol. 2021 Jul 7;27(25):3925-39.
3. Iqbal S et al. World J Gastrointest Endosc. 2020 Jan 16; 12(1):49-52.
More investment than payoff
Most large colorectal polyps are best managed by endoscopic mucosal resection (EMR) and do not require endoscopic submucosal dissection (ESD). EMR can provide complete, safe, and effective removal, preventing colorectal cancer while avoiding the risks of surgery or ESD. EMR has several advantages over ESD. It is minimally invasive, low cost, well tolerated, and allows excellent histopathologic examination. It is performed during colonoscopy in an outpatient endoscopy lab or ambulatory surgery center. There are several techniques that can be performed safely and efficiently using accessories that are readily available. It is easier to learn and perform, with lower risks and fewer resources. Endoscopists can effectively integrate EMR into a busy practice, without making significant additional investments.
EMR of large adenomas has improved morbidity, mortality, and cost compared to surgery.1-3 I first carefully inspect the lesion to plan the approach and exclude submucosal invasion, which should be referred for ESD or surgery instead. This includes understanding the size, location, morphology, and surface characteristics, using high-definition and narrow-band imaging or Fujinon intelligent chromoendoscopy. Conventional EMR utilizes submucosal injection to lift the polyp away from the underlying muscle layer before hot snare resection. Injection needles and snares of various shapes, sizes, and stiffness are available in most endoscopy labs. The goal is en bloc resection to achieve potential cure with complete histological assessment and low rate of recurrence. This can be achieved for lesions up to 2 cm in size, although larger lesions require piecemeal resection, which limits accurate histopathology and carries a recurrence rate up to 25%.1 Thermal ablation of the resection margins with argon plasma coagulation or snare-tip soft coagulation can reduce the rate of recurrence. Additionally, most recurrences are identified during early surveillance within 6 months and managed endoscopically. The rates of adverse events, including bleeding (6%-15%), perforation (1%-2%), and postpolypectomy syndrome (< 1%) remain at acceptable low levels.1,4
For many polyps, saline injection is safe, effective, and inexpensive, but it dissipates rapidly with limited duration of effect. Alternative agents can improve the lift, at additional cost.4 I prefer adding dye, such as methylene blue, to differentiate the submucosa from the muscularis, demarcate the lesion margins, and allow easier inspection of the defect. Dilute epinephrine can also be added to reduce intraprocedural bleeding and maintain a clean resection field. I reserve this for the duodenum, but it can be an important adjunct for some colorectal polyps. Submucosal injection also allows assessment for a “nonlifting sign,” which raises suspicion for invasive carcinoma but can also occur with benign submucosal fibrosis from previous biopsy, partial resection, or adjacent tattoo. In these cases, effective management can still be achieved using EMR in combination with avulsion and thermal ablation techniques.
Alternative techniques include cold EMR and underwater EMR.1,4 These are gaining popularity because of their excellent safety profile and favorable outcomes. Cold EMR involves submucosal injection followed by cold-snare resection, eliminating the use of cautery and its associated risks. Cold EMR is very safe and effective for small polyps, and we use this for progressively larger polyps given the low complication rate. Despite the need for piecemeal resection of polyps larger than 10 mm, local recurrence rates are comparable to conventional EMR. Sessile serrated polyps are especially ideal for piecemeal cold EMR. Meanwhile, underwater EMR eliminates the need for submucosal injection by utilizing water immersion, which elevates the mucosal lesion away from the muscularis layer. Either hot or cold snare resection can be performed. Benefits include reduced procedure time and cost, and relatively low complication and recurrence rates, compared with conventional EMR. I find this to be a nice option for laterally spreading polyps, with potentially higher rates of en bloc resection.1,4
ESD involves similar techniques but includes careful dissection of the submucosal layer beneath the lesion. In addition to the tools for EMR, a specialized electrosurgical knife is necessary, as well as dedicated training and mentorship that can be difficult to accommodate for an active endoscopist in practice. The primary advantage of ESD is higher en bloc resection rates for larger and potentially deeper lesions, with accurate histologic assessment and staging, and very low recurrence rates.1,4,5 However, ESD is more complex, technically challenging, and time and resource intensive, with higher risk of complications. Intraprocedural bleeding is common and requires immediate management. Additional risks include 2% risk of delayed bleeding and 5% risk of perforation.1,5 ESD involves an operating room, longer procedure times, and higher cost including surgical, anesthesia, and nursing costs. Some of this may be balanced by reduced frequency of surveillance and therapeutic procedures. While both EMR and ESD carry significant cost savings, compared with surgery, ESD is additionally disadvantaged by lack of reimbursement.
Regardless of the technique, EMR is easier to learn and perform than ESD, uses a limited number of devices that are readily available, and carries lower cost-burden. EMR is successful for most colorectal polyps, with the primary disadvantage being piecemeal resection of larger polyps. The rates of adverse events are lower, and appropriate surveillance is essential to ensuring complete resection and eliminating recurrence. Japanese and European guidelines endorse ESD for lesions that have a high likelihood of cancer invading the submucosa and for lesions that cannot be removed by EMR because of submucosal fibrosis. Ultimately, patients need to be treated individually with the most appropriate technique.
Dr. Tewani of Rockford Gastroenterology Associates is clinical assistant professor of medicine at the University of Illinois, Rockford. He has no relevant conflicts of interest to disclose.
References
1. Rashid MU et al. Surg Oncol. 2022 Mar 18;101742.
2. Law R et al. Gastrointest Endosc. 2016 Jun;83(6):1248-57.
3. Backes Y et al. BMC Gastroenterol. 2016 May 26;16(1):56.
4. Thiruvengadam SS et al. Gastroenterol Hepatol. 2022 Mar;18(3):133-44.
5. Wang J et al. World J Gastroenterol. 2014 Jul 7;20(25):8282-7l.
Dear colleagues,
Resection of polyps is the bread and butter of endoscopy. Advances in technology have enabled us to tackle larger and more complex lesions throughout the gastrointestinal tract, especially through endoscopic mucosal resection (EMR). Endoscopic submucosal dissection (ESD) is another technique that offers much promise for complex colorectal polyps and is being rapidly adopted in the West. But do its benefits outweigh the costs in time, money and additional training needed for successful ESD? How can we justify higher recurrence rates with EMR when ESD is available? Will reimbursement continue to favor EMR? In this issue of Perspectives, Dr. Alexis Bayudan and Dr. Craig A. Munroe make the case for adopting ESD, while Dr. Sumeet Tewani highlights all the benefits of EMR. I invite you to a great debate and look forward to hearing your own thoughts on Twitter @AGA_GIHN and by email at ginews@gastro.org.
Gyanprakash A. Ketwaroo, MD, MSc, is assistant professor of medicine at Baylor College of Medicine, Houston. He is an associate editor for GI & Hepatology News.
The future standard of care
BY ALEXIS BAYUDAN, MD, AND CRAIG A. MUNROE, MD
Endoscopic submucosal dissection (ESD) is a minimally invasive, organ-sparing, flexible endoscopic technique used to treat advanced neoplasia of the digestive tract, with the goal of en bloc resection for accurate histologic assessment. ESD was introduced over 25 years ago in Japan by a small group of innovative endoscopists.1 After its initial adoption and success with removing gastric lesions, ESD later evolved as a technique used for complete resection of lesions throughout the gastrointestinal tract.
The intent of ESD is to achieve clear pathologic evaluation of deep and lateral margins, which is generally lost when piecemeal EMR (pEMR) is performed on lesions larger than 2 cm. With growing global experience, the evidence is clear that ESD is advantageous when compared to pEMR in the resection of large colorectal lesions en bloc, leading to improved curative resection rates and less local recurrence.
From our own experience, and from the results of many studies, we know that although procedure time in ESD can be longer, the rate of complete resection is far superior. ESD was previously cited as having a 10% risk of perforation in the 1990s and early 2000s, but current rates are closer to 4.5%, as noted by Nimii et al., with nearly complete successful treatment with endoscopic closure.1 In a 2021 meta-analysis reviewing a total of 21 studies, Lim et. al demonstrate that, although there is an increased risk of perforation with ESD compared to EMR (risk ratio, 7.597; 95% confidence interval, 4.281-13.479; P < .001), there is no significant difference in bleeding risk between the two techniques (RR, 7.597; 95% CI, 4.281-13.479; P < .001).2
Since its inception, many refinements of the ESD technique have occurred through technology, and better understanding of anatomy and disease states. These include, but are not limited to, improvements in hemostatic and closure techniques, electrosurgical equipment, resection and traction devices, the use of carbon dioxide, the ability to perform full-thickness endoscopic surgery, and submucosal lifting.1 The realm of endoscopic innovation is moving at a rapid pace within commercial and noncommercial entities, and advancements in ESD devices will allow for further improvements in procedure times and decreased procedural complications. Conversely, there have been few advancements in EMR technique in decades.
Further developments in ESD will continue to democratize this intervention, so that it can be practiced in all medical centers, not just expert centers. However, for ESD to become standard of care in the Western world, it will require more exposure and training. ESD has rapidly spread throughout Japan because of the master-mentor relationship that fosters safe learning, in addition to an abundance of highly skilled EMR-experienced physicians who went on to acquire their skills under the supervision of ESD experts. Current methods of teaching ESD, such as using pig models to practice specific steps of the procedure, can be implemented in Western gastroenterology training programs and through GI and surgical society training programs to learn safe operation in the third space. Mentorship and proctorship are also mandatory. The incorporation of ESD into standard practice over pEMR is very akin to laparoscopic cholecystectomy revolutionizing gallbladder surgery, even though open cholecystectomy was known to be effective.
A major limitation in the adoption of ESD in the West is reimbursement. Despite mounting evidence of the superiority of ESD in well-trained hands, and the additional training needed to safely perform these procedures, there had not been a pathway forward for payment for the increased requirements needed to perform these procedures safely.3 This leads to more endoscopists performing pEMR in the West which is anti-innovative. In October 2021, the Centers for Medicare and Medicaid Services expanded the reimbursement for ESD (Healthcare Common Procedure Coding System C9779). The availability of billing codes paves the way for increasing patient access to these therapies. Hopefully, additional codes will follow.
With the mounting evidence demonstrating ESD is superior to pEMR in terms of curative resection and recurrence rates, we think it is time for ESD to be incorporated widely into Western practice. ESD is still evolving and improving; ESD will become both safer and more effective. ESD has revolutionized endoscopic resection, and we are just beginning to see the possibilities and value of these techniques.
Dr. Baydan is a second-year fellow, and Dr. Munroe is an associate professor, both at the University of California, San Francisco. They have no relevant conflicts of interest.
References
1. Ferreira J et al. Clin Colon Rectal Surg. 2015 Sep; 28(3):146-151.
2. Lim X et al. World J Gastroenterol. 2021 Jul 7;27(25):3925-39.
3. Iqbal S et al. World J Gastrointest Endosc. 2020 Jan 16; 12(1):49-52.
More investment than payoff
Most large colorectal polyps are best managed by endoscopic mucosal resection (EMR) and do not require endoscopic submucosal dissection (ESD). EMR can provide complete, safe, and effective removal, preventing colorectal cancer while avoiding the risks of surgery or ESD. EMR has several advantages over ESD. It is minimally invasive, low cost, well tolerated, and allows excellent histopathologic examination. It is performed during colonoscopy in an outpatient endoscopy lab or ambulatory surgery center. There are several techniques that can be performed safely and efficiently using accessories that are readily available. It is easier to learn and perform, with lower risks and fewer resources. Endoscopists can effectively integrate EMR into a busy practice, without making significant additional investments.
EMR of large adenomas has improved morbidity, mortality, and cost compared to surgery.1-3 I first carefully inspect the lesion to plan the approach and exclude submucosal invasion, which should be referred for ESD or surgery instead. This includes understanding the size, location, morphology, and surface characteristics, using high-definition and narrow-band imaging or Fujinon intelligent chromoendoscopy. Conventional EMR utilizes submucosal injection to lift the polyp away from the underlying muscle layer before hot snare resection. Injection needles and snares of various shapes, sizes, and stiffness are available in most endoscopy labs. The goal is en bloc resection to achieve potential cure with complete histological assessment and low rate of recurrence. This can be achieved for lesions up to 2 cm in size, although larger lesions require piecemeal resection, which limits accurate histopathology and carries a recurrence rate up to 25%.1 Thermal ablation of the resection margins with argon plasma coagulation or snare-tip soft coagulation can reduce the rate of recurrence. Additionally, most recurrences are identified during early surveillance within 6 months and managed endoscopically. The rates of adverse events, including bleeding (6%-15%), perforation (1%-2%), and postpolypectomy syndrome (< 1%) remain at acceptable low levels.1,4
For many polyps, saline injection is safe, effective, and inexpensive, but it dissipates rapidly with limited duration of effect. Alternative agents can improve the lift, at additional cost.4 I prefer adding dye, such as methylene blue, to differentiate the submucosa from the muscularis, demarcate the lesion margins, and allow easier inspection of the defect. Dilute epinephrine can also be added to reduce intraprocedural bleeding and maintain a clean resection field. I reserve this for the duodenum, but it can be an important adjunct for some colorectal polyps. Submucosal injection also allows assessment for a “nonlifting sign,” which raises suspicion for invasive carcinoma but can also occur with benign submucosal fibrosis from previous biopsy, partial resection, or adjacent tattoo. In these cases, effective management can still be achieved using EMR in combination with avulsion and thermal ablation techniques.
Alternative techniques include cold EMR and underwater EMR.1,4 These are gaining popularity because of their excellent safety profile and favorable outcomes. Cold EMR involves submucosal injection followed by cold-snare resection, eliminating the use of cautery and its associated risks. Cold EMR is very safe and effective for small polyps, and we use this for progressively larger polyps given the low complication rate. Despite the need for piecemeal resection of polyps larger than 10 mm, local recurrence rates are comparable to conventional EMR. Sessile serrated polyps are especially ideal for piecemeal cold EMR. Meanwhile, underwater EMR eliminates the need for submucosal injection by utilizing water immersion, which elevates the mucosal lesion away from the muscularis layer. Either hot or cold snare resection can be performed. Benefits include reduced procedure time and cost, and relatively low complication and recurrence rates, compared with conventional EMR. I find this to be a nice option for laterally spreading polyps, with potentially higher rates of en bloc resection.1,4
ESD involves similar techniques but includes careful dissection of the submucosal layer beneath the lesion. In addition to the tools for EMR, a specialized electrosurgical knife is necessary, as well as dedicated training and mentorship that can be difficult to accommodate for an active endoscopist in practice. The primary advantage of ESD is higher en bloc resection rates for larger and potentially deeper lesions, with accurate histologic assessment and staging, and very low recurrence rates.1,4,5 However, ESD is more complex, technically challenging, and time and resource intensive, with higher risk of complications. Intraprocedural bleeding is common and requires immediate management. Additional risks include 2% risk of delayed bleeding and 5% risk of perforation.1,5 ESD involves an operating room, longer procedure times, and higher cost including surgical, anesthesia, and nursing costs. Some of this may be balanced by reduced frequency of surveillance and therapeutic procedures. While both EMR and ESD carry significant cost savings, compared with surgery, ESD is additionally disadvantaged by lack of reimbursement.
Regardless of the technique, EMR is easier to learn and perform than ESD, uses a limited number of devices that are readily available, and carries lower cost-burden. EMR is successful for most colorectal polyps, with the primary disadvantage being piecemeal resection of larger polyps. The rates of adverse events are lower, and appropriate surveillance is essential to ensuring complete resection and eliminating recurrence. Japanese and European guidelines endorse ESD for lesions that have a high likelihood of cancer invading the submucosa and for lesions that cannot be removed by EMR because of submucosal fibrosis. Ultimately, patients need to be treated individually with the most appropriate technique.
Dr. Tewani of Rockford Gastroenterology Associates is clinical assistant professor of medicine at the University of Illinois, Rockford. He has no relevant conflicts of interest to disclose.
References
1. Rashid MU et al. Surg Oncol. 2022 Mar 18;101742.
2. Law R et al. Gastrointest Endosc. 2016 Jun;83(6):1248-57.
3. Backes Y et al. BMC Gastroenterol. 2016 May 26;16(1):56.
4. Thiruvengadam SS et al. Gastroenterol Hepatol. 2022 Mar;18(3):133-44.
5. Wang J et al. World J Gastroenterol. 2014 Jul 7;20(25):8282-7l.
Dear colleagues,
Resection of polyps is the bread and butter of endoscopy. Advances in technology have enabled us to tackle larger and more complex lesions throughout the gastrointestinal tract, especially through endoscopic mucosal resection (EMR). Endoscopic submucosal dissection (ESD) is another technique that offers much promise for complex colorectal polyps and is being rapidly adopted in the West. But do its benefits outweigh the costs in time, money and additional training needed for successful ESD? How can we justify higher recurrence rates with EMR when ESD is available? Will reimbursement continue to favor EMR? In this issue of Perspectives, Dr. Alexis Bayudan and Dr. Craig A. Munroe make the case for adopting ESD, while Dr. Sumeet Tewani highlights all the benefits of EMR. I invite you to a great debate and look forward to hearing your own thoughts on Twitter @AGA_GIHN and by email at ginews@gastro.org.
Gyanprakash A. Ketwaroo, MD, MSc, is assistant professor of medicine at Baylor College of Medicine, Houston. He is an associate editor for GI & Hepatology News.
The future standard of care
BY ALEXIS BAYUDAN, MD, AND CRAIG A. MUNROE, MD
Endoscopic submucosal dissection (ESD) is a minimally invasive, organ-sparing, flexible endoscopic technique used to treat advanced neoplasia of the digestive tract, with the goal of en bloc resection for accurate histologic assessment. ESD was introduced over 25 years ago in Japan by a small group of innovative endoscopists.1 After its initial adoption and success with removing gastric lesions, ESD later evolved as a technique used for complete resection of lesions throughout the gastrointestinal tract.
The intent of ESD is to achieve clear pathologic evaluation of deep and lateral margins, which is generally lost when piecemeal EMR (pEMR) is performed on lesions larger than 2 cm. With growing global experience, the evidence is clear that ESD is advantageous when compared to pEMR in the resection of large colorectal lesions en bloc, leading to improved curative resection rates and less local recurrence.
From our own experience, and from the results of many studies, we know that although procedure time in ESD can be longer, the rate of complete resection is far superior. ESD was previously cited as having a 10% risk of perforation in the 1990s and early 2000s, but current rates are closer to 4.5%, as noted by Nimii et al., with nearly complete successful treatment with endoscopic closure.1 In a 2021 meta-analysis reviewing a total of 21 studies, Lim et. al demonstrate that, although there is an increased risk of perforation with ESD compared to EMR (risk ratio, 7.597; 95% confidence interval, 4.281-13.479; P < .001), there is no significant difference in bleeding risk between the two techniques (RR, 7.597; 95% CI, 4.281-13.479; P < .001).2
Since its inception, many refinements of the ESD technique have occurred through technology, and better understanding of anatomy and disease states. These include, but are not limited to, improvements in hemostatic and closure techniques, electrosurgical equipment, resection and traction devices, the use of carbon dioxide, the ability to perform full-thickness endoscopic surgery, and submucosal lifting.1 The realm of endoscopic innovation is moving at a rapid pace within commercial and noncommercial entities, and advancements in ESD devices will allow for further improvements in procedure times and decreased procedural complications. Conversely, there have been few advancements in EMR technique in decades.
Further developments in ESD will continue to democratize this intervention, so that it can be practiced in all medical centers, not just expert centers. However, for ESD to become standard of care in the Western world, it will require more exposure and training. ESD has rapidly spread throughout Japan because of the master-mentor relationship that fosters safe learning, in addition to an abundance of highly skilled EMR-experienced physicians who went on to acquire their skills under the supervision of ESD experts. Current methods of teaching ESD, such as using pig models to practice specific steps of the procedure, can be implemented in Western gastroenterology training programs and through GI and surgical society training programs to learn safe operation in the third space. Mentorship and proctorship are also mandatory. The incorporation of ESD into standard practice over pEMR is very akin to laparoscopic cholecystectomy revolutionizing gallbladder surgery, even though open cholecystectomy was known to be effective.
A major limitation in the adoption of ESD in the West is reimbursement. Despite mounting evidence of the superiority of ESD in well-trained hands, and the additional training needed to safely perform these procedures, there had not been a pathway forward for payment for the increased requirements needed to perform these procedures safely.3 This leads to more endoscopists performing pEMR in the West which is anti-innovative. In October 2021, the Centers for Medicare and Medicaid Services expanded the reimbursement for ESD (Healthcare Common Procedure Coding System C9779). The availability of billing codes paves the way for increasing patient access to these therapies. Hopefully, additional codes will follow.
With the mounting evidence demonstrating ESD is superior to pEMR in terms of curative resection and recurrence rates, we think it is time for ESD to be incorporated widely into Western practice. ESD is still evolving and improving; ESD will become both safer and more effective. ESD has revolutionized endoscopic resection, and we are just beginning to see the possibilities and value of these techniques.
Dr. Baydan is a second-year fellow, and Dr. Munroe is an associate professor, both at the University of California, San Francisco. They have no relevant conflicts of interest.
References
1. Ferreira J et al. Clin Colon Rectal Surg. 2015 Sep; 28(3):146-151.
2. Lim X et al. World J Gastroenterol. 2021 Jul 7;27(25):3925-39.
3. Iqbal S et al. World J Gastrointest Endosc. 2020 Jan 16; 12(1):49-52.
More investment than payoff
Most large colorectal polyps are best managed by endoscopic mucosal resection (EMR) and do not require endoscopic submucosal dissection (ESD). EMR can provide complete, safe, and effective removal, preventing colorectal cancer while avoiding the risks of surgery or ESD. EMR has several advantages over ESD. It is minimally invasive, low cost, well tolerated, and allows excellent histopathologic examination. It is performed during colonoscopy in an outpatient endoscopy lab or ambulatory surgery center. There are several techniques that can be performed safely and efficiently using accessories that are readily available. It is easier to learn and perform, with lower risks and fewer resources. Endoscopists can effectively integrate EMR into a busy practice, without making significant additional investments.
EMR of large adenomas has improved morbidity, mortality, and cost compared to surgery.1-3 I first carefully inspect the lesion to plan the approach and exclude submucosal invasion, which should be referred for ESD or surgery instead. This includes understanding the size, location, morphology, and surface characteristics, using high-definition and narrow-band imaging or Fujinon intelligent chromoendoscopy. Conventional EMR utilizes submucosal injection to lift the polyp away from the underlying muscle layer before hot snare resection. Injection needles and snares of various shapes, sizes, and stiffness are available in most endoscopy labs. The goal is en bloc resection to achieve potential cure with complete histological assessment and low rate of recurrence. This can be achieved for lesions up to 2 cm in size, although larger lesions require piecemeal resection, which limits accurate histopathology and carries a recurrence rate up to 25%.1 Thermal ablation of the resection margins with argon plasma coagulation or snare-tip soft coagulation can reduce the rate of recurrence. Additionally, most recurrences are identified during early surveillance within 6 months and managed endoscopically. The rates of adverse events, including bleeding (6%-15%), perforation (1%-2%), and postpolypectomy syndrome (< 1%) remain at acceptable low levels.1,4
For many polyps, saline injection is safe, effective, and inexpensive, but it dissipates rapidly with limited duration of effect. Alternative agents can improve the lift, at additional cost.4 I prefer adding dye, such as methylene blue, to differentiate the submucosa from the muscularis, demarcate the lesion margins, and allow easier inspection of the defect. Dilute epinephrine can also be added to reduce intraprocedural bleeding and maintain a clean resection field. I reserve this for the duodenum, but it can be an important adjunct for some colorectal polyps. Submucosal injection also allows assessment for a “nonlifting sign,” which raises suspicion for invasive carcinoma but can also occur with benign submucosal fibrosis from previous biopsy, partial resection, or adjacent tattoo. In these cases, effective management can still be achieved using EMR in combination with avulsion and thermal ablation techniques.
Alternative techniques include cold EMR and underwater EMR.1,4 These are gaining popularity because of their excellent safety profile and favorable outcomes. Cold EMR involves submucosal injection followed by cold-snare resection, eliminating the use of cautery and its associated risks. Cold EMR is very safe and effective for small polyps, and we use this for progressively larger polyps given the low complication rate. Despite the need for piecemeal resection of polyps larger than 10 mm, local recurrence rates are comparable to conventional EMR. Sessile serrated polyps are especially ideal for piecemeal cold EMR. Meanwhile, underwater EMR eliminates the need for submucosal injection by utilizing water immersion, which elevates the mucosal lesion away from the muscularis layer. Either hot or cold snare resection can be performed. Benefits include reduced procedure time and cost, and relatively low complication and recurrence rates, compared with conventional EMR. I find this to be a nice option for laterally spreading polyps, with potentially higher rates of en bloc resection.1,4
ESD involves similar techniques but includes careful dissection of the submucosal layer beneath the lesion. In addition to the tools for EMR, a specialized electrosurgical knife is necessary, as well as dedicated training and mentorship that can be difficult to accommodate for an active endoscopist in practice. The primary advantage of ESD is higher en bloc resection rates for larger and potentially deeper lesions, with accurate histologic assessment and staging, and very low recurrence rates.1,4,5 However, ESD is more complex, technically challenging, and time and resource intensive, with higher risk of complications. Intraprocedural bleeding is common and requires immediate management. Additional risks include 2% risk of delayed bleeding and 5% risk of perforation.1,5 ESD involves an operating room, longer procedure times, and higher cost including surgical, anesthesia, and nursing costs. Some of this may be balanced by reduced frequency of surveillance and therapeutic procedures. While both EMR and ESD carry significant cost savings, compared with surgery, ESD is additionally disadvantaged by lack of reimbursement.
Regardless of the technique, EMR is easier to learn and perform than ESD, uses a limited number of devices that are readily available, and carries lower cost-burden. EMR is successful for most colorectal polyps, with the primary disadvantage being piecemeal resection of larger polyps. The rates of adverse events are lower, and appropriate surveillance is essential to ensuring complete resection and eliminating recurrence. Japanese and European guidelines endorse ESD for lesions that have a high likelihood of cancer invading the submucosa and for lesions that cannot be removed by EMR because of submucosal fibrosis. Ultimately, patients need to be treated individually with the most appropriate technique.
Dr. Tewani of Rockford Gastroenterology Associates is clinical assistant professor of medicine at the University of Illinois, Rockford. He has no relevant conflicts of interest to disclose.
References
1. Rashid MU et al. Surg Oncol. 2022 Mar 18;101742.
2. Law R et al. Gastrointest Endosc. 2016 Jun;83(6):1248-57.
3. Backes Y et al. BMC Gastroenterol. 2016 May 26;16(1):56.
4. Thiruvengadam SS et al. Gastroenterol Hepatol. 2022 Mar;18(3):133-44.
5. Wang J et al. World J Gastroenterol. 2014 Jul 7;20(25):8282-7l.
Commentary: Evaluating New Treatments and Cardiovascular Risk in PsA, July 2022
Advanced targeted therapies have proven safety and efficacy over conventional therapies, often dramatically improving signs and symptoms. However, it is also desirable that such expensive therapies also show benefit in other outcomes, such as work productivity and quality of life. To evaluate work productivity and daily activity impairment and health-related quality of life in patients with inflammatory arthritis (rheumatoid arthritis, n = 95; PsA, n = 69, and axial spondyloarthritis, n = 95) treated with golimumab, Dejaco and colleagues conducted a prospective, multicenter study in Austria. A total of 110 of these patients were followed for 24 months. At 24 months after golimumab initiation, there was significant improvement in total work productivity, presenteeism, activity impairment, and quality-of-life scores. Thus, golimumab, in addition to reducing disease activity, improved work productivity, activity, and health-related quality of life in patients with inflammatory arthritis, including PsA.
Cardiovascular disease (CVD) remains a major comorbidity in patients with PsA. This observation was once again confirmed in an observational, cross-sectional, case-control study including 207 patients with PsA and 414 matched controls from France. Degboe and colleagues demonstrated that patients with PsA had a higher prevalence of cardiovascular events and cardiovascular risk factors, such as high body mass index, triglyceride level, and hypertension, compared with controls. The proportion of patients with PsA who were estimated to have very high cardiovascular risk factors (≥ 10%) increased when SCORE (European Society of Cardiology Systematic Coronary Risk Evaluation) and QRISK2 (British Heart Foundation) equations considered the additional risk attributable to PsA. However, risk predictions scores such as SCORE and QRISK2 perform poorly in patients with PsA. To identify novel inflammatory and metabolic parameters associated with cardiovascular disease, Schwartz and colleagues looked at 18F-fluorodeoxyglucose (FDG) PET-CT uptake in a cross-sectional analysis of a prospective study including 39 patients with biologic-treatment-naive PsA and 56 age-sex matched controls without PsA. They found that coronary artery disease (CAD) was significantly associated with visceral adiposity and FDG uptake in the bone marrow, liver, spleen, and subcutaneous adipose tissue. Thus, inflammatory and metabolic parameters, including visceral adiposity, potentially contribute to subclinical CAD in patients with PsA and may in the future be used to refine CVD risk and be targets for CAD preventive treatments.
Advanced targeted therapies have proven safety and efficacy over conventional therapies, often dramatically improving signs and symptoms. However, it is also desirable that such expensive therapies also show benefit in other outcomes, such as work productivity and quality of life. To evaluate work productivity and daily activity impairment and health-related quality of life in patients with inflammatory arthritis (rheumatoid arthritis, n = 95; PsA, n = 69, and axial spondyloarthritis, n = 95) treated with golimumab, Dejaco and colleagues conducted a prospective, multicenter study in Austria. A total of 110 of these patients were followed for 24 months. At 24 months after golimumab initiation, there was significant improvement in total work productivity, presenteeism, activity impairment, and quality-of-life scores. Thus, golimumab, in addition to reducing disease activity, improved work productivity, activity, and health-related quality of life in patients with inflammatory arthritis, including PsA.
Cardiovascular disease (CVD) remains a major comorbidity in patients with PsA. This observation was once again confirmed in an observational, cross-sectional, case-control study including 207 patients with PsA and 414 matched controls from France. Degboe and colleagues demonstrated that patients with PsA had a higher prevalence of cardiovascular events and cardiovascular risk factors, such as high body mass index, triglyceride level, and hypertension, compared with controls. The proportion of patients with PsA who were estimated to have very high cardiovascular risk factors (≥ 10%) increased when SCORE (European Society of Cardiology Systematic Coronary Risk Evaluation) and QRISK2 (British Heart Foundation) equations considered the additional risk attributable to PsA. However, risk predictions scores such as SCORE and QRISK2 perform poorly in patients with PsA. To identify novel inflammatory and metabolic parameters associated with cardiovascular disease, Schwartz and colleagues looked at 18F-fluorodeoxyglucose (FDG) PET-CT uptake in a cross-sectional analysis of a prospective study including 39 patients with biologic-treatment-naive PsA and 56 age-sex matched controls without PsA. They found that coronary artery disease (CAD) was significantly associated with visceral adiposity and FDG uptake in the bone marrow, liver, spleen, and subcutaneous adipose tissue. Thus, inflammatory and metabolic parameters, including visceral adiposity, potentially contribute to subclinical CAD in patients with PsA and may in the future be used to refine CVD risk and be targets for CAD preventive treatments.
Advanced targeted therapies have proven safety and efficacy over conventional therapies, often dramatically improving signs and symptoms. However, it is also desirable that such expensive therapies also show benefit in other outcomes, such as work productivity and quality of life. To evaluate work productivity and daily activity impairment and health-related quality of life in patients with inflammatory arthritis (rheumatoid arthritis, n = 95; PsA, n = 69, and axial spondyloarthritis, n = 95) treated with golimumab, Dejaco and colleagues conducted a prospective, multicenter study in Austria. A total of 110 of these patients were followed for 24 months. At 24 months after golimumab initiation, there was significant improvement in total work productivity, presenteeism, activity impairment, and quality-of-life scores. Thus, golimumab, in addition to reducing disease activity, improved work productivity, activity, and health-related quality of life in patients with inflammatory arthritis, including PsA.
Cardiovascular disease (CVD) remains a major comorbidity in patients with PsA. This observation was once again confirmed in an observational, cross-sectional, case-control study including 207 patients with PsA and 414 matched controls from France. Degboe and colleagues demonstrated that patients with PsA had a higher prevalence of cardiovascular events and cardiovascular risk factors, such as high body mass index, triglyceride level, and hypertension, compared with controls. The proportion of patients with PsA who were estimated to have very high cardiovascular risk factors (≥ 10%) increased when SCORE (European Society of Cardiology Systematic Coronary Risk Evaluation) and QRISK2 (British Heart Foundation) equations considered the additional risk attributable to PsA. However, risk predictions scores such as SCORE and QRISK2 perform poorly in patients with PsA. To identify novel inflammatory and metabolic parameters associated with cardiovascular disease, Schwartz and colleagues looked at 18F-fluorodeoxyglucose (FDG) PET-CT uptake in a cross-sectional analysis of a prospective study including 39 patients with biologic-treatment-naive PsA and 56 age-sex matched controls without PsA. They found that coronary artery disease (CAD) was significantly associated with visceral adiposity and FDG uptake in the bone marrow, liver, spleen, and subcutaneous adipose tissue. Thus, inflammatory and metabolic parameters, including visceral adiposity, potentially contribute to subclinical CAD in patients with PsA and may in the future be used to refine CVD risk and be targets for CAD preventive treatments.
ASCO outlines optimal treatments for patients with metastatic clear cell renal cell carcinoma
.
This year in the U.S., it is estimated that 79,000 men and women will be diagnosed with kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype and is a leading source of morbidity and mortality. It is also commonly used to study new targeted molecular therapies. The resulting influx of phase III trial results has transformed ccRCC care. “We have an array of different treatment options, and the structure in which these treatments would be applied needed to have expert input. It is an exciting time for kidney cancer, and optimizing therapy now has immediate and meaningful impact into patients longevity,” guideline lead author W. Kimryn Rathmell, MD, PhD, said in an interview.
“The key developments are the emergence of targeted therapies in addition to immune therapies as well as combinations. The order of treatments matters and different patients will have different needs,” said Dr. Rathmell, professor of medicine at Vanderbilt University, Nashville, Tenn.
Dr. Rathmell highlighted the section of the guideline that discusses the need for robust tissue-based diagnosis, as well as active surveillance or cytoreductive nephrectomy. She also emphasized sections on differentiating courses of treatment and plans the use of International Metastatic RCC Database Consortium (IMDC) risk model.
Cytoreductive nephrectomy is an option for patients with one risk factor in which a significant majority of the tumor is within the kidney. The patients should also have good Eastern Cooperative Oncology Group (ECOG) performance status, and no brain, bone, or liver metastases.
Some with metastatic ccRCC can be offered active surveillance. Defining characteristics include favorable or immediate risk, few or no symptoms, a favorable histologic profile, a long interval between nephrectomy and onset of metastasis, or low burden of metastatic disease.
The guidelines also discuss the need to stratify patients within risk groups. Patients rated as intermediate or poor risk in the first line setting should be treated with two immune checkpoint inhibitors (ICI) or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI). ICI combined with a VEGFR TKI can be appropriate for patients with favorable risk but requiring systemic therapy. Those with favorable risk or another medical condition can be offered monotherapy with a VEGFR TKI or an ICI. Another first-line option is high-dose interleukin 2, but there are no established criteria for determining which patients are most likely to benefit.
The guideline discusses second- or later-line therapy options, metastasis-directed therapies, and metastatic subsets including bone, brain, and sarcomatoid carcinomas.
The authors pointed out that significant disparity exists among patients with ccRCC, with some patients having much less access to health care because of racial, geographic, or socioeconomic inequities. There are also known biases within ccRCC care: Females and African Americans are less likely than are males to receive systemic therapy and more likely to receive no treatment; African Americans are less likely to receive systemic therapy; and non-Hispanic African Americans and Hispanics less often undergo cytoreductive nephropathy. African Americans with ccRCC have a pattern of worse survival outcomes than do Whites.
The recommendations cannot be applied to renal cell carcinoma with non-clear cell histology.
“It is important to be comfortable with all of the treatment options for ccRCC, because applying them in the best order, and with the most informed ability to determine efficacy, will have a real impact on patient survival. We are near a goal to offer cure to an increasing number of patients, so choosing therapies that offer that option when it may be possible is important, and when cure is not on the table, we can rationally select therapies that allow patients to have more time with their families, with side effects that are manageable,” Dr. Rathmell said.
The IMDC risk stratification methodology needs to be more widely used in routine practice, Dr. Rathmell said.
“The impact was not significant in patient care until we reached a point of having multiple competing options for treatment. The stakes are higher now, so using this resource is important until we get to the next level with biological classifications,” he said.
Similarly, since the stakes are so high, having an accurate diagnosis is important. Even experts in the field are fooled by imaging findings, and over- or undertreatment of patients has a major impact on outcomes. “This is a message that we need to share for establishing best practices,” he said.
“Just because we have agents, the time to use them is as important as the selection of agent. Similarly, for the cytoreductive nephrectomy issue, new data both clarified and caused some confusion. Not every patient has the luxury of a comprehensive and multidisciplinary tumor board, so we felt it was important to provide some guidance that help making those complex decisions,” Dr. Rathmell said.
Dr. Rathmell has no relevant financial disclosures.
.
This year in the U.S., it is estimated that 79,000 men and women will be diagnosed with kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype and is a leading source of morbidity and mortality. It is also commonly used to study new targeted molecular therapies. The resulting influx of phase III trial results has transformed ccRCC care. “We have an array of different treatment options, and the structure in which these treatments would be applied needed to have expert input. It is an exciting time for kidney cancer, and optimizing therapy now has immediate and meaningful impact into patients longevity,” guideline lead author W. Kimryn Rathmell, MD, PhD, said in an interview.
“The key developments are the emergence of targeted therapies in addition to immune therapies as well as combinations. The order of treatments matters and different patients will have different needs,” said Dr. Rathmell, professor of medicine at Vanderbilt University, Nashville, Tenn.
Dr. Rathmell highlighted the section of the guideline that discusses the need for robust tissue-based diagnosis, as well as active surveillance or cytoreductive nephrectomy. She also emphasized sections on differentiating courses of treatment and plans the use of International Metastatic RCC Database Consortium (IMDC) risk model.
Cytoreductive nephrectomy is an option for patients with one risk factor in which a significant majority of the tumor is within the kidney. The patients should also have good Eastern Cooperative Oncology Group (ECOG) performance status, and no brain, bone, or liver metastases.
Some with metastatic ccRCC can be offered active surveillance. Defining characteristics include favorable or immediate risk, few or no symptoms, a favorable histologic profile, a long interval between nephrectomy and onset of metastasis, or low burden of metastatic disease.
The guidelines also discuss the need to stratify patients within risk groups. Patients rated as intermediate or poor risk in the first line setting should be treated with two immune checkpoint inhibitors (ICI) or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI). ICI combined with a VEGFR TKI can be appropriate for patients with favorable risk but requiring systemic therapy. Those with favorable risk or another medical condition can be offered monotherapy with a VEGFR TKI or an ICI. Another first-line option is high-dose interleukin 2, but there are no established criteria for determining which patients are most likely to benefit.
The guideline discusses second- or later-line therapy options, metastasis-directed therapies, and metastatic subsets including bone, brain, and sarcomatoid carcinomas.
The authors pointed out that significant disparity exists among patients with ccRCC, with some patients having much less access to health care because of racial, geographic, or socioeconomic inequities. There are also known biases within ccRCC care: Females and African Americans are less likely than are males to receive systemic therapy and more likely to receive no treatment; African Americans are less likely to receive systemic therapy; and non-Hispanic African Americans and Hispanics less often undergo cytoreductive nephropathy. African Americans with ccRCC have a pattern of worse survival outcomes than do Whites.
The recommendations cannot be applied to renal cell carcinoma with non-clear cell histology.
“It is important to be comfortable with all of the treatment options for ccRCC, because applying them in the best order, and with the most informed ability to determine efficacy, will have a real impact on patient survival. We are near a goal to offer cure to an increasing number of patients, so choosing therapies that offer that option when it may be possible is important, and when cure is not on the table, we can rationally select therapies that allow patients to have more time with their families, with side effects that are manageable,” Dr. Rathmell said.
The IMDC risk stratification methodology needs to be more widely used in routine practice, Dr. Rathmell said.
“The impact was not significant in patient care until we reached a point of having multiple competing options for treatment. The stakes are higher now, so using this resource is important until we get to the next level with biological classifications,” he said.
Similarly, since the stakes are so high, having an accurate diagnosis is important. Even experts in the field are fooled by imaging findings, and over- or undertreatment of patients has a major impact on outcomes. “This is a message that we need to share for establishing best practices,” he said.
“Just because we have agents, the time to use them is as important as the selection of agent. Similarly, for the cytoreductive nephrectomy issue, new data both clarified and caused some confusion. Not every patient has the luxury of a comprehensive and multidisciplinary tumor board, so we felt it was important to provide some guidance that help making those complex decisions,” Dr. Rathmell said.
Dr. Rathmell has no relevant financial disclosures.
.
This year in the U.S., it is estimated that 79,000 men and women will be diagnosed with kidney cancer. Clear cell renal cell carcinoma (ccRCC) is the most common subtype and is a leading source of morbidity and mortality. It is also commonly used to study new targeted molecular therapies. The resulting influx of phase III trial results has transformed ccRCC care. “We have an array of different treatment options, and the structure in which these treatments would be applied needed to have expert input. It is an exciting time for kidney cancer, and optimizing therapy now has immediate and meaningful impact into patients longevity,” guideline lead author W. Kimryn Rathmell, MD, PhD, said in an interview.
“The key developments are the emergence of targeted therapies in addition to immune therapies as well as combinations. The order of treatments matters and different patients will have different needs,” said Dr. Rathmell, professor of medicine at Vanderbilt University, Nashville, Tenn.
Dr. Rathmell highlighted the section of the guideline that discusses the need for robust tissue-based diagnosis, as well as active surveillance or cytoreductive nephrectomy. She also emphasized sections on differentiating courses of treatment and plans the use of International Metastatic RCC Database Consortium (IMDC) risk model.
Cytoreductive nephrectomy is an option for patients with one risk factor in which a significant majority of the tumor is within the kidney. The patients should also have good Eastern Cooperative Oncology Group (ECOG) performance status, and no brain, bone, or liver metastases.
Some with metastatic ccRCC can be offered active surveillance. Defining characteristics include favorable or immediate risk, few or no symptoms, a favorable histologic profile, a long interval between nephrectomy and onset of metastasis, or low burden of metastatic disease.
The guidelines also discuss the need to stratify patients within risk groups. Patients rated as intermediate or poor risk in the first line setting should be treated with two immune checkpoint inhibitors (ICI) or an ICI combined with a vascular endothelial growth factor tyrosine kinase inhibitor (VEGFR TKI). ICI combined with a VEGFR TKI can be appropriate for patients with favorable risk but requiring systemic therapy. Those with favorable risk or another medical condition can be offered monotherapy with a VEGFR TKI or an ICI. Another first-line option is high-dose interleukin 2, but there are no established criteria for determining which patients are most likely to benefit.
The guideline discusses second- or later-line therapy options, metastasis-directed therapies, and metastatic subsets including bone, brain, and sarcomatoid carcinomas.
The authors pointed out that significant disparity exists among patients with ccRCC, with some patients having much less access to health care because of racial, geographic, or socioeconomic inequities. There are also known biases within ccRCC care: Females and African Americans are less likely than are males to receive systemic therapy and more likely to receive no treatment; African Americans are less likely to receive systemic therapy; and non-Hispanic African Americans and Hispanics less often undergo cytoreductive nephropathy. African Americans with ccRCC have a pattern of worse survival outcomes than do Whites.
The recommendations cannot be applied to renal cell carcinoma with non-clear cell histology.
“It is important to be comfortable with all of the treatment options for ccRCC, because applying them in the best order, and with the most informed ability to determine efficacy, will have a real impact on patient survival. We are near a goal to offer cure to an increasing number of patients, so choosing therapies that offer that option when it may be possible is important, and when cure is not on the table, we can rationally select therapies that allow patients to have more time with their families, with side effects that are manageable,” Dr. Rathmell said.
The IMDC risk stratification methodology needs to be more widely used in routine practice, Dr. Rathmell said.
“The impact was not significant in patient care until we reached a point of having multiple competing options for treatment. The stakes are higher now, so using this resource is important until we get to the next level with biological classifications,” he said.
Similarly, since the stakes are so high, having an accurate diagnosis is important. Even experts in the field are fooled by imaging findings, and over- or undertreatment of patients has a major impact on outcomes. “This is a message that we need to share for establishing best practices,” he said.
“Just because we have agents, the time to use them is as important as the selection of agent. Similarly, for the cytoreductive nephrectomy issue, new data both clarified and caused some confusion. Not every patient has the luxury of a comprehensive and multidisciplinary tumor board, so we felt it was important to provide some guidance that help making those complex decisions,” Dr. Rathmell said.
Dr. Rathmell has no relevant financial disclosures.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
‘The Rock’ assumes the presidency of AGA
We’re honored to announce that John M. Carethers, MD, AGAF, affectionately nicknamed ‘The Rock,’ will begin his term as the 117th president of the AGA Institute on June 1, 2022.
He currently serves as John G. Searle professor of internal medicine and chair of the department of internal medicine at the University of Michigan Health System, a position he has held since 2009.
Dr. Carethers’ research programs focus on familial colon cancer and polyposis syndromes. His research encompasses Lynch syndrome, juvenile polyposis, hyperplastic polyposis, and colorectal cancer. He has published more than 182 articles.
A native of Detroit, Dr. Carethers earned his undergraduate degree in molecular biology and biophysics at Wayne State University. He remained there for medical school, where he graduated at the top of his class. His ability to stay focused on his work earned him the moniker ‘The Rock’. It’s a strength that’s made him an outstanding role model and exemplary leader.
An active member of AGA for more than 20 years, Dr. Carethers received the AGA Gastrointestinal Oncology Section Research Mentor Award as well as the AGA Distinguished Mentor Award in 2017. He has served on several AGA committees, including the AGA Nominating Committee, AGA Underrepresented Minorities Committee, AGA Research Policy Committee, AGA Institute Council and the AGA Trainee & Young GI Committee. He has also served as senior associate editor of Gastroenterology.
His academic career began at the University of California, San Diego, preceded by a gastroenterology fellowship at University of Michigan in Ann Arbor and residency at Massachusetts General Hospital in Boston. From the beginning, he has inspired others with his strong work ethic and intense dedication.
Dr. Carethers joined the AGA Governing Board in June 2020 as vice president and served as president-elect prior to assuming the top leadership role.
We’re honored to announce that John M. Carethers, MD, AGAF, affectionately nicknamed ‘The Rock,’ will begin his term as the 117th president of the AGA Institute on June 1, 2022.
He currently serves as John G. Searle professor of internal medicine and chair of the department of internal medicine at the University of Michigan Health System, a position he has held since 2009.
Dr. Carethers’ research programs focus on familial colon cancer and polyposis syndromes. His research encompasses Lynch syndrome, juvenile polyposis, hyperplastic polyposis, and colorectal cancer. He has published more than 182 articles.
A native of Detroit, Dr. Carethers earned his undergraduate degree in molecular biology and biophysics at Wayne State University. He remained there for medical school, where he graduated at the top of his class. His ability to stay focused on his work earned him the moniker ‘The Rock’. It’s a strength that’s made him an outstanding role model and exemplary leader.
An active member of AGA for more than 20 years, Dr. Carethers received the AGA Gastrointestinal Oncology Section Research Mentor Award as well as the AGA Distinguished Mentor Award in 2017. He has served on several AGA committees, including the AGA Nominating Committee, AGA Underrepresented Minorities Committee, AGA Research Policy Committee, AGA Institute Council and the AGA Trainee & Young GI Committee. He has also served as senior associate editor of Gastroenterology.
His academic career began at the University of California, San Diego, preceded by a gastroenterology fellowship at University of Michigan in Ann Arbor and residency at Massachusetts General Hospital in Boston. From the beginning, he has inspired others with his strong work ethic and intense dedication.
Dr. Carethers joined the AGA Governing Board in June 2020 as vice president and served as president-elect prior to assuming the top leadership role.
We’re honored to announce that John M. Carethers, MD, AGAF, affectionately nicknamed ‘The Rock,’ will begin his term as the 117th president of the AGA Institute on June 1, 2022.
He currently serves as John G. Searle professor of internal medicine and chair of the department of internal medicine at the University of Michigan Health System, a position he has held since 2009.
Dr. Carethers’ research programs focus on familial colon cancer and polyposis syndromes. His research encompasses Lynch syndrome, juvenile polyposis, hyperplastic polyposis, and colorectal cancer. He has published more than 182 articles.
A native of Detroit, Dr. Carethers earned his undergraduate degree in molecular biology and biophysics at Wayne State University. He remained there for medical school, where he graduated at the top of his class. His ability to stay focused on his work earned him the moniker ‘The Rock’. It’s a strength that’s made him an outstanding role model and exemplary leader.
An active member of AGA for more than 20 years, Dr. Carethers received the AGA Gastrointestinal Oncology Section Research Mentor Award as well as the AGA Distinguished Mentor Award in 2017. He has served on several AGA committees, including the AGA Nominating Committee, AGA Underrepresented Minorities Committee, AGA Research Policy Committee, AGA Institute Council and the AGA Trainee & Young GI Committee. He has also served as senior associate editor of Gastroenterology.
His academic career began at the University of California, San Diego, preceded by a gastroenterology fellowship at University of Michigan in Ann Arbor and residency at Massachusetts General Hospital in Boston. From the beginning, he has inspired others with his strong work ethic and intense dedication.
Dr. Carethers joined the AGA Governing Board in June 2020 as vice president and served as president-elect prior to assuming the top leadership role.
First-line nivolumab monotherapy effective in some kidney cancers
The anti–PD-1 agent nivolumab may have some utility as monotherapy in the treatment of naive advanced clear cell renal cell carcinoma (ccRCC), according results from a new phase 2 clinical trial (HCRN GU16-260).
Patients received nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy in the first phase of the study, with qualifying patients moving on to dual therapy with nivolumab and the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb).
“At the moment, monotherapy with anti–PD-1 is not FDA approved in patients with treatment-naive ccRCC. Based on the results of this study, it might be applicable in patients with favorable risk disease where only tyrosine kinase inhibitors or TKI-containing combinations are approved,” lead investigator Michael Atkins, MD, said in an interview. The study was published online in the Journal of Clinical Oncology.
“It shows the contribution of [nivolumab] to the combination in treatment-naive patients. This data was not previously available as nivolumab monotherapy had only been formally tested in patients with prior history of TKI therapy. It also gives valuable information on the role of PD-L1 as a biomarker in response and landmark progression-free survival in patients treated with anti–PD-1 monotherapy,” said Dr. Atkins, who serves as deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.
Patients with higher expression rates of PD-L1 had a higher overall response rate and higher probability of progression-free survival at 1 year.
“ but there is concern about risk of toxicity if ipilimumab is added. These might include elderly patients and those with a history or autoimmune conditions,” Dr. Atkins said.
Next on the agenda for the researchers are more extensive biomarker studies of the tissues obtained in the phase 2 study. They hope to identify factors that predict response and resistance in the absence of confounders like combination therapy, primary versus metastatic tumors, and use of nonimmunotherapy endpoints. They will also track treatment-free survival following cessation of therapy at 2 years.
The study “provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies,” Martin Voss, MD, wrote in an accompanying editorial. Further studies currently in progress should shed even more light on monotherapy in this patient population. These include the phase 3 CheckMate 8Y8 trial comparing nivolumab with ipilimumab/nivolumab in untreated patients, and the phase 3 PDIGREE23 trial, which is comparing upfront, response-adaptive ipilimumab/nivolumab with escalation through addition of TKIs in patients with progressive disease and de-escalation to nivolumab monotherapy in patients who achieve a complete response, and randomization between the two strategies for nonprogressive disease and non–complete response patients.
However, these phase 3 studies are limited to intermediate- to poor-risk patients. For favorable-risk patients, small cohort studies like HCRN GU16-260 represent the best currently available guide to treatment, Dr. Voss wrote.
In part A of the study, 123 patients received nivolumab for 96 weeks. 35 patients who experienced progressive disease or had a best response of stable disease at 48 weeks became eligible for part B, in which they received the combination of nivolumab and ipilimumab for 12 weeks, and then nivolumab monotherapy for 48 weeks. All patients underwent PD-L1 testing, and tumors were categorized by percentage of tumor cells expressing PD-L1 as 0%, 1%-5%, greater than 5%-20%, and greater than 20%.
The overall objective response rate was 34.1%. 6.5% had a complete response. Patients categorized by International Metastatic RCC Database Consortium category as intermediate or poor risk had an ORR of 25.0%. Those categorized as favorable risk had an ORR of 57.1%, with a complete response rate of 11.4%. Just one patient with favorable risk had progressive disease at their 12-week CT scan. The ORR was higher with increasing percentages of PD-L1 expression, from 26.9% in PD-L1 0 to 50% in PD-L1 1-20 and 75.0% in PD-L1 greater than 20% (P = .002). Five of 7 (71.4%) patients with PD-L1 values of 1 or more had a tumor response to nivolumab monotherapy, but 14 of 23 (60.9%) of those with favorable risk disease and PD-L1 of zero also responded.
The median duration of response was 27.6 months, and progression-free survival was 34.6% at 1 year in the PD-L1 0 and 75.0% in the PD-L1 greater than 20 categories (P = .050). Among patients eligible for part B, the ORR was 11.4%.
Dr. Atkins has consulted or been on the advisory board for Bristol-Myers Squibb.
The anti–PD-1 agent nivolumab may have some utility as monotherapy in the treatment of naive advanced clear cell renal cell carcinoma (ccRCC), according results from a new phase 2 clinical trial (HCRN GU16-260).
Patients received nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy in the first phase of the study, with qualifying patients moving on to dual therapy with nivolumab and the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb).
“At the moment, monotherapy with anti–PD-1 is not FDA approved in patients with treatment-naive ccRCC. Based on the results of this study, it might be applicable in patients with favorable risk disease where only tyrosine kinase inhibitors or TKI-containing combinations are approved,” lead investigator Michael Atkins, MD, said in an interview. The study was published online in the Journal of Clinical Oncology.
“It shows the contribution of [nivolumab] to the combination in treatment-naive patients. This data was not previously available as nivolumab monotherapy had only been formally tested in patients with prior history of TKI therapy. It also gives valuable information on the role of PD-L1 as a biomarker in response and landmark progression-free survival in patients treated with anti–PD-1 monotherapy,” said Dr. Atkins, who serves as deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.
Patients with higher expression rates of PD-L1 had a higher overall response rate and higher probability of progression-free survival at 1 year.
“ but there is concern about risk of toxicity if ipilimumab is added. These might include elderly patients and those with a history or autoimmune conditions,” Dr. Atkins said.
Next on the agenda for the researchers are more extensive biomarker studies of the tissues obtained in the phase 2 study. They hope to identify factors that predict response and resistance in the absence of confounders like combination therapy, primary versus metastatic tumors, and use of nonimmunotherapy endpoints. They will also track treatment-free survival following cessation of therapy at 2 years.
The study “provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies,” Martin Voss, MD, wrote in an accompanying editorial. Further studies currently in progress should shed even more light on monotherapy in this patient population. These include the phase 3 CheckMate 8Y8 trial comparing nivolumab with ipilimumab/nivolumab in untreated patients, and the phase 3 PDIGREE23 trial, which is comparing upfront, response-adaptive ipilimumab/nivolumab with escalation through addition of TKIs in patients with progressive disease and de-escalation to nivolumab monotherapy in patients who achieve a complete response, and randomization between the two strategies for nonprogressive disease and non–complete response patients.
However, these phase 3 studies are limited to intermediate- to poor-risk patients. For favorable-risk patients, small cohort studies like HCRN GU16-260 represent the best currently available guide to treatment, Dr. Voss wrote.
In part A of the study, 123 patients received nivolumab for 96 weeks. 35 patients who experienced progressive disease or had a best response of stable disease at 48 weeks became eligible for part B, in which they received the combination of nivolumab and ipilimumab for 12 weeks, and then nivolumab monotherapy for 48 weeks. All patients underwent PD-L1 testing, and tumors were categorized by percentage of tumor cells expressing PD-L1 as 0%, 1%-5%, greater than 5%-20%, and greater than 20%.
The overall objective response rate was 34.1%. 6.5% had a complete response. Patients categorized by International Metastatic RCC Database Consortium category as intermediate or poor risk had an ORR of 25.0%. Those categorized as favorable risk had an ORR of 57.1%, with a complete response rate of 11.4%. Just one patient with favorable risk had progressive disease at their 12-week CT scan. The ORR was higher with increasing percentages of PD-L1 expression, from 26.9% in PD-L1 0 to 50% in PD-L1 1-20 and 75.0% in PD-L1 greater than 20% (P = .002). Five of 7 (71.4%) patients with PD-L1 values of 1 or more had a tumor response to nivolumab monotherapy, but 14 of 23 (60.9%) of those with favorable risk disease and PD-L1 of zero also responded.
The median duration of response was 27.6 months, and progression-free survival was 34.6% at 1 year in the PD-L1 0 and 75.0% in the PD-L1 greater than 20 categories (P = .050). Among patients eligible for part B, the ORR was 11.4%.
Dr. Atkins has consulted or been on the advisory board for Bristol-Myers Squibb.
The anti–PD-1 agent nivolumab may have some utility as monotherapy in the treatment of naive advanced clear cell renal cell carcinoma (ccRCC), according results from a new phase 2 clinical trial (HCRN GU16-260).
Patients received nivolumab (Opdivo, Bristol-Myers Squibb) monotherapy in the first phase of the study, with qualifying patients moving on to dual therapy with nivolumab and the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb).
“At the moment, monotherapy with anti–PD-1 is not FDA approved in patients with treatment-naive ccRCC. Based on the results of this study, it might be applicable in patients with favorable risk disease where only tyrosine kinase inhibitors or TKI-containing combinations are approved,” lead investigator Michael Atkins, MD, said in an interview. The study was published online in the Journal of Clinical Oncology.
“It shows the contribution of [nivolumab] to the combination in treatment-naive patients. This data was not previously available as nivolumab monotherapy had only been formally tested in patients with prior history of TKI therapy. It also gives valuable information on the role of PD-L1 as a biomarker in response and landmark progression-free survival in patients treated with anti–PD-1 monotherapy,” said Dr. Atkins, who serves as deputy director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C.
Patients with higher expression rates of PD-L1 had a higher overall response rate and higher probability of progression-free survival at 1 year.
“ but there is concern about risk of toxicity if ipilimumab is added. These might include elderly patients and those with a history or autoimmune conditions,” Dr. Atkins said.
Next on the agenda for the researchers are more extensive biomarker studies of the tissues obtained in the phase 2 study. They hope to identify factors that predict response and resistance in the absence of confounders like combination therapy, primary versus metastatic tumors, and use of nonimmunotherapy endpoints. They will also track treatment-free survival following cessation of therapy at 2 years.
The study “provides much needed first-line data for check point inhibitor monotherapy in an era that is heavily invested in combination strategies,” Martin Voss, MD, wrote in an accompanying editorial. Further studies currently in progress should shed even more light on monotherapy in this patient population. These include the phase 3 CheckMate 8Y8 trial comparing nivolumab with ipilimumab/nivolumab in untreated patients, and the phase 3 PDIGREE23 trial, which is comparing upfront, response-adaptive ipilimumab/nivolumab with escalation through addition of TKIs in patients with progressive disease and de-escalation to nivolumab monotherapy in patients who achieve a complete response, and randomization between the two strategies for nonprogressive disease and non–complete response patients.
However, these phase 3 studies are limited to intermediate- to poor-risk patients. For favorable-risk patients, small cohort studies like HCRN GU16-260 represent the best currently available guide to treatment, Dr. Voss wrote.
In part A of the study, 123 patients received nivolumab for 96 weeks. 35 patients who experienced progressive disease or had a best response of stable disease at 48 weeks became eligible for part B, in which they received the combination of nivolumab and ipilimumab for 12 weeks, and then nivolumab monotherapy for 48 weeks. All patients underwent PD-L1 testing, and tumors were categorized by percentage of tumor cells expressing PD-L1 as 0%, 1%-5%, greater than 5%-20%, and greater than 20%.
The overall objective response rate was 34.1%. 6.5% had a complete response. Patients categorized by International Metastatic RCC Database Consortium category as intermediate or poor risk had an ORR of 25.0%. Those categorized as favorable risk had an ORR of 57.1%, with a complete response rate of 11.4%. Just one patient with favorable risk had progressive disease at their 12-week CT scan. The ORR was higher with increasing percentages of PD-L1 expression, from 26.9% in PD-L1 0 to 50% in PD-L1 1-20 and 75.0% in PD-L1 greater than 20% (P = .002). Five of 7 (71.4%) patients with PD-L1 values of 1 or more had a tumor response to nivolumab monotherapy, but 14 of 23 (60.9%) of those with favorable risk disease and PD-L1 of zero also responded.
The median duration of response was 27.6 months, and progression-free survival was 34.6% at 1 year in the PD-L1 0 and 75.0% in the PD-L1 greater than 20 categories (P = .050). Among patients eligible for part B, the ORR was 11.4%.
Dr. Atkins has consulted or been on the advisory board for Bristol-Myers Squibb.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
New AGA Research Foundation Executive Board members
We’re pleased to share that Michael Camilleri, MD, AGAF, will be taking over the AGA Research Foundation chair role beginning this month. He has recruited five members to be part of the 2022-2024 AGA Research Foundation Executive Board.
Meet the new Foundation Executive Board members
- Michael Camilleri, MD, AGAF, Mayo Clinic, Rochester, MN.
- Aline Charabaty, MD, AGAF, Johns Hopkins School of Medicine, Washington, D.C.
- Eric Esrailian, MD, MPH, AGAF, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Robert A. Ganz, MD, MASGE, MNGI Digestive Health, Minnetonka, MN
- Aja S. McCutchen, MD, Atlanta Gastroenterology Associates, Hoschton, GA
- Michael L. Kochman, MD, AGAF, University of Pennsylvania, Philadelphia, PA
We’re pleased to share that Michael Camilleri, MD, AGAF, will be taking over the AGA Research Foundation chair role beginning this month. He has recruited five members to be part of the 2022-2024 AGA Research Foundation Executive Board.
Meet the new Foundation Executive Board members
- Michael Camilleri, MD, AGAF, Mayo Clinic, Rochester, MN.
- Aline Charabaty, MD, AGAF, Johns Hopkins School of Medicine, Washington, D.C.
- Eric Esrailian, MD, MPH, AGAF, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Robert A. Ganz, MD, MASGE, MNGI Digestive Health, Minnetonka, MN
- Aja S. McCutchen, MD, Atlanta Gastroenterology Associates, Hoschton, GA
- Michael L. Kochman, MD, AGAF, University of Pennsylvania, Philadelphia, PA
We’re pleased to share that Michael Camilleri, MD, AGAF, will be taking over the AGA Research Foundation chair role beginning this month. He has recruited five members to be part of the 2022-2024 AGA Research Foundation Executive Board.
Meet the new Foundation Executive Board members
- Michael Camilleri, MD, AGAF, Mayo Clinic, Rochester, MN.
- Aline Charabaty, MD, AGAF, Johns Hopkins School of Medicine, Washington, D.C.
- Eric Esrailian, MD, MPH, AGAF, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Robert A. Ganz, MD, MASGE, MNGI Digestive Health, Minnetonka, MN
- Aja S. McCutchen, MD, Atlanta Gastroenterology Associates, Hoschton, GA
- Michael L. Kochman, MD, AGAF, University of Pennsylvania, Philadelphia, PA
Murder of physician raises the stress level for all clinicians
As if it weren’t enough that doctors work in a profession where it’s almost more a question of when they’ll be sued than if they’ll be sued – where COVID, staff shortages, long hours, and patients frustrated over canceled procedures have caused unrelenting fatigue and stress – they now have to worry that an unhappy patient is going to buy a gun, walk into their office, and kill them.
That’s exactly what happened in Tulsa, Okla., where a patient complaining of pain after back surgery murdered his doctor and several others who happened to be in the wrong place at the wrong time.
The temptation in the aftermath of such tragedies is to think about preventive measures: Make medical facilities “hardened” targets, like schools have become, with armed guards, metal detectors, automatically locking doors, physical barriers within, security cameras, and buzzers for entry – although hardening a large medical center where members of the community routinely come and go would be challenging.
What about the enormous stress on doctors, nurses, and others in the medical workplace? Physicians who have been sued for malpractice often describe how it changes the way they interact with patients: They now size patients up and make judgments about their potential litigiousness. Will the physicians now look over their patients’ shoulders at the video feed from a security camera when they’re taking a history? Will medical professionals be forced to make snap judgments about patients’ psychological state before deciding whether to treat them?
Remember, there was a time when school shootings were unimaginable. Once one person crosses that line, others inevitably follow.
It could be a drug-seeking patient complaining of ongoing pain, angry because he can’t get a new prescription. It could be a patient whose unpaid bill was turned over to a collection agency, angry because he’s now getting calls from collectors. It could be someone who blames a physician for the loss of a loved one. It could be someone who would otherwise have filed a lawsuit, who now thinks he has a more effective option for exacting retribution.
Most of us would find it unbearable to live and work under the kind of stress faced by medical professionals today. And unfortunately, there is no short-term, systemic relief on the horizon. But there are methods of relieving at least some of the psychological burden being carried by these dedicated individuals.
For starters, the government should provide funds to improve safety and security at medical facilities. It’s sad but it’s a fact of life. The physical structure of schools, along with emergency procedures, have been changed since Columbine and Sandy Hook, and our children and their teachers undergo active shooter drills. Health care facilities will need to adopt similar strategies.
But if we don’t also support the individuals who work in health care, we’ll no longer have even partially staffed health care facilities. Hospitals and medical groups need to be conscious of the effects stress may have on them. Medical staff and administrators need to recognize changes in their colleagues’ behavior and refer those cohorts to professional stress coaches who can get them back on track.
Medical personnel should be picking up on warning signs, like irritability, depression, sudden weight gain or loss, lack of motivation and job satisfaction, obsessiveness, unusual levels of fatigue, alcohol or drug use, and, of course, avoidable medical errors.
In addition, colleagues in the medical workplace need to know each other well. They are usually the first ones to notice if something is off and may be in the best position to refer coworkers for help. Also, medical malpractice insurance carriers should consider encouraging and covering coaching sessions, because helping physicians cope with this heightened stress will prevent medical errors and the lawsuits that inevitably accompany mistakes.
This needn’t be a long-term process like ongoing psychotherapy; a few sessions with a well-trained coach may help psychologically challenged peers restore their focus and perspective. It won’t eliminate the threat any more than litigation stress coaching eliminates the threat of being sued, but it can prevent that stress from leading to avoidable errors. It also can prevent physicians’ personal lives and relationships from going off the rails and driving them out of the medical profession.
None of us can afford to ignore the impacts that these new stressors are having and simply act as if it’s business as usual. The people in the trenches need our help.
Ms. Fiore is President of Winning Focus in Murrysville, Pa. She has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
As if it weren’t enough that doctors work in a profession where it’s almost more a question of when they’ll be sued than if they’ll be sued – where COVID, staff shortages, long hours, and patients frustrated over canceled procedures have caused unrelenting fatigue and stress – they now have to worry that an unhappy patient is going to buy a gun, walk into their office, and kill them.
That’s exactly what happened in Tulsa, Okla., where a patient complaining of pain after back surgery murdered his doctor and several others who happened to be in the wrong place at the wrong time.
The temptation in the aftermath of such tragedies is to think about preventive measures: Make medical facilities “hardened” targets, like schools have become, with armed guards, metal detectors, automatically locking doors, physical barriers within, security cameras, and buzzers for entry – although hardening a large medical center where members of the community routinely come and go would be challenging.
What about the enormous stress on doctors, nurses, and others in the medical workplace? Physicians who have been sued for malpractice often describe how it changes the way they interact with patients: They now size patients up and make judgments about their potential litigiousness. Will the physicians now look over their patients’ shoulders at the video feed from a security camera when they’re taking a history? Will medical professionals be forced to make snap judgments about patients’ psychological state before deciding whether to treat them?
Remember, there was a time when school shootings were unimaginable. Once one person crosses that line, others inevitably follow.
It could be a drug-seeking patient complaining of ongoing pain, angry because he can’t get a new prescription. It could be a patient whose unpaid bill was turned over to a collection agency, angry because he’s now getting calls from collectors. It could be someone who blames a physician for the loss of a loved one. It could be someone who would otherwise have filed a lawsuit, who now thinks he has a more effective option for exacting retribution.
Most of us would find it unbearable to live and work under the kind of stress faced by medical professionals today. And unfortunately, there is no short-term, systemic relief on the horizon. But there are methods of relieving at least some of the psychological burden being carried by these dedicated individuals.
For starters, the government should provide funds to improve safety and security at medical facilities. It’s sad but it’s a fact of life. The physical structure of schools, along with emergency procedures, have been changed since Columbine and Sandy Hook, and our children and their teachers undergo active shooter drills. Health care facilities will need to adopt similar strategies.
But if we don’t also support the individuals who work in health care, we’ll no longer have even partially staffed health care facilities. Hospitals and medical groups need to be conscious of the effects stress may have on them. Medical staff and administrators need to recognize changes in their colleagues’ behavior and refer those cohorts to professional stress coaches who can get them back on track.
Medical personnel should be picking up on warning signs, like irritability, depression, sudden weight gain or loss, lack of motivation and job satisfaction, obsessiveness, unusual levels of fatigue, alcohol or drug use, and, of course, avoidable medical errors.
In addition, colleagues in the medical workplace need to know each other well. They are usually the first ones to notice if something is off and may be in the best position to refer coworkers for help. Also, medical malpractice insurance carriers should consider encouraging and covering coaching sessions, because helping physicians cope with this heightened stress will prevent medical errors and the lawsuits that inevitably accompany mistakes.
This needn’t be a long-term process like ongoing psychotherapy; a few sessions with a well-trained coach may help psychologically challenged peers restore their focus and perspective. It won’t eliminate the threat any more than litigation stress coaching eliminates the threat of being sued, but it can prevent that stress from leading to avoidable errors. It also can prevent physicians’ personal lives and relationships from going off the rails and driving them out of the medical profession.
None of us can afford to ignore the impacts that these new stressors are having and simply act as if it’s business as usual. The people in the trenches need our help.
Ms. Fiore is President of Winning Focus in Murrysville, Pa. She has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
As if it weren’t enough that doctors work in a profession where it’s almost more a question of when they’ll be sued than if they’ll be sued – where COVID, staff shortages, long hours, and patients frustrated over canceled procedures have caused unrelenting fatigue and stress – they now have to worry that an unhappy patient is going to buy a gun, walk into their office, and kill them.
That’s exactly what happened in Tulsa, Okla., where a patient complaining of pain after back surgery murdered his doctor and several others who happened to be in the wrong place at the wrong time.
The temptation in the aftermath of such tragedies is to think about preventive measures: Make medical facilities “hardened” targets, like schools have become, with armed guards, metal detectors, automatically locking doors, physical barriers within, security cameras, and buzzers for entry – although hardening a large medical center where members of the community routinely come and go would be challenging.
What about the enormous stress on doctors, nurses, and others in the medical workplace? Physicians who have been sued for malpractice often describe how it changes the way they interact with patients: They now size patients up and make judgments about their potential litigiousness. Will the physicians now look over their patients’ shoulders at the video feed from a security camera when they’re taking a history? Will medical professionals be forced to make snap judgments about patients’ psychological state before deciding whether to treat them?
Remember, there was a time when school shootings were unimaginable. Once one person crosses that line, others inevitably follow.
It could be a drug-seeking patient complaining of ongoing pain, angry because he can’t get a new prescription. It could be a patient whose unpaid bill was turned over to a collection agency, angry because he’s now getting calls from collectors. It could be someone who blames a physician for the loss of a loved one. It could be someone who would otherwise have filed a lawsuit, who now thinks he has a more effective option for exacting retribution.
Most of us would find it unbearable to live and work under the kind of stress faced by medical professionals today. And unfortunately, there is no short-term, systemic relief on the horizon. But there are methods of relieving at least some of the psychological burden being carried by these dedicated individuals.
For starters, the government should provide funds to improve safety and security at medical facilities. It’s sad but it’s a fact of life. The physical structure of schools, along with emergency procedures, have been changed since Columbine and Sandy Hook, and our children and their teachers undergo active shooter drills. Health care facilities will need to adopt similar strategies.
But if we don’t also support the individuals who work in health care, we’ll no longer have even partially staffed health care facilities. Hospitals and medical groups need to be conscious of the effects stress may have on them. Medical staff and administrators need to recognize changes in their colleagues’ behavior and refer those cohorts to professional stress coaches who can get them back on track.
Medical personnel should be picking up on warning signs, like irritability, depression, sudden weight gain or loss, lack of motivation and job satisfaction, obsessiveness, unusual levels of fatigue, alcohol or drug use, and, of course, avoidable medical errors.
In addition, colleagues in the medical workplace need to know each other well. They are usually the first ones to notice if something is off and may be in the best position to refer coworkers for help. Also, medical malpractice insurance carriers should consider encouraging and covering coaching sessions, because helping physicians cope with this heightened stress will prevent medical errors and the lawsuits that inevitably accompany mistakes.
This needn’t be a long-term process like ongoing psychotherapy; a few sessions with a well-trained coach may help psychologically challenged peers restore their focus and perspective. It won’t eliminate the threat any more than litigation stress coaching eliminates the threat of being sued, but it can prevent that stress from leading to avoidable errors. It also can prevent physicians’ personal lives and relationships from going off the rails and driving them out of the medical profession.
None of us can afford to ignore the impacts that these new stressors are having and simply act as if it’s business as usual. The people in the trenches need our help.
Ms. Fiore is President of Winning Focus in Murrysville, Pa. She has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.