Ob.Gyn. News

FAIRFAX, VIRGINIA — Nearly 30 years ago, in a 1995 paper, the British physician-epidemiologist David Barker, MD, PhD, wrote about his fetal origins hypothesis — the idea that programs to address fetal undernutrition and low birth weight produced later coronary heart disease (BMJ 1995;311:171-4).

His hypothesis and subsequent research led to the concept of adult diseases of fetal origins, which today extends beyond low birth weight and implicates the in utero environment as a significant determinant of risk for adverse childhood and adult metabolic outcomes and for major chronic diseases, including diabetes and obesity. Studies have shown that the offspring of pregnant mothers with diabetes have a higher risk of developing obesity and diabetes themselves.

“It’s a whole discipline [of research],” E. Albert Reece, MD, PhD, MBA, of the University of Maryland School of Medicine (UMSOM), said in an interview. “But what we’ve never quite understood is the ‘how’ and ‘why’? What are the mechanisms driving the fetal origins of such adverse outcomes in offspring?

At the biennial meeting of the Diabetes in Pregnancy Study Group of North America (DPSG), investigators described studies underway that are digging deeper into the associations between the intrauterine milieu and longer-term offspring health — and that are searching for biological and molecular processes that may be involved.

The studies are like “branches of the Barker hypothesis,” said Dr. Reece, former dean of UMSOM and current director of the UMSOM Center for Advanced Research Training and Innovation, who co-organized the DPSG meeting. “They’re taking the hypothesis and dissecting it by asking, for instance, it is possible that transgenerational obesity may align with the Barker hypothesis? Is it possible that it involves epigenetics regulation? Could we find biomarkers?”

The need for a better understanding of the fetal origins framework — and its subsequent transgenerational impact — is urgent. From 2000 to 2018, the prevalence of childhood obesity increased from 14.7% to 19.2% (a 31% increase) and the prevalence of severe childhood obesity rose from 3.9% to 6.1% (a 56% increase), according to data from the U.S. National Health and Nutrition Examination Survey (Obes Facts. 2022;15[4]:560-9).

Children aged 2-5 years have had an especially sharp increase in obesity (Pediatrics 2018;141[3]:e20173459), Christine Wey Hockett, PhD, of the University of South Dakota School of Medicine, said at the DPSG meeting (Figure 1).

Deeper Dives Into Associations, Potential Mechanisms

The EPOCH prospective cohort study with which Dr. Hockett was involved gave her a front-seat view of the transgenerational adverse effects of in utero exposure to hyperglycemia. The study recruited ethnically diverse maternal/child dyads from the Kaiser Permanente of Colorado perinatal database from 1992 to 2002 and assessed 418 offspring at two points — a mean age of 10.5 years and 16.5 years — for fasting blood glucose, adiposity, and diet and physical activity. The second visit also involved an oral glucose tolerance test.

The 77 offspring who had been exposed in utero to GDM had a homeostatic model assessment of insulin resistance (HOMA-IR) that was 18% higher, a 19% lower Matsuda index, and a 9% greater HOMA of β-cell function (HOMA-β) than the 341 offspring whose mothers did not have diabetes. Each 5-kg/m² increase in prepregnancy body mass index predicted increased insulin resistance, but there was no combined effect of both maternal obesity and diabetes in utero.

Exposed offspring had a higher BMI and increased adiposity, but when BMI was controlled for in the analysis of metabolic outcomes, maternal diabetes was still associated with 12% higher HOMA-IR and a 17% lower Matsuda index. “So [the metabolic outcomes] are a direct effect of maternal diabetes,” Dr. Hockett said at the DPSG meeting, noting the fetal overnutrition hypothesis in which maternal glucose, but not maternal insulin, freely passes through the placenta, promoting growth and adiposity in the fetus.

[The EPOCH results on metabolic outcomes and offspring adiposity were published in 2017 and 2019, respectively (Diabet Med. 2017;34:1392-9; Diabetologia. 2019;62:2017-24). In 2020, EPOCH researchers reported sex-specific effects on cardiovascular outcomes, with GDM exposure associated with higher total and LDL cholesterol in girls and higher systolic blood pressure in boys (Pediatr Obes. 2020;15[5]:e12611).]

Now, a new longitudinal cohort study underway in Phoenix, is taking a deeper dive, trying to pinpoint what exactly influences childhood obesity and metabolic risk by following Hispanic and American Indian maternal/child dyads from pregnancy until 18 years postpartum. Researchers are looking not only at associations between maternal risk factors (pregnancy BMI, gestational weight gain, and diabetes in pregnancy) and offspring BMI, adiposity, and growth patterns, but also how various factors during pregnancy — clinical, genetic, lifestyle, biochemical — ”may mediate the associations,” said lead investigator Madhumita Sinha, MD.

“We need a better understanding at the molecular level of the biological processes that lead to obesity in children and that cause metabolic dysfunction,” said Dr. Sinha, who heads the Diabetes Epidemiology and Clinical Research Section of the of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch in Phoenix.

The populations being enrolled in the ETCHED study (for Early Tracking of Childhood Health Determinants) are at especially high risk of childhood obesity and metabolic dysfunction. Research conducted decades ago by the NIDDK in Phoenix showed that approximately 50% of Pima Indian children from diabetic pregnancies develop type 2 diabetes by age 25 (N Engl J Med. 1983;308:242-5). Years later, to tease out possible genetic factors, researchers compared siblings born before and after their mother was found to have type 2 diabetes, and found significantly higher rates of diabetes in those born after the mother’s diagnosis, affirming the role of in utero toxicity (Diabetes 2000;49:2208-11).

In the new study, the researchers will look at adipokines and inflammatory biomarkers in the mothers and offspring in addition to traditional anthropometric and glycemic measures. They’ll analyze placental tissue, breast milk, and the gut microbiome longitudinally, and they’ll lean heavily on genomics/epigenomics, proteomics, and metabolomics. “There’s potential,” Dr. Sinha said, “to develop a more accurate predictive and prognostic model of childhood obesity.”

The researchers also will study the role of family, socioeconomics, and environmental factors in influencing child growth patterns and they’ll look at neurodevelopment in infancy and childhood. As of October 2023, almost 80 pregnant women, most with obesity and almost one-third with type 2 diabetes, had enrolled in the study. Over the next several years, the study aims to enroll 750 dyads.
 

The Timing of In Utero Exposure

Shelley Ehrlich, MD, ScD, MPH, of the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, is aiming, meanwhile, to learn how the timing of in utero exposure to hyperglycemia predicts specific metabolic and cardiovascular morbidities in the adult offspring of diabetic mothers.

“While we know that exposure to maternal diabetes, regardless of type, increases the risk of obesity, insulin resistance, diabetes, renal compromise, and cardiovascular disease in the offspring, there is little known about the level and timing of hyperglycemic exposure during fetal development that triggers these adverse outcomes,” said Dr. Ehrlich. A goal, she said, is to identify gestational profiles that predict phenotypes of offspring at risk for morbidity in later life.

She and other investigators with the TEAM (Transgenerational Effect on Adult Morbidity) study have recruited over 170 offspring of mothers who participated in the Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati Medical Center from 1978 to 1995 — a landmark study that demonstrated the effect of strict glucose control in reducing major congenital malformations.

The women in the PPG study had frequent glucose monitoring (up to 6-8 times a day) throughout their pregnancies, and now, their recruited offspring, who are up to 43 years of age, are being assessed for obesity, diabetes/metabolic health, cardiovascular disease/cardiac and peripheral vascular structure and function, and other outcomes including those that may be amenable to secondary prevention (J Diabetes Res. Nov 1;2021:6590431).

Preliminary findings from over 170 offspring recruited between 2017 and 2022 suggest that in utero exposure to dysglycemia (as measured by standard deviations of glycohemoglobin) in the third trimester appears to increase the risk of morbid obesity in adulthood, while exposure to dysglycemia in the first trimester increases the risk of impaired glucose tolerance. The risk of B-cell dysfunction, meanwhile, appears to be linked to dysglycemia in the first and third trimesters — particularly the first — Dr. Ehrlich reported.

Cognitive outcomes in offspring have also been assessed and here it appears that dysglycemia in the third trimester is linked to worse scores on the Wechsler Abbreviated Scale of Intelligence (WASI-II), said Katherine Bowers, PhD, MPH, a TEAM study coinvestigator, also of Cincinnati Children’s Hospital Medical Center.

“We’ve already observed [an association between] diabetes in pregnancy and cognition in early childhood and through adolescence, but [the question has been] does this association persist into adulthood?” she said.

Preliminary analyses of 104 offspring show no statistically significant associations between maternal dysglycemia in the first or second trimesters and offspring cognition, but “consistent inverse associations between maternal glycohemoglobin in the third trimester across two [WASI-II] subscales and composite measures of cognition,” Dr. Bowers said.

Their analysis adjusted for a variety of factors, including maternal age, prepregnancy and first trimester BMI, race, family history of diabetes, and diabetes severity/macrovascular complications.
 

Back In The Laboratory

At the other end of the research spectrum, basic research scientists are also investigating the mechanisms and sequelae of in utero hyperglycemia and other injuries, including congenital malformations, placental adaptive responses and fetal programming. Researchers are asking, for instance, what does placental metabolic reprogramming entail? What role do placental extracellular vesicles play in GDM? Can we alter the in utero environment and thus improve the short and long-term fetal/infant outcomes?

Animal research done at the UMSOM Center for Birth Defects Research, led by Dr. Reece and Peixin Yang, PhD, suggests that “a good portion of in utero injury is due to epigenetics,” Dr. Reece said in the interview. “We’ve shown that under conditions of hyperglycemia, for example, genetic regulation and genetic function can be altered.”

Through in vivo research, they have also shown that antioxidants or membrane stabilizers such as arachidonic acid or myo-inositol, or experimental inhibitors to certain pro-apoptotic intermediates, can individually or collectively result in reduced malformations. “It is highly likely that understanding the biological impact of various altered in utero environments, and then modifying or reversing those environments, will result in short and long-term outcome improvements similar to those shown with congenital malformations,” Dr. Reece said.

FAIRFAX, VIRGINIA — Nearly 30 years ago, in a 1995 paper, the British physician-epidemiologist David Barker, MD, PhD, wrote about his fetal origins hypothesis — the idea that programs to address fetal undernutrition and low birth weight produced later coronary heart disease (BMJ 1995;311:171-4).

His hypothesis and subsequent research led to the concept of adult diseases of fetal origins, which today extends beyond low birth weight and implicates the in utero environment as a significant determinant of risk for adverse childhood and adult metabolic outcomes and for major chronic diseases, including diabetes and obesity. Studies have shown that the offspring of pregnant mothers with diabetes have a higher risk of developing obesity and diabetes themselves.

“It’s a whole discipline [of research],” E. Albert Reece, MD, PhD, MBA, of the University of Maryland School of Medicine (UMSOM), said in an interview. “But what we’ve never quite understood is the ‘how’ and ‘why’? What are the mechanisms driving the fetal origins of such adverse outcomes in offspring?

At the biennial meeting of the Diabetes in Pregnancy Study Group of North America (DPSG), investigators described studies underway that are digging deeper into the associations between the intrauterine milieu and longer-term offspring health — and that are searching for biological and molecular processes that may be involved.

The studies are like “branches of the Barker hypothesis,” said Dr. Reece, former dean of UMSOM and current director of the UMSOM Center for Advanced Research Training and Innovation, who co-organized the DPSG meeting. “They’re taking the hypothesis and dissecting it by asking, for instance, it is possible that transgenerational obesity may align with the Barker hypothesis? Is it possible that it involves epigenetics regulation? Could we find biomarkers?”

The need for a better understanding of the fetal origins framework — and its subsequent transgenerational impact — is urgent. From 2000 to 2018, the prevalence of childhood obesity increased from 14.7% to 19.2% (a 31% increase) and the prevalence of severe childhood obesity rose from 3.9% to 6.1% (a 56% increase), according to data from the U.S. National Health and Nutrition Examination Survey (Obes Facts. 2022;15[4]:560-9).

Children aged 2-5 years have had an especially sharp increase in obesity (Pediatrics 2018;141[3]:e20173459), Christine Wey Hockett, PhD, of the University of South Dakota School of Medicine, said at the DPSG meeting (Figure 1).

Deeper Dives Into Associations, Potential Mechanisms

The EPOCH prospective cohort study with which Dr. Hockett was involved gave her a front-seat view of the transgenerational adverse effects of in utero exposure to hyperglycemia. The study recruited ethnically diverse maternal/child dyads from the Kaiser Permanente of Colorado perinatal database from 1992 to 2002 and assessed 418 offspring at two points — a mean age of 10.5 years and 16.5 years — for fasting blood glucose, adiposity, and diet and physical activity. The second visit also involved an oral glucose tolerance test.

The 77 offspring who had been exposed in utero to GDM had a homeostatic model assessment of insulin resistance (HOMA-IR) that was 18% higher, a 19% lower Matsuda index, and a 9% greater HOMA of β-cell function (HOMA-β) than the 341 offspring whose mothers did not have diabetes. Each 5-kg/m² increase in prepregnancy body mass index predicted increased insulin resistance, but there was no combined effect of both maternal obesity and diabetes in utero.

Exposed offspring had a higher BMI and increased adiposity, but when BMI was controlled for in the analysis of metabolic outcomes, maternal diabetes was still associated with 12% higher HOMA-IR and a 17% lower Matsuda index. “So [the metabolic outcomes] are a direct effect of maternal diabetes,” Dr. Hockett said at the DPSG meeting, noting the fetal overnutrition hypothesis in which maternal glucose, but not maternal insulin, freely passes through the placenta, promoting growth and adiposity in the fetus.

[The EPOCH results on metabolic outcomes and offspring adiposity were published in 2017 and 2019, respectively (Diabet Med. 2017;34:1392-9; Diabetologia. 2019;62:2017-24). In 2020, EPOCH researchers reported sex-specific effects on cardiovascular outcomes, with GDM exposure associated with higher total and LDL cholesterol in girls and higher systolic blood pressure in boys (Pediatr Obes. 2020;15[5]:e12611).]

Now, a new longitudinal cohort study underway in Phoenix, is taking a deeper dive, trying to pinpoint what exactly influences childhood obesity and metabolic risk by following Hispanic and American Indian maternal/child dyads from pregnancy until 18 years postpartum. Researchers are looking not only at associations between maternal risk factors (pregnancy BMI, gestational weight gain, and diabetes in pregnancy) and offspring BMI, adiposity, and growth patterns, but also how various factors during pregnancy — clinical, genetic, lifestyle, biochemical — ”may mediate the associations,” said lead investigator Madhumita Sinha, MD.

“We need a better understanding at the molecular level of the biological processes that lead to obesity in children and that cause metabolic dysfunction,” said Dr. Sinha, who heads the Diabetes Epidemiology and Clinical Research Section of the of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch in Phoenix.

The populations being enrolled in the ETCHED study (for Early Tracking of Childhood Health Determinants) are at especially high risk of childhood obesity and metabolic dysfunction. Research conducted decades ago by the NIDDK in Phoenix showed that approximately 50% of Pima Indian children from diabetic pregnancies develop type 2 diabetes by age 25 (N Engl J Med. 1983;308:242-5). Years later, to tease out possible genetic factors, researchers compared siblings born before and after their mother was found to have type 2 diabetes, and found significantly higher rates of diabetes in those born after the mother’s diagnosis, affirming the role of in utero toxicity (Diabetes 2000;49:2208-11).

In the new study, the researchers will look at adipokines and inflammatory biomarkers in the mothers and offspring in addition to traditional anthropometric and glycemic measures. They’ll analyze placental tissue, breast milk, and the gut microbiome longitudinally, and they’ll lean heavily on genomics/epigenomics, proteomics, and metabolomics. “There’s potential,” Dr. Sinha said, “to develop a more accurate predictive and prognostic model of childhood obesity.”

The researchers also will study the role of family, socioeconomics, and environmental factors in influencing child growth patterns and they’ll look at neurodevelopment in infancy and childhood. As of October 2023, almost 80 pregnant women, most with obesity and almost one-third with type 2 diabetes, had enrolled in the study. Over the next several years, the study aims to enroll 750 dyads.
 

The Timing of In Utero Exposure

Shelley Ehrlich, MD, ScD, MPH, of the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, is aiming, meanwhile, to learn how the timing of in utero exposure to hyperglycemia predicts specific metabolic and cardiovascular morbidities in the adult offspring of diabetic mothers.

“While we know that exposure to maternal diabetes, regardless of type, increases the risk of obesity, insulin resistance, diabetes, renal compromise, and cardiovascular disease in the offspring, there is little known about the level and timing of hyperglycemic exposure during fetal development that triggers these adverse outcomes,” said Dr. Ehrlich. A goal, she said, is to identify gestational profiles that predict phenotypes of offspring at risk for morbidity in later life.

She and other investigators with the TEAM (Transgenerational Effect on Adult Morbidity) study have recruited over 170 offspring of mothers who participated in the Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati Medical Center from 1978 to 1995 — a landmark study that demonstrated the effect of strict glucose control in reducing major congenital malformations.

The women in the PPG study had frequent glucose monitoring (up to 6-8 times a day) throughout their pregnancies, and now, their recruited offspring, who are up to 43 years of age, are being assessed for obesity, diabetes/metabolic health, cardiovascular disease/cardiac and peripheral vascular structure and function, and other outcomes including those that may be amenable to secondary prevention (J Diabetes Res. Nov 1;2021:6590431).

Preliminary findings from over 170 offspring recruited between 2017 and 2022 suggest that in utero exposure to dysglycemia (as measured by standard deviations of glycohemoglobin) in the third trimester appears to increase the risk of morbid obesity in adulthood, while exposure to dysglycemia in the first trimester increases the risk of impaired glucose tolerance. The risk of B-cell dysfunction, meanwhile, appears to be linked to dysglycemia in the first and third trimesters — particularly the first — Dr. Ehrlich reported.

Cognitive outcomes in offspring have also been assessed and here it appears that dysglycemia in the third trimester is linked to worse scores on the Wechsler Abbreviated Scale of Intelligence (WASI-II), said Katherine Bowers, PhD, MPH, a TEAM study coinvestigator, also of Cincinnati Children’s Hospital Medical Center.

“We’ve already observed [an association between] diabetes in pregnancy and cognition in early childhood and through adolescence, but [the question has been] does this association persist into adulthood?” she said.

Preliminary analyses of 104 offspring show no statistically significant associations between maternal dysglycemia in the first or second trimesters and offspring cognition, but “consistent inverse associations between maternal glycohemoglobin in the third trimester across two [WASI-II] subscales and composite measures of cognition,” Dr. Bowers said.

Their analysis adjusted for a variety of factors, including maternal age, prepregnancy and first trimester BMI, race, family history of diabetes, and diabetes severity/macrovascular complications.
 

Back In The Laboratory

At the other end of the research spectrum, basic research scientists are also investigating the mechanisms and sequelae of in utero hyperglycemia and other injuries, including congenital malformations, placental adaptive responses and fetal programming. Researchers are asking, for instance, what does placental metabolic reprogramming entail? What role do placental extracellular vesicles play in GDM? Can we alter the in utero environment and thus improve the short and long-term fetal/infant outcomes?

Animal research done at the UMSOM Center for Birth Defects Research, led by Dr. Reece and Peixin Yang, PhD, suggests that “a good portion of in utero injury is due to epigenetics,” Dr. Reece said in the interview. “We’ve shown that under conditions of hyperglycemia, for example, genetic regulation and genetic function can be altered.”

Through in vivo research, they have also shown that antioxidants or membrane stabilizers such as arachidonic acid or myo-inositol, or experimental inhibitors to certain pro-apoptotic intermediates, can individually or collectively result in reduced malformations. “It is highly likely that understanding the biological impact of various altered in utero environments, and then modifying or reversing those environments, will result in short and long-term outcome improvements similar to those shown with congenital malformations,” Dr. Reece said.

FAIRFAX, VIRGINIA — Nearly 30 years ago, in a 1995 paper, the British physician-epidemiologist David Barker, MD, PhD, wrote about his fetal origins hypothesis — the idea that programs to address fetal undernutrition and low birth weight produced later coronary heart disease (BMJ 1995;311:171-4).

His hypothesis and subsequent research led to the concept of adult diseases of fetal origins, which today extends beyond low birth weight and implicates the in utero environment as a significant determinant of risk for adverse childhood and adult metabolic outcomes and for major chronic diseases, including diabetes and obesity. Studies have shown that the offspring of pregnant mothers with diabetes have a higher risk of developing obesity and diabetes themselves.

“It’s a whole discipline [of research],” E. Albert Reece, MD, PhD, MBA, of the University of Maryland School of Medicine (UMSOM), said in an interview. “But what we’ve never quite understood is the ‘how’ and ‘why’? What are the mechanisms driving the fetal origins of such adverse outcomes in offspring?

At the biennial meeting of the Diabetes in Pregnancy Study Group of North America (DPSG), investigators described studies underway that are digging deeper into the associations between the intrauterine milieu and longer-term offspring health — and that are searching for biological and molecular processes that may be involved.

The studies are like “branches of the Barker hypothesis,” said Dr. Reece, former dean of UMSOM and current director of the UMSOM Center for Advanced Research Training and Innovation, who co-organized the DPSG meeting. “They’re taking the hypothesis and dissecting it by asking, for instance, it is possible that transgenerational obesity may align with the Barker hypothesis? Is it possible that it involves epigenetics regulation? Could we find biomarkers?”

The need for a better understanding of the fetal origins framework — and its subsequent transgenerational impact — is urgent. From 2000 to 2018, the prevalence of childhood obesity increased from 14.7% to 19.2% (a 31% increase) and the prevalence of severe childhood obesity rose from 3.9% to 6.1% (a 56% increase), according to data from the U.S. National Health and Nutrition Examination Survey (Obes Facts. 2022;15[4]:560-9).

Children aged 2-5 years have had an especially sharp increase in obesity (Pediatrics 2018;141[3]:e20173459), Christine Wey Hockett, PhD, of the University of South Dakota School of Medicine, said at the DPSG meeting (Figure 1).

Deeper Dives Into Associations, Potential Mechanisms

The EPOCH prospective cohort study with which Dr. Hockett was involved gave her a front-seat view of the transgenerational adverse effects of in utero exposure to hyperglycemia. The study recruited ethnically diverse maternal/child dyads from the Kaiser Permanente of Colorado perinatal database from 1992 to 2002 and assessed 418 offspring at two points — a mean age of 10.5 years and 16.5 years — for fasting blood glucose, adiposity, and diet and physical activity. The second visit also involved an oral glucose tolerance test.

The 77 offspring who had been exposed in utero to GDM had a homeostatic model assessment of insulin resistance (HOMA-IR) that was 18% higher, a 19% lower Matsuda index, and a 9% greater HOMA of β-cell function (HOMA-β) than the 341 offspring whose mothers did not have diabetes. Each 5-kg/m² increase in prepregnancy body mass index predicted increased insulin resistance, but there was no combined effect of both maternal obesity and diabetes in utero.

Exposed offspring had a higher BMI and increased adiposity, but when BMI was controlled for in the analysis of metabolic outcomes, maternal diabetes was still associated with 12% higher HOMA-IR and a 17% lower Matsuda index. “So [the metabolic outcomes] are a direct effect of maternal diabetes,” Dr. Hockett said at the DPSG meeting, noting the fetal overnutrition hypothesis in which maternal glucose, but not maternal insulin, freely passes through the placenta, promoting growth and adiposity in the fetus.

[The EPOCH results on metabolic outcomes and offspring adiposity were published in 2017 and 2019, respectively (Diabet Med. 2017;34:1392-9; Diabetologia. 2019;62:2017-24). In 2020, EPOCH researchers reported sex-specific effects on cardiovascular outcomes, with GDM exposure associated with higher total and LDL cholesterol in girls and higher systolic blood pressure in boys (Pediatr Obes. 2020;15[5]:e12611).]

Now, a new longitudinal cohort study underway in Phoenix, is taking a deeper dive, trying to pinpoint what exactly influences childhood obesity and metabolic risk by following Hispanic and American Indian maternal/child dyads from pregnancy until 18 years postpartum. Researchers are looking not only at associations between maternal risk factors (pregnancy BMI, gestational weight gain, and diabetes in pregnancy) and offspring BMI, adiposity, and growth patterns, but also how various factors during pregnancy — clinical, genetic, lifestyle, biochemical — ”may mediate the associations,” said lead investigator Madhumita Sinha, MD.

“We need a better understanding at the molecular level of the biological processes that lead to obesity in children and that cause metabolic dysfunction,” said Dr. Sinha, who heads the Diabetes Epidemiology and Clinical Research Section of the of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch in Phoenix.

The populations being enrolled in the ETCHED study (for Early Tracking of Childhood Health Determinants) are at especially high risk of childhood obesity and metabolic dysfunction. Research conducted decades ago by the NIDDK in Phoenix showed that approximately 50% of Pima Indian children from diabetic pregnancies develop type 2 diabetes by age 25 (N Engl J Med. 1983;308:242-5). Years later, to tease out possible genetic factors, researchers compared siblings born before and after their mother was found to have type 2 diabetes, and found significantly higher rates of diabetes in those born after the mother’s diagnosis, affirming the role of in utero toxicity (Diabetes 2000;49:2208-11).

In the new study, the researchers will look at adipokines and inflammatory biomarkers in the mothers and offspring in addition to traditional anthropometric and glycemic measures. They’ll analyze placental tissue, breast milk, and the gut microbiome longitudinally, and they’ll lean heavily on genomics/epigenomics, proteomics, and metabolomics. “There’s potential,” Dr. Sinha said, “to develop a more accurate predictive and prognostic model of childhood obesity.”

The researchers also will study the role of family, socioeconomics, and environmental factors in influencing child growth patterns and they’ll look at neurodevelopment in infancy and childhood. As of October 2023, almost 80 pregnant women, most with obesity and almost one-third with type 2 diabetes, had enrolled in the study. Over the next several years, the study aims to enroll 750 dyads.
 

The Timing of In Utero Exposure

Shelley Ehrlich, MD, ScD, MPH, of the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, is aiming, meanwhile, to learn how the timing of in utero exposure to hyperglycemia predicts specific metabolic and cardiovascular morbidities in the adult offspring of diabetic mothers.

“While we know that exposure to maternal diabetes, regardless of type, increases the risk of obesity, insulin resistance, diabetes, renal compromise, and cardiovascular disease in the offspring, there is little known about the level and timing of hyperglycemic exposure during fetal development that triggers these adverse outcomes,” said Dr. Ehrlich. A goal, she said, is to identify gestational profiles that predict phenotypes of offspring at risk for morbidity in later life.

She and other investigators with the TEAM (Transgenerational Effect on Adult Morbidity) study have recruited over 170 offspring of mothers who participated in the Diabetes in Pregnancy Program Project Grant (PPG) at the University of Cincinnati Medical Center from 1978 to 1995 — a landmark study that demonstrated the effect of strict glucose control in reducing major congenital malformations.

The women in the PPG study had frequent glucose monitoring (up to 6-8 times a day) throughout their pregnancies, and now, their recruited offspring, who are up to 43 years of age, are being assessed for obesity, diabetes/metabolic health, cardiovascular disease/cardiac and peripheral vascular structure and function, and other outcomes including those that may be amenable to secondary prevention (J Diabetes Res. Nov 1;2021:6590431).

Preliminary findings from over 170 offspring recruited between 2017 and 2022 suggest that in utero exposure to dysglycemia (as measured by standard deviations of glycohemoglobin) in the third trimester appears to increase the risk of morbid obesity in adulthood, while exposure to dysglycemia in the first trimester increases the risk of impaired glucose tolerance. The risk of B-cell dysfunction, meanwhile, appears to be linked to dysglycemia in the first and third trimesters — particularly the first — Dr. Ehrlich reported.

Cognitive outcomes in offspring have also been assessed and here it appears that dysglycemia in the third trimester is linked to worse scores on the Wechsler Abbreviated Scale of Intelligence (WASI-II), said Katherine Bowers, PhD, MPH, a TEAM study coinvestigator, also of Cincinnati Children’s Hospital Medical Center.

“We’ve already observed [an association between] diabetes in pregnancy and cognition in early childhood and through adolescence, but [the question has been] does this association persist into adulthood?” she said.

Preliminary analyses of 104 offspring show no statistically significant associations between maternal dysglycemia in the first or second trimesters and offspring cognition, but “consistent inverse associations between maternal glycohemoglobin in the third trimester across two [WASI-II] subscales and composite measures of cognition,” Dr. Bowers said.

Their analysis adjusted for a variety of factors, including maternal age, prepregnancy and first trimester BMI, race, family history of diabetes, and diabetes severity/macrovascular complications.
 

Back In The Laboratory

At the other end of the research spectrum, basic research scientists are also investigating the mechanisms and sequelae of in utero hyperglycemia and other injuries, including congenital malformations, placental adaptive responses and fetal programming. Researchers are asking, for instance, what does placental metabolic reprogramming entail? What role do placental extracellular vesicles play in GDM? Can we alter the in utero environment and thus improve the short and long-term fetal/infant outcomes?

Animal research done at the UMSOM Center for Birth Defects Research, led by Dr. Reece and Peixin Yang, PhD, suggests that “a good portion of in utero injury is due to epigenetics,” Dr. Reece said in the interview. “We’ve shown that under conditions of hyperglycemia, for example, genetic regulation and genetic function can be altered.”

Through in vivo research, they have also shown that antioxidants or membrane stabilizers such as arachidonic acid or myo-inositol, or experimental inhibitors to certain pro-apoptotic intermediates, can individually or collectively result in reduced malformations. “It is highly likely that understanding the biological impact of various altered in utero environments, and then modifying or reversing those environments, will result in short and long-term outcome improvements similar to those shown with congenital malformations,” Dr. Reece said.

Although tubal sterilization is common, especially among those with lower income and education levels, misunderstandings persist about the reversibility of the procedure, and previous studies suggest that many pregnant individuals are not making well-informed decisions, wrote Sonya Borrero, MD, of the University of Pittsburgh, and colleagues.

In a study published in JAMA Network Open, the researchers randomized 350 pregnant individuals with Medicaid insurance to usual care or usual care plus a web-based decision aid in English or Spanish called MyDecision/MiDecisión that included written, audio, and video information about tubal sterilization. The tool also included an interactive table comparing tubal sterilization to other contraceptive options, exercises to clarify patients’ values, knowledge checks, and a final summary report.

The two primary outcomes were knowledge of tubal sterilization based on a 10-question true/false test and decisional conflict about contraceptive choices using the low-literacy Decision Conflict Scale. The participants ranged in age from 21 to 45 years, with a mean age of 29.7 years. Participants were randomized prior to 24 weeks’ gestation, and those in the intervention group completed the intervention immediately using a personal device or a university device in the clinical setting. Further assessments occurred by phone during the third trimester and at 3 months postpartum.

Participants in the decision aid group showed significantly greater knowledge of tubal sterilization compared with controls, with a mean of 76.5% correct responses to the knowledge questions, vs. 55.6% in the control group (P < .001). Decisional conflict scores also were significantly lower in the intervention group compared with controls (mean 12.7 vs. 18.7, P = .002).

The most dramatic knowledge gap related to permanence of tubal sterilization; 90.1% of participants in the intervention group answered correctly that the procedure is not easily reversible, compared to 39.3% of the controls. Similarly, 86.6% of the intervention group responded correctly that the tubes do not “come untied” spontaneously, vs. 33.7% of controls (P < .001 for both).

The findings were limited by several factors including the focus only on pregnant Medicaid patients, the presentation of the decision tool only at a point early in pregnancy, which may have been too soon for some participants to consider tubal sterilization, and a lack of data on long-term satisfaction or regret about tubal sterilization decisions, the researchers noted.

However, the knowledge differences between the intervention and control groups remained significant at the third trimester assessment, they said.

More research is needed in other populations and using other time points, but the current study results suggest that use of the MyDecision/MiDecisión tool in a real-world clinical setting at the actual time of decision-making could improve knowledge and inform patients’ choices, the researchers concluded. Improved patient education also could inform policy decisions about the potential elimination of the 30-day waiting period for sterilization procedures, they said.

The study was supported by the National Institute on Minority Health and Health Disparities. The researchers had no financial conflicts to disclose.

Although tubal sterilization is common, especially among those with lower income and education levels, misunderstandings persist about the reversibility of the procedure, and previous studies suggest that many pregnant individuals are not making well-informed decisions, wrote Sonya Borrero, MD, of the University of Pittsburgh, and colleagues.

In a study published in JAMA Network Open, the researchers randomized 350 pregnant individuals with Medicaid insurance to usual care or usual care plus a web-based decision aid in English or Spanish called MyDecision/MiDecisión that included written, audio, and video information about tubal sterilization. The tool also included an interactive table comparing tubal sterilization to other contraceptive options, exercises to clarify patients’ values, knowledge checks, and a final summary report.

The two primary outcomes were knowledge of tubal sterilization based on a 10-question true/false test and decisional conflict about contraceptive choices using the low-literacy Decision Conflict Scale. The participants ranged in age from 21 to 45 years, with a mean age of 29.7 years. Participants were randomized prior to 24 weeks’ gestation, and those in the intervention group completed the intervention immediately using a personal device or a university device in the clinical setting. Further assessments occurred by phone during the third trimester and at 3 months postpartum.

Participants in the decision aid group showed significantly greater knowledge of tubal sterilization compared with controls, with a mean of 76.5% correct responses to the knowledge questions, vs. 55.6% in the control group (P < .001). Decisional conflict scores also were significantly lower in the intervention group compared with controls (mean 12.7 vs. 18.7, P = .002).

The most dramatic knowledge gap related to permanence of tubal sterilization; 90.1% of participants in the intervention group answered correctly that the procedure is not easily reversible, compared to 39.3% of the controls. Similarly, 86.6% of the intervention group responded correctly that the tubes do not “come untied” spontaneously, vs. 33.7% of controls (P < .001 for both).

The findings were limited by several factors including the focus only on pregnant Medicaid patients, the presentation of the decision tool only at a point early in pregnancy, which may have been too soon for some participants to consider tubal sterilization, and a lack of data on long-term satisfaction or regret about tubal sterilization decisions, the researchers noted.

However, the knowledge differences between the intervention and control groups remained significant at the third trimester assessment, they said.

More research is needed in other populations and using other time points, but the current study results suggest that use of the MyDecision/MiDecisión tool in a real-world clinical setting at the actual time of decision-making could improve knowledge and inform patients’ choices, the researchers concluded. Improved patient education also could inform policy decisions about the potential elimination of the 30-day waiting period for sterilization procedures, they said.

The study was supported by the National Institute on Minority Health and Health Disparities. The researchers had no financial conflicts to disclose.

Although tubal sterilization is common, especially among those with lower income and education levels, misunderstandings persist about the reversibility of the procedure, and previous studies suggest that many pregnant individuals are not making well-informed decisions, wrote Sonya Borrero, MD, of the University of Pittsburgh, and colleagues.

In a study published in JAMA Network Open, the researchers randomized 350 pregnant individuals with Medicaid insurance to usual care or usual care plus a web-based decision aid in English or Spanish called MyDecision/MiDecisión that included written, audio, and video information about tubal sterilization. The tool also included an interactive table comparing tubal sterilization to other contraceptive options, exercises to clarify patients’ values, knowledge checks, and a final summary report.

The two primary outcomes were knowledge of tubal sterilization based on a 10-question true/false test and decisional conflict about contraceptive choices using the low-literacy Decision Conflict Scale. The participants ranged in age from 21 to 45 years, with a mean age of 29.7 years. Participants were randomized prior to 24 weeks’ gestation, and those in the intervention group completed the intervention immediately using a personal device or a university device in the clinical setting. Further assessments occurred by phone during the third trimester and at 3 months postpartum.

Participants in the decision aid group showed significantly greater knowledge of tubal sterilization compared with controls, with a mean of 76.5% correct responses to the knowledge questions, vs. 55.6% in the control group (P < .001). Decisional conflict scores also were significantly lower in the intervention group compared with controls (mean 12.7 vs. 18.7, P = .002).

The most dramatic knowledge gap related to permanence of tubal sterilization; 90.1% of participants in the intervention group answered correctly that the procedure is not easily reversible, compared to 39.3% of the controls. Similarly, 86.6% of the intervention group responded correctly that the tubes do not “come untied” spontaneously, vs. 33.7% of controls (P < .001 for both).

The findings were limited by several factors including the focus only on pregnant Medicaid patients, the presentation of the decision tool only at a point early in pregnancy, which may have been too soon for some participants to consider tubal sterilization, and a lack of data on long-term satisfaction or regret about tubal sterilization decisions, the researchers noted.

However, the knowledge differences between the intervention and control groups remained significant at the third trimester assessment, they said.

More research is needed in other populations and using other time points, but the current study results suggest that use of the MyDecision/MiDecisión tool in a real-world clinical setting at the actual time of decision-making could improve knowledge and inform patients’ choices, the researchers concluded. Improved patient education also could inform policy decisions about the potential elimination of the 30-day waiting period for sterilization procedures, they said.

The study was supported by the National Institute on Minority Health and Health Disparities. The researchers had no financial conflicts to disclose.

Adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancer does not harm quality of life, according to patient-reported outcome analyses from the KEYNOTE-A18 trial.

Progression-free survival data from the trial, reported at the 2023 meeting of the European Society for Medical Oncology, showed a 30% reduction in the risk for progression (P =.002) with the addition of pembrolizumab vs placebo, as well as favorable overall survival trends, reported Leslie Randall, MD, with VCU Health in Richmond, Virginia. Now the new analyses bring the “voices of the patients from this large phase 3 study.”

“I think the data can put us at ease and give patients a measure of comfort because there was no detriment in the quality of life,” said Dr. Randall, who presented the data on March 17 at the Society of Gynecologic Oncology (SGO) 2024 conference.

The phase 3 KEYNOTE-A18 trial enrolled 1060 patients new to treatment who had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease. They were randomly allocated to receive pembrolizumab or placebo plus concurrent chemoradiotherapy.

Patient-reported outcome instruments used in the study were the European Organization for Research and Treatment of Cancer (EORTC) 30-item quality-of-life (QOL) core questionnaire (QLQ-C30), the EORTC cervical cancer–specific module (QLQ-CX24), and the EuroQol EQ-5D-5L visual analog scale (VAS). 

Prespecified secondary study endpoints were changes from baseline to week 36 in QLQ-C30 global health status/QOL (GHS/QOL) and physical functioning, and the QLQ-CX24 symptom-experience scale.

At baseline, patient-reported outcome scores were similar between treatment groups. Patients in both treatment groups had an initial decrease in QLQ-C30 GHS/QOL and physical functioning subscale and EQ-5D-5L VAS scores at weeks 3 and 6, but these improved relative to baseline at week 12 and subsequent weeks. 

A similar number of patients in the pembrolizumab and placebo groups had improved or stable scores for QLQ-C30 GHS/QOL (76% vs 75%), QLQ-C30 physical functioning (77% vs 77%), QLQ-CX24 symptom experience (85% vs 85%) and EQ-5D-5L VAS (73% vs 76%). 

Across all QOL instruments evaluated, there were no meaningful differences in patient-reported outcomes among patients who received pembrolizumab compared with those who received placebo, said Dr. Randall.

The improvement in progression-free survival, coupled with the patient-reported outcomes showing no additional harms to quality of life, support pembrolizumab plus concurrent chemoradiotherapy as a “new standard of care” for patients with high-risk locally advanced cervical cancer, she told attendees. 

“We have had stunning success in cervical cancer treatments over the past 10-15 years, and now we see that the addition of pembrolizumab to standard chemotherapy not only improves outcome but very importantly does not significantly impact the quality of life in our patients,” said study discussant R. Wendel Naumann, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Funding for KEYNOTE-A18 was provided by Merck. Dr. Randall has disclosed relationships with Seagen/Genmab, Merck, GSK, ImmunoGen, AstraZeneca, and On Target Laboratories. Dr. Naumann has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancer does not harm quality of life, according to patient-reported outcome analyses from the KEYNOTE-A18 trial.

Progression-free survival data from the trial, reported at the 2023 meeting of the European Society for Medical Oncology, showed a 30% reduction in the risk for progression (P =.002) with the addition of pembrolizumab vs placebo, as well as favorable overall survival trends, reported Leslie Randall, MD, with VCU Health in Richmond, Virginia. Now the new analyses bring the “voices of the patients from this large phase 3 study.”

“I think the data can put us at ease and give patients a measure of comfort because there was no detriment in the quality of life,” said Dr. Randall, who presented the data on March 17 at the Society of Gynecologic Oncology (SGO) 2024 conference.

The phase 3 KEYNOTE-A18 trial enrolled 1060 patients new to treatment who had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease. They were randomly allocated to receive pembrolizumab or placebo plus concurrent chemoradiotherapy.

Patient-reported outcome instruments used in the study were the European Organization for Research and Treatment of Cancer (EORTC) 30-item quality-of-life (QOL) core questionnaire (QLQ-C30), the EORTC cervical cancer–specific module (QLQ-CX24), and the EuroQol EQ-5D-5L visual analog scale (VAS). 

Prespecified secondary study endpoints were changes from baseline to week 36 in QLQ-C30 global health status/QOL (GHS/QOL) and physical functioning, and the QLQ-CX24 symptom-experience scale.

At baseline, patient-reported outcome scores were similar between treatment groups. Patients in both treatment groups had an initial decrease in QLQ-C30 GHS/QOL and physical functioning subscale and EQ-5D-5L VAS scores at weeks 3 and 6, but these improved relative to baseline at week 12 and subsequent weeks. 

A similar number of patients in the pembrolizumab and placebo groups had improved or stable scores for QLQ-C30 GHS/QOL (76% vs 75%), QLQ-C30 physical functioning (77% vs 77%), QLQ-CX24 symptom experience (85% vs 85%) and EQ-5D-5L VAS (73% vs 76%). 

Across all QOL instruments evaluated, there were no meaningful differences in patient-reported outcomes among patients who received pembrolizumab compared with those who received placebo, said Dr. Randall.

The improvement in progression-free survival, coupled with the patient-reported outcomes showing no additional harms to quality of life, support pembrolizumab plus concurrent chemoradiotherapy as a “new standard of care” for patients with high-risk locally advanced cervical cancer, she told attendees. 

“We have had stunning success in cervical cancer treatments over the past 10-15 years, and now we see that the addition of pembrolizumab to standard chemotherapy not only improves outcome but very importantly does not significantly impact the quality of life in our patients,” said study discussant R. Wendel Naumann, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Funding for KEYNOTE-A18 was provided by Merck. Dr. Randall has disclosed relationships with Seagen/Genmab, Merck, GSK, ImmunoGen, AstraZeneca, and On Target Laboratories. Dr. Naumann has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Adding pembrolizumab (Keytruda) to concurrent chemoradiotherapy in patients with high-risk locally advanced cervical cancer does not harm quality of life, according to patient-reported outcome analyses from the KEYNOTE-A18 trial.

Progression-free survival data from the trial, reported at the 2023 meeting of the European Society for Medical Oncology, showed a 30% reduction in the risk for progression (P =.002) with the addition of pembrolizumab vs placebo, as well as favorable overall survival trends, reported Leslie Randall, MD, with VCU Health in Richmond, Virginia. Now the new analyses bring the “voices of the patients from this large phase 3 study.”

“I think the data can put us at ease and give patients a measure of comfort because there was no detriment in the quality of life,” said Dr. Randall, who presented the data on March 17 at the Society of Gynecologic Oncology (SGO) 2024 conference.

The phase 3 KEYNOTE-A18 trial enrolled 1060 patients new to treatment who had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease. They were randomly allocated to receive pembrolizumab or placebo plus concurrent chemoradiotherapy.

Patient-reported outcome instruments used in the study were the European Organization for Research and Treatment of Cancer (EORTC) 30-item quality-of-life (QOL) core questionnaire (QLQ-C30), the EORTC cervical cancer–specific module (QLQ-CX24), and the EuroQol EQ-5D-5L visual analog scale (VAS). 

Prespecified secondary study endpoints were changes from baseline to week 36 in QLQ-C30 global health status/QOL (GHS/QOL) and physical functioning, and the QLQ-CX24 symptom-experience scale.

At baseline, patient-reported outcome scores were similar between treatment groups. Patients in both treatment groups had an initial decrease in QLQ-C30 GHS/QOL and physical functioning subscale and EQ-5D-5L VAS scores at weeks 3 and 6, but these improved relative to baseline at week 12 and subsequent weeks. 

A similar number of patients in the pembrolizumab and placebo groups had improved or stable scores for QLQ-C30 GHS/QOL (76% vs 75%), QLQ-C30 physical functioning (77% vs 77%), QLQ-CX24 symptom experience (85% vs 85%) and EQ-5D-5L VAS (73% vs 76%). 

Across all QOL instruments evaluated, there were no meaningful differences in patient-reported outcomes among patients who received pembrolizumab compared with those who received placebo, said Dr. Randall.

The improvement in progression-free survival, coupled with the patient-reported outcomes showing no additional harms to quality of life, support pembrolizumab plus concurrent chemoradiotherapy as a “new standard of care” for patients with high-risk locally advanced cervical cancer, she told attendees. 

“We have had stunning success in cervical cancer treatments over the past 10-15 years, and now we see that the addition of pembrolizumab to standard chemotherapy not only improves outcome but very importantly does not significantly impact the quality of life in our patients,” said study discussant R. Wendel Naumann, MD, Atrium Health Levine Cancer Institute, Charlotte, North Carolina.

Funding for KEYNOTE-A18 was provided by Merck. Dr. Randall has disclosed relationships with Seagen/Genmab, Merck, GSK, ImmunoGen, AstraZeneca, and On Target Laboratories. Dr. Naumann has no relevant disclosures.
 

A version of this article appeared on Medscape.com.

Primary care clinicians have largely welcomed the arrival of Opill, the first over-the-counter (OTC) birth control pill from Perrigo, which will reach US pharmacy shelves this month. Although the medicine has a long-track record of safe use, physicians and nurse practitioners may want to ready themselves to answer questions from patients about shifting to the option.

The switch to OTC status for the norgestrel-only contraceptive has the support of many physician groups, including the American Medical Association, the American Academy of Family Physicians, and the American College of Obstetricians and Gynecologists (ACOG).

The end of the prescription-requirement removes a barrier to access for many women, especially those who lack insurance. But it also will take away a chief reason many women in their childbearing years make appointments with doctors, as they will no longer need prescriptions for birth control pills.

Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology at University of Washington School of Medicine, in Seattle, Washington, said she is also worried that the availability of an OTC pill will lead to missed opportunities to help patients avoid sexually transmitted diseases. For example, patients can get counseling about the need for testing for sexually transmitted diseases at the start of new relationships during a visit made to obtain a prescription for the pill.

“My hope is that they still follow our recommendations, which is to get tested with every partner,” said Dr. Oelschlager, who cares for many patients in their teens. “Adolescents are at a particularly high risk of infection compared to older ones.”

When clinicians do see patients, they may want to raise the issue of the OTC option and proper use. Patients will need to closely read materials provided for Opill, a step they might skip due to the ready access, according to Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research, which scrutinizes the safety of medical products.

“When something is sold over the counter, it’s perceived by individuals as being safe,” Dr. Zuckerman told this news organization. “There’s less concern and a little less interest in reading the instructions and reading the warnings.”
 

Considerations for Safety

The US Food and Drug Administration (FDA) in July approved the sales of a daily 0.075 mg norgestrel tablet without prescription. Perrigo told this news organization that it spent the intervening months ensuring retailers and consumers will receive education on the drug.

One of the biggest challenges for people using Opill may be sticking with the dosing schedule, according to Dr. Oelschlager.

“There are going to be people that have a harder time remembering to take a pill every day,” at the same time, said Dr. Oelschlager, who is chair of ACOG’s Clinical Consensus Gynecology Committee. “We need to watch and see what happens as it becomes more widely available, and people start using it.”

Unexpected vaginal bleeding is the most common adverse event linked to this form of birth control, with over one fifth of participants from one study of the OTC drug reporting this side effect, according to an FDA memo.

“It is more likely to be a tolerability issue rather than a safety issue,” the FDA wrote.

Many prescription of birth control options contain estrogen, which is associated with venous thromboembolism (VTE). But Opill contains only norgestrel, a form of progestin, which is not associated with thrombosis. Patients may be more likely to overestimate their potential risks for VTE than to underestimate them, according to Kwuan Paruchabutr, DNP, president of National Association of Nurse Practitioners in Women’s Health and an assistant professor at Georgetown University in Washington, DC.

“This is a progesterone-only pill: The risk is relatively low” of VTE, Dr. Paruchabutr said.

Clinicians should also take special care with patients who are prescribed drugs for seizures, tuberculosis, HIV/AIDS, and pulmonary hypertension or who are taking supplements containing St John’s wort.

Patients in their childbearing years who take isotretinoin are already expected to use some form of birth control.

“All patients on isotretinoin must be registered in the iPLEDGE program, which mandates monthly contraception counseling and monthly pregnancy tests for persons of childbearing potential,” Terrence A. Cronin, Jr, MD, president of the American Academy of Dermatology, told news organization through email.

Dr. Oelschlager noted that many patients who take isotretinoin may benefit from taking a birth control pill containing estrogen, for which they will need a prescription. At least three pills have an FDA-approved indication for treating moderate acne, including Ortho Tri-Cyclen, Estrostep, and Yaz.

The FDA has posted consumer-friendly information about the OTC pill that clinicians can refer their patients to. For clinicians who want more information, ACOG released a practice advisory about the switch in status for this progestin-only pill.
 

The Cost

While federal laws mandate employer-based and Medicaid plans cover prescription birth control pills for free, the OTC version will carry a cost, according to A. Mark Fendrick, MD, director of the University of Michigan Center for Value-Based Insurance Design in Ann Arbor, Michigan. 

Seven states, including New Mexico and New York, already have laws in effect that require health plans to cover certain OTC contraceptives without a prescription, according to a tally kept by the nonprofit research organization KFF.

Dr. Fendrick said it would be helpful for health plans to offer coverage for the OTC pill without copays even if they are not required to do so.

Priced at about $20 a month, Opill “is likely out of reach for many of the individuals who would most benefit from an OTC option,” Dr. Fendrick told this news organization in an email.

The new pill may be utilized most by those who do not have health insurance or have low incomes and cannot afford to see a doctor for a prescription, according to Sally Rafie, PharmD, a pharmacist specialist at University of California San Diego Health and founder of the Birth Control Pharmacist.

The manufacturer’s suggested retail prices will be $19.99 for a 1-month supply and $49.99 for a 3-month supply. Dublin-based Perrigo said it plans to offer a cost-assistance program for the drug in the coming weeks for people who have low incomes and lack insurance.

A version of this article appeared on Medscape.com.

Primary care clinicians have largely welcomed the arrival of Opill, the first over-the-counter (OTC) birth control pill from Perrigo, which will reach US pharmacy shelves this month. Although the medicine has a long-track record of safe use, physicians and nurse practitioners may want to ready themselves to answer questions from patients about shifting to the option.

The switch to OTC status for the norgestrel-only contraceptive has the support of many physician groups, including the American Medical Association, the American Academy of Family Physicians, and the American College of Obstetricians and Gynecologists (ACOG).

The end of the prescription-requirement removes a barrier to access for many women, especially those who lack insurance. But it also will take away a chief reason many women in their childbearing years make appointments with doctors, as they will no longer need prescriptions for birth control pills.

Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology at University of Washington School of Medicine, in Seattle, Washington, said she is also worried that the availability of an OTC pill will lead to missed opportunities to help patients avoid sexually transmitted diseases. For example, patients can get counseling about the need for testing for sexually transmitted diseases at the start of new relationships during a visit made to obtain a prescription for the pill.

“My hope is that they still follow our recommendations, which is to get tested with every partner,” said Dr. Oelschlager, who cares for many patients in their teens. “Adolescents are at a particularly high risk of infection compared to older ones.”

When clinicians do see patients, they may want to raise the issue of the OTC option and proper use. Patients will need to closely read materials provided for Opill, a step they might skip due to the ready access, according to Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research, which scrutinizes the safety of medical products.

“When something is sold over the counter, it’s perceived by individuals as being safe,” Dr. Zuckerman told this news organization. “There’s less concern and a little less interest in reading the instructions and reading the warnings.”
 

Considerations for Safety

The US Food and Drug Administration (FDA) in July approved the sales of a daily 0.075 mg norgestrel tablet without prescription. Perrigo told this news organization that it spent the intervening months ensuring retailers and consumers will receive education on the drug.

One of the biggest challenges for people using Opill may be sticking with the dosing schedule, according to Dr. Oelschlager.

“There are going to be people that have a harder time remembering to take a pill every day,” at the same time, said Dr. Oelschlager, who is chair of ACOG’s Clinical Consensus Gynecology Committee. “We need to watch and see what happens as it becomes more widely available, and people start using it.”

Unexpected vaginal bleeding is the most common adverse event linked to this form of birth control, with over one fifth of participants from one study of the OTC drug reporting this side effect, according to an FDA memo.

“It is more likely to be a tolerability issue rather than a safety issue,” the FDA wrote.

Many prescription of birth control options contain estrogen, which is associated with venous thromboembolism (VTE). But Opill contains only norgestrel, a form of progestin, which is not associated with thrombosis. Patients may be more likely to overestimate their potential risks for VTE than to underestimate them, according to Kwuan Paruchabutr, DNP, president of National Association of Nurse Practitioners in Women’s Health and an assistant professor at Georgetown University in Washington, DC.

“This is a progesterone-only pill: The risk is relatively low” of VTE, Dr. Paruchabutr said.

Clinicians should also take special care with patients who are prescribed drugs for seizures, tuberculosis, HIV/AIDS, and pulmonary hypertension or who are taking supplements containing St John’s wort.

Patients in their childbearing years who take isotretinoin are already expected to use some form of birth control.

“All patients on isotretinoin must be registered in the iPLEDGE program, which mandates monthly contraception counseling and monthly pregnancy tests for persons of childbearing potential,” Terrence A. Cronin, Jr, MD, president of the American Academy of Dermatology, told news organization through email.

Dr. Oelschlager noted that many patients who take isotretinoin may benefit from taking a birth control pill containing estrogen, for which they will need a prescription. At least three pills have an FDA-approved indication for treating moderate acne, including Ortho Tri-Cyclen, Estrostep, and Yaz.

The FDA has posted consumer-friendly information about the OTC pill that clinicians can refer their patients to. For clinicians who want more information, ACOG released a practice advisory about the switch in status for this progestin-only pill.
 

The Cost

While federal laws mandate employer-based and Medicaid plans cover prescription birth control pills for free, the OTC version will carry a cost, according to A. Mark Fendrick, MD, director of the University of Michigan Center for Value-Based Insurance Design in Ann Arbor, Michigan. 

Seven states, including New Mexico and New York, already have laws in effect that require health plans to cover certain OTC contraceptives without a prescription, according to a tally kept by the nonprofit research organization KFF.

Dr. Fendrick said it would be helpful for health plans to offer coverage for the OTC pill without copays even if they are not required to do so.

Priced at about $20 a month, Opill “is likely out of reach for many of the individuals who would most benefit from an OTC option,” Dr. Fendrick told this news organization in an email.

The new pill may be utilized most by those who do not have health insurance or have low incomes and cannot afford to see a doctor for a prescription, according to Sally Rafie, PharmD, a pharmacist specialist at University of California San Diego Health and founder of the Birth Control Pharmacist.

The manufacturer’s suggested retail prices will be $19.99 for a 1-month supply and $49.99 for a 3-month supply. Dublin-based Perrigo said it plans to offer a cost-assistance program for the drug in the coming weeks for people who have low incomes and lack insurance.

A version of this article appeared on Medscape.com.

Primary care clinicians have largely welcomed the arrival of Opill, the first over-the-counter (OTC) birth control pill from Perrigo, which will reach US pharmacy shelves this month. Although the medicine has a long-track record of safe use, physicians and nurse practitioners may want to ready themselves to answer questions from patients about shifting to the option.

The switch to OTC status for the norgestrel-only contraceptive has the support of many physician groups, including the American Medical Association, the American Academy of Family Physicians, and the American College of Obstetricians and Gynecologists (ACOG).

The end of the prescription-requirement removes a barrier to access for many women, especially those who lack insurance. But it also will take away a chief reason many women in their childbearing years make appointments with doctors, as they will no longer need prescriptions for birth control pills.

Anne-Marie Amies Oelschlager, MD, professor of obstetrics and gynecology at University of Washington School of Medicine, in Seattle, Washington, said she is also worried that the availability of an OTC pill will lead to missed opportunities to help patients avoid sexually transmitted diseases. For example, patients can get counseling about the need for testing for sexually transmitted diseases at the start of new relationships during a visit made to obtain a prescription for the pill.

“My hope is that they still follow our recommendations, which is to get tested with every partner,” said Dr. Oelschlager, who cares for many patients in their teens. “Adolescents are at a particularly high risk of infection compared to older ones.”

When clinicians do see patients, they may want to raise the issue of the OTC option and proper use. Patients will need to closely read materials provided for Opill, a step they might skip due to the ready access, according to Diana Zuckerman, PhD, president of the nonprofit National Center for Health Research, which scrutinizes the safety of medical products.

“When something is sold over the counter, it’s perceived by individuals as being safe,” Dr. Zuckerman told this news organization. “There’s less concern and a little less interest in reading the instructions and reading the warnings.”
 

Considerations for Safety

The US Food and Drug Administration (FDA) in July approved the sales of a daily 0.075 mg norgestrel tablet without prescription. Perrigo told this news organization that it spent the intervening months ensuring retailers and consumers will receive education on the drug.

One of the biggest challenges for people using Opill may be sticking with the dosing schedule, according to Dr. Oelschlager.

“There are going to be people that have a harder time remembering to take a pill every day,” at the same time, said Dr. Oelschlager, who is chair of ACOG’s Clinical Consensus Gynecology Committee. “We need to watch and see what happens as it becomes more widely available, and people start using it.”

Unexpected vaginal bleeding is the most common adverse event linked to this form of birth control, with over one fifth of participants from one study of the OTC drug reporting this side effect, according to an FDA memo.

“It is more likely to be a tolerability issue rather than a safety issue,” the FDA wrote.

Many prescription of birth control options contain estrogen, which is associated with venous thromboembolism (VTE). But Opill contains only norgestrel, a form of progestin, which is not associated with thrombosis. Patients may be more likely to overestimate their potential risks for VTE than to underestimate them, according to Kwuan Paruchabutr, DNP, president of National Association of Nurse Practitioners in Women’s Health and an assistant professor at Georgetown University in Washington, DC.

“This is a progesterone-only pill: The risk is relatively low” of VTE, Dr. Paruchabutr said.

Clinicians should also take special care with patients who are prescribed drugs for seizures, tuberculosis, HIV/AIDS, and pulmonary hypertension or who are taking supplements containing St John’s wort.

Patients in their childbearing years who take isotretinoin are already expected to use some form of birth control.

“All patients on isotretinoin must be registered in the iPLEDGE program, which mandates monthly contraception counseling and monthly pregnancy tests for persons of childbearing potential,” Terrence A. Cronin, Jr, MD, president of the American Academy of Dermatology, told news organization through email.

Dr. Oelschlager noted that many patients who take isotretinoin may benefit from taking a birth control pill containing estrogen, for which they will need a prescription. At least three pills have an FDA-approved indication for treating moderate acne, including Ortho Tri-Cyclen, Estrostep, and Yaz.

The FDA has posted consumer-friendly information about the OTC pill that clinicians can refer their patients to. For clinicians who want more information, ACOG released a practice advisory about the switch in status for this progestin-only pill.
 

The Cost

While federal laws mandate employer-based and Medicaid plans cover prescription birth control pills for free, the OTC version will carry a cost, according to A. Mark Fendrick, MD, director of the University of Michigan Center for Value-Based Insurance Design in Ann Arbor, Michigan. 

Seven states, including New Mexico and New York, already have laws in effect that require health plans to cover certain OTC contraceptives without a prescription, according to a tally kept by the nonprofit research organization KFF.

Dr. Fendrick said it would be helpful for health plans to offer coverage for the OTC pill without copays even if they are not required to do so.

Priced at about $20 a month, Opill “is likely out of reach for many of the individuals who would most benefit from an OTC option,” Dr. Fendrick told this news organization in an email.

The new pill may be utilized most by those who do not have health insurance or have low incomes and cannot afford to see a doctor for a prescription, according to Sally Rafie, PharmD, a pharmacist specialist at University of California San Diego Health and founder of the Birth Control Pharmacist.

The manufacturer’s suggested retail prices will be $19.99 for a 1-month supply and $49.99 for a 3-month supply. Dublin-based Perrigo said it plans to offer a cost-assistance program for the drug in the coming weeks for people who have low incomes and lack insurance.

A version of this article appeared on Medscape.com.

Adding an immune checkpoint inhibitor to platinum-based chemotherapy resulted in a more than 1-year gain in median overall survival for women with primary advanced or recurrent endometrial cancer.

The benefit of the combination of the programmed death protein 1 (PD-1) inhibitor dostarlimab (Jemperli) and chemotherapy was even more pronounced among patients with DNA mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) tumors.

These results, from the second interim analysis of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial, were cheered by audience members when they were reported at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer, held in San Diego, California.

“Overall survival benefit to the addition of PD-1 inhibitor to chemotherapy upfront for patients with advanced and recurrent MSI-high endometrial cancer: SOLD!” said invited discussant Gini Fleming, medical director of gynecologic oncology at the University of Chicago.

“I think this is a huge win for our patients. It’s something that none of us have seen before over many years of working with endometrial cancer and should be incorporated into everybody’s practice as of yesterday,” she said.

Continued Improvement

Results from the first interim analysis of the trial showed that dostarlimab and chemotherapy significantly improved progression-free survival (PFS) in the dMMR/MSI-H population, and there was an early trend toward improved overall survival, compared with chemotherapy plus placebo.

As Matthew A. Powell, MD from Washington University School of Medicine in Saint Louis, Missouri reported at SGO 2024, that early trend has become an undeniable survival advantage.

At a median follow-up of 37.2 months, the median overall survival was 44.6 months for patients randomized to the combination, compared with 28.2 months for those assigned to chemotherapy plus placebo.

The respective 3-year overall survival (OS) rates were 54.9% and 42.9%, translating into a hazard ratio (HR) for death with dostarlimab/chemotherapy of 0.69 (P = .002).

Among the subset of patients with dMMR/MSI-H tumors the survival benefit conferred by the combination was even greater, with median OS not reached in the dostarlimab group vs 31.4 months in the chemotherapy-alone arm, with respective 3-year OS rates of 78% and 46%. This difference translated into a HR for death with the combination of 0.32 (P = .0002) for patients with deficient mismatch-repair cancers.

“Dostarlimab plus carboplatin-paclitaxel chemotherapy demonstrated statistically significant and clinically meaningful overall survival improvements in the overall population, a substantial unprecedented overall survival benefit in patients with defective mismatch-repair tumors, and a clinically meaningful; 7-month improvement in the OS difference in patients with proficient mismatch-repair tumors,” Dr. Powell said.

RUBY Details

The trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m² of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or dostarlimab placebo every 6 weeks for up to 3 years.

Within the cohort, 118 patients (23.9%) had dMMR/MSI-H tumors.

At the time of the first interim analysis the estimated progression-free survival at 24 months in the dMMR–MSI-H subgroup was 61.4% in the dostarlimab group vs 15.7 in the placebo group (HR for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < .001).

A prespecified exploratory analysis of progression-free survival in proficient MMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.

Overall survival at that time also favored dostarlimab, although it was only mature for 33% of the population. But at 24 months, OS rates were 71.3% vs 56.0% among placebo recipients; this difference approached but did not reach statistical significance.

The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR/MSS population.

The most common adverse events observed were nausea, alopecia, and fatigue. Grade 3 and higher adverse events at the most recent follow-up were more frequent in the dostarlimab group than in the placebo group (72.2% vs 60.2%).

“Importantly, safety was maintained” at the second interim analysis, Dr. Powell said.

“No new safety signals were noted, no new deaths related to therapy were noted with the subsequent 1-year additional analysis time,” he said.

What’s Next?

Dr. Fleming reviewed potential strategies for further improving care of patients with advanced or recurrent endometrial cancer during her discussion.

“What are the next directions for patients with MSI-high disease? Well, obviously could we use immune checkpoint inhibitors without chemotherapy and not compromise results? There are two ongoing trials or trials that we’re awaiting results of that have compared single-agent immune checkpoint inhibitor to just chemotherapy in mismatch repair-deficient advanced disease, and hopefully we can extrapolate from these trials to determine if this might be a more patient-friendly and equally effective strategy, but we don’t yet know,” she said.

Dr. Fleming also noted that ongoing or planned clinical trials will address questions about potential options for patients with MSI-H tumors whose disease progresses on frontline chemotherapy and immunotherapy. Other trials are assessing whether combining radiotherapy with checkpoint inhibitors will be effective in treating patients with earlier-stage tumors, or whether the addition of a PARP inhibitor might offer additional benefit for these patients.

“Immune checkpoint inhibitor should be given first line to patients with advanced/recurrent microsatellite [instability] endometrial cancer, and they should be considered as front line in patients with microsatellite stable disease. At this point, unfortunately, we have no reasonable predictive factors to know which of those patients with microsatellite stable disease will truly benefit. Multiple other agents are being tested in this setting, and will hopefully prove useful in subgroups,” she said.

The study is funded by GlaxoSmithKline. Dr. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. Dr. Fleming reports serving as an institutional principal investigator for trials sponsored by multiple companies, not including GSK.

Adding an immune checkpoint inhibitor to platinum-based chemotherapy resulted in a more than 1-year gain in median overall survival for women with primary advanced or recurrent endometrial cancer.

The benefit of the combination of the programmed death protein 1 (PD-1) inhibitor dostarlimab (Jemperli) and chemotherapy was even more pronounced among patients with DNA mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) tumors.

These results, from the second interim analysis of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial, were cheered by audience members when they were reported at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer, held in San Diego, California.

“Overall survival benefit to the addition of PD-1 inhibitor to chemotherapy upfront for patients with advanced and recurrent MSI-high endometrial cancer: SOLD!” said invited discussant Gini Fleming, medical director of gynecologic oncology at the University of Chicago.

“I think this is a huge win for our patients. It’s something that none of us have seen before over many years of working with endometrial cancer and should be incorporated into everybody’s practice as of yesterday,” she said.

Continued Improvement

Results from the first interim analysis of the trial showed that dostarlimab and chemotherapy significantly improved progression-free survival (PFS) in the dMMR/MSI-H population, and there was an early trend toward improved overall survival, compared with chemotherapy plus placebo.

As Matthew A. Powell, MD from Washington University School of Medicine in Saint Louis, Missouri reported at SGO 2024, that early trend has become an undeniable survival advantage.

At a median follow-up of 37.2 months, the median overall survival was 44.6 months for patients randomized to the combination, compared with 28.2 months for those assigned to chemotherapy plus placebo.

The respective 3-year overall survival (OS) rates were 54.9% and 42.9%, translating into a hazard ratio (HR) for death with dostarlimab/chemotherapy of 0.69 (P = .002).

Among the subset of patients with dMMR/MSI-H tumors the survival benefit conferred by the combination was even greater, with median OS not reached in the dostarlimab group vs 31.4 months in the chemotherapy-alone arm, with respective 3-year OS rates of 78% and 46%. This difference translated into a HR for death with the combination of 0.32 (P = .0002) for patients with deficient mismatch-repair cancers.

“Dostarlimab plus carboplatin-paclitaxel chemotherapy demonstrated statistically significant and clinically meaningful overall survival improvements in the overall population, a substantial unprecedented overall survival benefit in patients with defective mismatch-repair tumors, and a clinically meaningful; 7-month improvement in the OS difference in patients with proficient mismatch-repair tumors,” Dr. Powell said.

RUBY Details

The trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m² of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or dostarlimab placebo every 6 weeks for up to 3 years.

Within the cohort, 118 patients (23.9%) had dMMR/MSI-H tumors.

At the time of the first interim analysis the estimated progression-free survival at 24 months in the dMMR–MSI-H subgroup was 61.4% in the dostarlimab group vs 15.7 in the placebo group (HR for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < .001).

A prespecified exploratory analysis of progression-free survival in proficient MMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.

Overall survival at that time also favored dostarlimab, although it was only mature for 33% of the population. But at 24 months, OS rates were 71.3% vs 56.0% among placebo recipients; this difference approached but did not reach statistical significance.

The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR/MSS population.

The most common adverse events observed were nausea, alopecia, and fatigue. Grade 3 and higher adverse events at the most recent follow-up were more frequent in the dostarlimab group than in the placebo group (72.2% vs 60.2%).

“Importantly, safety was maintained” at the second interim analysis, Dr. Powell said.

“No new safety signals were noted, no new deaths related to therapy were noted with the subsequent 1-year additional analysis time,” he said.

What’s Next?

Dr. Fleming reviewed potential strategies for further improving care of patients with advanced or recurrent endometrial cancer during her discussion.

“What are the next directions for patients with MSI-high disease? Well, obviously could we use immune checkpoint inhibitors without chemotherapy and not compromise results? There are two ongoing trials or trials that we’re awaiting results of that have compared single-agent immune checkpoint inhibitor to just chemotherapy in mismatch repair-deficient advanced disease, and hopefully we can extrapolate from these trials to determine if this might be a more patient-friendly and equally effective strategy, but we don’t yet know,” she said.

Dr. Fleming also noted that ongoing or planned clinical trials will address questions about potential options for patients with MSI-H tumors whose disease progresses on frontline chemotherapy and immunotherapy. Other trials are assessing whether combining radiotherapy with checkpoint inhibitors will be effective in treating patients with earlier-stage tumors, or whether the addition of a PARP inhibitor might offer additional benefit for these patients.

“Immune checkpoint inhibitor should be given first line to patients with advanced/recurrent microsatellite [instability] endometrial cancer, and they should be considered as front line in patients with microsatellite stable disease. At this point, unfortunately, we have no reasonable predictive factors to know which of those patients with microsatellite stable disease will truly benefit. Multiple other agents are being tested in this setting, and will hopefully prove useful in subgroups,” she said.

The study is funded by GlaxoSmithKline. Dr. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. Dr. Fleming reports serving as an institutional principal investigator for trials sponsored by multiple companies, not including GSK.

Adding an immune checkpoint inhibitor to platinum-based chemotherapy resulted in a more than 1-year gain in median overall survival for women with primary advanced or recurrent endometrial cancer.

The benefit of the combination of the programmed death protein 1 (PD-1) inhibitor dostarlimab (Jemperli) and chemotherapy was even more pronounced among patients with DNA mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) tumors.

These results, from the second interim analysis of the phase 3 ENGOT-EN6-NSGO/GOG-3031/RUBY trial, were cheered by audience members when they were reported at the Society of Gynecologic Oncology (SGO)’s Annual Meeting on Women’s Cancer, held in San Diego, California.

“Overall survival benefit to the addition of PD-1 inhibitor to chemotherapy upfront for patients with advanced and recurrent MSI-high endometrial cancer: SOLD!” said invited discussant Gini Fleming, medical director of gynecologic oncology at the University of Chicago.

“I think this is a huge win for our patients. It’s something that none of us have seen before over many years of working with endometrial cancer and should be incorporated into everybody’s practice as of yesterday,” she said.

Continued Improvement

Results from the first interim analysis of the trial showed that dostarlimab and chemotherapy significantly improved progression-free survival (PFS) in the dMMR/MSI-H population, and there was an early trend toward improved overall survival, compared with chemotherapy plus placebo.

As Matthew A. Powell, MD from Washington University School of Medicine in Saint Louis, Missouri reported at SGO 2024, that early trend has become an undeniable survival advantage.

At a median follow-up of 37.2 months, the median overall survival was 44.6 months for patients randomized to the combination, compared with 28.2 months for those assigned to chemotherapy plus placebo.

The respective 3-year overall survival (OS) rates were 54.9% and 42.9%, translating into a hazard ratio (HR) for death with dostarlimab/chemotherapy of 0.69 (P = .002).

Among the subset of patients with dMMR/MSI-H tumors the survival benefit conferred by the combination was even greater, with median OS not reached in the dostarlimab group vs 31.4 months in the chemotherapy-alone arm, with respective 3-year OS rates of 78% and 46%. This difference translated into a HR for death with the combination of 0.32 (P = .0002) for patients with deficient mismatch-repair cancers.

“Dostarlimab plus carboplatin-paclitaxel chemotherapy demonstrated statistically significant and clinically meaningful overall survival improvements in the overall population, a substantial unprecedented overall survival benefit in patients with defective mismatch-repair tumors, and a clinically meaningful; 7-month improvement in the OS difference in patients with proficient mismatch-repair tumors,” Dr. Powell said.

RUBY Details

The trial was conducted in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer who received first-line treatment with standard chemotherapy with carboplatin (area under the concentration–time curve, 5 mg/mL per minute) and paclitaxel (175 mg/m² of body surface area), every 3 weeks (six cycles). They were also randomized to receive either dostarlimab (1000 mg) or dostarlimab placebo every 6 weeks for up to 3 years.

Within the cohort, 118 patients (23.9%) had dMMR/MSI-H tumors.

At the time of the first interim analysis the estimated progression-free survival at 24 months in the dMMR–MSI-H subgroup was 61.4% in the dostarlimab group vs 15.7 in the placebo group (HR for progression or death, 0.28; P < .001). For the entire cohort, progression-free survival at 24 months was 36.1% vs 18.1% (HR, 0.64; P < .001).

A prespecified exploratory analysis of progression-free survival in proficient MMR, microsatellite stable (MSS) patients was also done, and a clinically relevant benefit was observed.

Overall survival at that time also favored dostarlimab, although it was only mature for 33% of the population. But at 24 months, OS rates were 71.3% vs 56.0% among placebo recipients; this difference approached but did not reach statistical significance.

The overall response rate in the dMMR–MSI-H population vs the placebo group was 77.6% vs 69%, respectively, and 68.1% and 63.4% in the pMMR/MSS population.

The most common adverse events observed were nausea, alopecia, and fatigue. Grade 3 and higher adverse events at the most recent follow-up were more frequent in the dostarlimab group than in the placebo group (72.2% vs 60.2%).

“Importantly, safety was maintained” at the second interim analysis, Dr. Powell said.

“No new safety signals were noted, no new deaths related to therapy were noted with the subsequent 1-year additional analysis time,” he said.

What’s Next?

Dr. Fleming reviewed potential strategies for further improving care of patients with advanced or recurrent endometrial cancer during her discussion.

“What are the next directions for patients with MSI-high disease? Well, obviously could we use immune checkpoint inhibitors without chemotherapy and not compromise results? There are two ongoing trials or trials that we’re awaiting results of that have compared single-agent immune checkpoint inhibitor to just chemotherapy in mismatch repair-deficient advanced disease, and hopefully we can extrapolate from these trials to determine if this might be a more patient-friendly and equally effective strategy, but we don’t yet know,” she said.

Dr. Fleming also noted that ongoing or planned clinical trials will address questions about potential options for patients with MSI-H tumors whose disease progresses on frontline chemotherapy and immunotherapy. Other trials are assessing whether combining radiotherapy with checkpoint inhibitors will be effective in treating patients with earlier-stage tumors, or whether the addition of a PARP inhibitor might offer additional benefit for these patients.

“Immune checkpoint inhibitor should be given first line to patients with advanced/recurrent microsatellite [instability] endometrial cancer, and they should be considered as front line in patients with microsatellite stable disease. At this point, unfortunately, we have no reasonable predictive factors to know which of those patients with microsatellite stable disease will truly benefit. Multiple other agents are being tested in this setting, and will hopefully prove useful in subgroups,” she said.

The study is funded by GlaxoSmithKline. Dr. Powell reports grants/research support from GSK and honoraria/consultation fees from AstraZeneca, Clovis Oncology, Eisai, GSK, Immunogen, and Merck. Dr. Fleming reports serving as an institutional principal investigator for trials sponsored by multiple companies, not including GSK.

Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the safety of combining these newer agents alongside radiotherapy.

One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.

If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.

Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.

Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.

1. Immunotherapy plus radiotherapy likely safe but evidence is limited

Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.

The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.

Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.

Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.

2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others

CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.

“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.

However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.

Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.

“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.

The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.

3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting

PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.

But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.

One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.

“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.

Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”

But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.

4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy

Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.

For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”

ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.

5. Combining older HER2-targeted drugs and radiotherapy generally safe

The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.

One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.

For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.

The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.

As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.

Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.

A version of this article appeared on Medscape.com.

Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the safety of combining these newer agents alongside radiotherapy.

One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.

If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.

Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.

Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.

1. Immunotherapy plus radiotherapy likely safe but evidence is limited

Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.

The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.

Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.

Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.

2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others

CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.

“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.

However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.

Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.

“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.

The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.

3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting

PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.

But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.

One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.

“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.

Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”

But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.

4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy

Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.

For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”

ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.

5. Combining older HER2-targeted drugs and radiotherapy generally safe

The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.

One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.

For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.

The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.

As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.

Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.

A version of this article appeared on Medscape.com.

Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the safety of combining these newer agents alongside radiotherapy.

One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.

If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.

Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.

Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.

1. Immunotherapy plus radiotherapy likely safe but evidence is limited

Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.

The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.

Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.

Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.

2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others

CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.

“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.

However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.

Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.

“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.

The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.

3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting

PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.

But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.

One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.

“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.

Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”

But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.

4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy

Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.

For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”

ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.

5. Combining older HER2-targeted drugs and radiotherapy generally safe

The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.

One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.

For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.

The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.

As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.

Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.

A version of this article appeared on Medscape.com.

As US medical school graduates learned Friday, March 15, where they would spend their residencies, new Match Day 2024 data showed a loss of interest in pediatrics, whereas emergency medicine regained popularity after concern over last year’s unfilled positions.

Hospitals and medical groups offered 41,503 residency positions in 2024, a 3% increase from last year, according to the data released by the National Resident Matching Program. 

Emergency medicine reversed its recent decline, with only 135 unfilled positions, a 13.9% improvement over last year.

But though the number of pediatric residency slots increased slightly from last year, 8% of available positions remained unfilled in 2024 compared with about 3% last year. 

Physician leaders and policymakers alike pay keen attention to Match Day results because they can signal future shortages in certain specialties, including primary care. Unfilled slots also can raise concerns over too many residency programs in a specialty. 

Medical students’ interest in pediatrics continues to decline in part because it pays less than other specialties, Bryan Carmody, MD, MPH, a pediatric nephrologist known for his medical school commentaries, told this news organization. The number of pediatric applicants from US medical schools peaked in 2015 and has fallen since, he said.

“There’s been a lot of soul searching ... this week, with people speculating about lots of (reasons),” Dr. Carmody said. “I don’t think it’s even debt. You can look at the number of unfilled positions, and it correlates with the expected earning potential of those specialties.” 

Family medicine, for example, filled about 88% of its positions this year.

Ob.gyn. residencies retained their popularity despite concerns over abortion and reproductive health rights in many states. The specialty filled 99.6% of its positions, a very slight improvement over last year’s 99% rate. 

Though ob.gyn. applicants might prefer programs in states where there are more liberal policies around reproductive health, many won’t be in a position where they can choose that because of the limited number of ob.gyn. slots, Dr. Carmody said.

Unfilled residency slots likely will be filled through the Supplemental Offer and Acceptance Program (SOAP). Applicants who did not match in the first round participate in SOAP for one of the 2562 positions in 787 programs that went unfilled after the matching algorithm was processed. A total of 2575 positions were placed in SOAP, including positions in programs that did not participate in the algorithm phase of the process. There were 83 fewer positions in SOAP in 2024, a decrease of 3.1% compared with last year’s Match. More detailed data on SOAP results will be released later this year.

A version of this article appeared on Medscape.com.

As US medical school graduates learned Friday, March 15, where they would spend their residencies, new Match Day 2024 data showed a loss of interest in pediatrics, whereas emergency medicine regained popularity after concern over last year’s unfilled positions.

Hospitals and medical groups offered 41,503 residency positions in 2024, a 3% increase from last year, according to the data released by the National Resident Matching Program. 

Emergency medicine reversed its recent decline, with only 135 unfilled positions, a 13.9% improvement over last year.

But though the number of pediatric residency slots increased slightly from last year, 8% of available positions remained unfilled in 2024 compared with about 3% last year. 

Physician leaders and policymakers alike pay keen attention to Match Day results because they can signal future shortages in certain specialties, including primary care. Unfilled slots also can raise concerns over too many residency programs in a specialty. 

Medical students’ interest in pediatrics continues to decline in part because it pays less than other specialties, Bryan Carmody, MD, MPH, a pediatric nephrologist known for his medical school commentaries, told this news organization. The number of pediatric applicants from US medical schools peaked in 2015 and has fallen since, he said.

“There’s been a lot of soul searching ... this week, with people speculating about lots of (reasons),” Dr. Carmody said. “I don’t think it’s even debt. You can look at the number of unfilled positions, and it correlates with the expected earning potential of those specialties.” 

Family medicine, for example, filled about 88% of its positions this year.

Ob.gyn. residencies retained their popularity despite concerns over abortion and reproductive health rights in many states. The specialty filled 99.6% of its positions, a very slight improvement over last year’s 99% rate. 

Though ob.gyn. applicants might prefer programs in states where there are more liberal policies around reproductive health, many won’t be in a position where they can choose that because of the limited number of ob.gyn. slots, Dr. Carmody said.

Unfilled residency slots likely will be filled through the Supplemental Offer and Acceptance Program (SOAP). Applicants who did not match in the first round participate in SOAP for one of the 2562 positions in 787 programs that went unfilled after the matching algorithm was processed. A total of 2575 positions were placed in SOAP, including positions in programs that did not participate in the algorithm phase of the process. There were 83 fewer positions in SOAP in 2024, a decrease of 3.1% compared with last year’s Match. More detailed data on SOAP results will be released later this year.

A version of this article appeared on Medscape.com.

As US medical school graduates learned Friday, March 15, where they would spend their residencies, new Match Day 2024 data showed a loss of interest in pediatrics, whereas emergency medicine regained popularity after concern over last year’s unfilled positions.

Hospitals and medical groups offered 41,503 residency positions in 2024, a 3% increase from last year, according to the data released by the National Resident Matching Program. 

Emergency medicine reversed its recent decline, with only 135 unfilled positions, a 13.9% improvement over last year.

But though the number of pediatric residency slots increased slightly from last year, 8% of available positions remained unfilled in 2024 compared with about 3% last year. 

Physician leaders and policymakers alike pay keen attention to Match Day results because they can signal future shortages in certain specialties, including primary care. Unfilled slots also can raise concerns over too many residency programs in a specialty. 

Medical students’ interest in pediatrics continues to decline in part because it pays less than other specialties, Bryan Carmody, MD, MPH, a pediatric nephrologist known for his medical school commentaries, told this news organization. The number of pediatric applicants from US medical schools peaked in 2015 and has fallen since, he said.

“There’s been a lot of soul searching ... this week, with people speculating about lots of (reasons),” Dr. Carmody said. “I don’t think it’s even debt. You can look at the number of unfilled positions, and it correlates with the expected earning potential of those specialties.” 

Family medicine, for example, filled about 88% of its positions this year.

Ob.gyn. residencies retained their popularity despite concerns over abortion and reproductive health rights in many states. The specialty filled 99.6% of its positions, a very slight improvement over last year’s 99% rate. 

Though ob.gyn. applicants might prefer programs in states where there are more liberal policies around reproductive health, many won’t be in a position where they can choose that because of the limited number of ob.gyn. slots, Dr. Carmody said.

Unfilled residency slots likely will be filled through the Supplemental Offer and Acceptance Program (SOAP). Applicants who did not match in the first round participate in SOAP for one of the 2562 positions in 787 programs that went unfilled after the matching algorithm was processed. A total of 2575 positions were placed in SOAP, including positions in programs that did not participate in the algorithm phase of the process. There were 83 fewer positions in SOAP in 2024, a decrease of 3.1% compared with last year’s Match. More detailed data on SOAP results will be released later this year.

A version of this article appeared on Medscape.com.

With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.

More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.

And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.

Many of today’s healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. “An entire generation of physicians — including myself — did not see any cases until we were well out of our training,” Dr. Park reported. “We’re really playing catch-up.”
 

A Centuries-Old Ailment

Dr. Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: “Test, test, test.”

Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Dr. Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.

Following the CDC’s new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. “If you can’t account for new symptoms in a sexually active patient, order a test,” said Dr. Park.
 

Complicated Cases

The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. “When you don’t have to deal with something for a while, you forget how to deal with it,” he added.

At CROI, Dr. Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient’s antigen titers are being “unruly.”

With potential ocular or otic syphilis, you shouldn’t wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. “You don’t want to dilly-dally with those conditions,” Dr. Ghanem said.

Closely monitoring a patient’s rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers “don’t do what you think they should be doing” and fail to decline or even go up after treatment.

“You don’t know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab,” he said. “It can be challenging to interpret.”

To decipher confusing test results, Dr. Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. “Based on the answers, you can determine what the most rational approach to treatment would be,” he shared.
 

Drug Shortages

Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.

Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.

In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.

The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. “Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy,” Dr. Ghanem said.
 

A version of this article appeared on Medscape.com.

With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.

More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.

And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.

Many of today’s healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. “An entire generation of physicians — including myself — did not see any cases until we were well out of our training,” Dr. Park reported. “We’re really playing catch-up.”
 

A Centuries-Old Ailment

Dr. Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: “Test, test, test.”

Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Dr. Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.

Following the CDC’s new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. “If you can’t account for new symptoms in a sexually active patient, order a test,” said Dr. Park.
 

Complicated Cases

The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. “When you don’t have to deal with something for a while, you forget how to deal with it,” he added.

At CROI, Dr. Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient’s antigen titers are being “unruly.”

With potential ocular or otic syphilis, you shouldn’t wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. “You don’t want to dilly-dally with those conditions,” Dr. Ghanem said.

Closely monitoring a patient’s rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers “don’t do what you think they should be doing” and fail to decline or even go up after treatment.

“You don’t know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab,” he said. “It can be challenging to interpret.”

To decipher confusing test results, Dr. Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. “Based on the answers, you can determine what the most rational approach to treatment would be,” he shared.
 

Drug Shortages

Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.

Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.

In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.

The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. “Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy,” Dr. Ghanem said.
 

A version of this article appeared on Medscape.com.

With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.

More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.

And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.

Many of today’s healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. “An entire generation of physicians — including myself — did not see any cases until we were well out of our training,” Dr. Park reported. “We’re really playing catch-up.”
 

A Centuries-Old Ailment

Dr. Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: “Test, test, test.”

Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Dr. Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.

Following the CDC’s new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. “If you can’t account for new symptoms in a sexually active patient, order a test,” said Dr. Park.
 

Complicated Cases

The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. “When you don’t have to deal with something for a while, you forget how to deal with it,” he added.

At CROI, Dr. Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient’s antigen titers are being “unruly.”

With potential ocular or otic syphilis, you shouldn’t wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. “You don’t want to dilly-dally with those conditions,” Dr. Ghanem said.

Closely monitoring a patient’s rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers “don’t do what you think they should be doing” and fail to decline or even go up after treatment.

“You don’t know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab,” he said. “It can be challenging to interpret.”

To decipher confusing test results, Dr. Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. “Based on the answers, you can determine what the most rational approach to treatment would be,” he shared.
 

Drug Shortages

Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.

Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.

In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.

The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. “Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy,” Dr. Ghanem said.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A new study published in JAMA Network Open showed that an intervention including cognitive behavioral therapy improved the quality of life for women with overactive bladder (OAB).

METHODOLOGY:

• A total of 79 women with moderate to severe OAB were randomized to the control group or the intervention, which was composed of four 30-minute sessions using strategies including cognitive behavioral therapy (CBT).
• The first and second sessions provided education on OAB and CBT, lifestyle modifications such as limiting coffee intake, pelvic floor muscle training, and introduced exposure training.
• The third and fourth sessions continued exposure and pelvic floor muscle training and education on relapse prevention.
• Researchers assessed outcomes using the health-related quality of life (HRQOL), in which participants answered questions regarding their degree of distress, emotions, and physical and social limitations related to OAB symptoms.

TAKEAWAY:

• Participants who received the intervention on average improved in their HRQOL score by 12.6 points higher than those in the control group (usual care) from baseline to week 13 (between-group difference estimate, 12.6 [95% CI, 6.6-18.6] points; P < .001).
• The average age of participants was 63.5 years, and more than 87% of women in each group had moderate OAB.
• Patient-reported improvement and satisfaction scores were also more improved in the intervention group than in the control group; most participants in both groups had no change in the pharmacotherapy during the trial.

IN PRACTICE:

Urologists and other primary care clinicians who treat women with OAB may consider a multicomponent intervention that includes cognitive components and exposure-based bladder training or could refer to a cognitive behavioral therapist or pelvic floor physical therapist experienced in these techniques.

SOURCE:

Satoshi Funada, MD, PhD, and Takashi Kobayashi, MD, PhD, both with the Department of Urology at Kyoto University Graduate School of Medicine in Kyoto, Japan, are the corresponding authors. The study was published online in JAMA Network Open.

LIMITATIONS:

The trial was open label, and the use of a waiting list control group is known to produce greater differences between the two groups. The trial included patients both taking and not taking medication for OAB. The sample size was also relatively small, and the intervention was performed by a single clinician, possibly limiting the generalizability of results.

DISCLOSURES:

The study was funded by the Japan Society for the Promotion of Science (JSPS). Various study authors reported receiving grants from the Pfizer Health Research Foundation, AstraZeneca, and JSPS. Other study authors reported receiving personal fees from Eisai, Sawai Pharmaceutical, Statcom, and others. One author reported pending patents for intellectual properties for the Kokoro app licensed to Mitsubishi Tanabe Pharma.

A version of this article appeared on Medscape.com.

TOPLINE:

A new study published in JAMA Network Open showed that an intervention including cognitive behavioral therapy improved the quality of life for women with overactive bladder (OAB).

METHODOLOGY:

• A total of 79 women with moderate to severe OAB were randomized to the control group or the intervention, which was composed of four 30-minute sessions using strategies including cognitive behavioral therapy (CBT).
• The first and second sessions provided education on OAB and CBT, lifestyle modifications such as limiting coffee intake, pelvic floor muscle training, and introduced exposure training.
• The third and fourth sessions continued exposure and pelvic floor muscle training and education on relapse prevention.
• Researchers assessed outcomes using the health-related quality of life (HRQOL), in which participants answered questions regarding their degree of distress, emotions, and physical and social limitations related to OAB symptoms.

TAKEAWAY:

• Participants who received the intervention on average improved in their HRQOL score by 12.6 points higher than those in the control group (usual care) from baseline to week 13 (between-group difference estimate, 12.6 [95% CI, 6.6-18.6] points; P < .001).
• The average age of participants was 63.5 years, and more than 87% of women in each group had moderate OAB.
• Patient-reported improvement and satisfaction scores were also more improved in the intervention group than in the control group; most participants in both groups had no change in the pharmacotherapy during the trial.

IN PRACTICE:

Urologists and other primary care clinicians who treat women with OAB may consider a multicomponent intervention that includes cognitive components and exposure-based bladder training or could refer to a cognitive behavioral therapist or pelvic floor physical therapist experienced in these techniques.

SOURCE:

Satoshi Funada, MD, PhD, and Takashi Kobayashi, MD, PhD, both with the Department of Urology at Kyoto University Graduate School of Medicine in Kyoto, Japan, are the corresponding authors. The study was published online in JAMA Network Open.

LIMITATIONS:

The trial was open label, and the use of a waiting list control group is known to produce greater differences between the two groups. The trial included patients both taking and not taking medication for OAB. The sample size was also relatively small, and the intervention was performed by a single clinician, possibly limiting the generalizability of results.

DISCLOSURES:

The study was funded by the Japan Society for the Promotion of Science (JSPS). Various study authors reported receiving grants from the Pfizer Health Research Foundation, AstraZeneca, and JSPS. Other study authors reported receiving personal fees from Eisai, Sawai Pharmaceutical, Statcom, and others. One author reported pending patents for intellectual properties for the Kokoro app licensed to Mitsubishi Tanabe Pharma.

A version of this article appeared on Medscape.com.

TOPLINE:

A new study published in JAMA Network Open showed that an intervention including cognitive behavioral therapy improved the quality of life for women with overactive bladder (OAB).

METHODOLOGY:

• A total of 79 women with moderate to severe OAB were randomized to the control group or the intervention, which was composed of four 30-minute sessions using strategies including cognitive behavioral therapy (CBT).
• The first and second sessions provided education on OAB and CBT, lifestyle modifications such as limiting coffee intake, pelvic floor muscle training, and introduced exposure training.
• The third and fourth sessions continued exposure and pelvic floor muscle training and education on relapse prevention.
• Researchers assessed outcomes using the health-related quality of life (HRQOL), in which participants answered questions regarding their degree of distress, emotions, and physical and social limitations related to OAB symptoms.

TAKEAWAY:

• Participants who received the intervention on average improved in their HRQOL score by 12.6 points higher than those in the control group (usual care) from baseline to week 13 (between-group difference estimate, 12.6 [95% CI, 6.6-18.6] points; P < .001).
• The average age of participants was 63.5 years, and more than 87% of women in each group had moderate OAB.
• Patient-reported improvement and satisfaction scores were also more improved in the intervention group than in the control group; most participants in both groups had no change in the pharmacotherapy during the trial.

IN PRACTICE:

Urologists and other primary care clinicians who treat women with OAB may consider a multicomponent intervention that includes cognitive components and exposure-based bladder training or could refer to a cognitive behavioral therapist or pelvic floor physical therapist experienced in these techniques.

SOURCE:

Satoshi Funada, MD, PhD, and Takashi Kobayashi, MD, PhD, both with the Department of Urology at Kyoto University Graduate School of Medicine in Kyoto, Japan, are the corresponding authors. The study was published online in JAMA Network Open.

LIMITATIONS:

The trial was open label, and the use of a waiting list control group is known to produce greater differences between the two groups. The trial included patients both taking and not taking medication for OAB. The sample size was also relatively small, and the intervention was performed by a single clinician, possibly limiting the generalizability of results.

DISCLOSURES:

The study was funded by the Japan Society for the Promotion of Science (JSPS). Various study authors reported receiving grants from the Pfizer Health Research Foundation, AstraZeneca, and JSPS. Other study authors reported receiving personal fees from Eisai, Sawai Pharmaceutical, Statcom, and others. One author reported pending patents for intellectual properties for the Kokoro app licensed to Mitsubishi Tanabe Pharma.

A version of this article appeared on Medscape.com.

A phase 3 trial of a maternal vaccine candidate for respiratory syncytial virus (RSV) has been stopped early because the risk for preterm births is higher in the candidate vaccine group than in the placebo group.

By the time enrollment was stopped on February 25, 2022 because of the safety signal of preterm birth, 5328 pregnant women had been vaccinated, about half of the intended 10,000 enrollees. Of these, 3557 received the candidate vaccine RSV prefusion F protein–based maternal vaccine, and another 1771 received a placebo.

Data from the trial, sponsored by GSK, were immediately made available when recruitment and vaccination were stopped, and investigation of the preterm birth risk followed. Results of that analysis, led by Ilse Dieussaert, IR, vice president for vaccine development at GSK in Wavre, Belgium, are published online on March 13 in The New England Journal of Medicine. 

“We have discontinued our work on this RSV maternal candidate vaccine, and we are closing out all ongoing trials with the exception of the MAT-015 follow-on study to monitor subsequent pregnancies,” a GSK spokesperson said in an interview.

The trial was conducted in pregnant women aged 18-49 years to assess the efficacy and safety of the vaccine. The women were randomly assigned 2:1 to receive the candidate vaccine or placebo between 24 and 34 weeks’ gestation.
 

Preterm Births

The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract infection in infants from birth to 6 months and safety in infants from birth to 12 months.

According to the data, preterm birth occurred in 6.8% of the infants in the vaccine group and in 4.9% of those in the placebo group (relative risk [RR], 1.37; 95% CI, 1.08-1.74; P = .01). Neonatal death occurred in 0.4% in the vaccine group and 0.2% in the placebo group (RR, 2.16; 95% CI, 0.62-7.56; P = .23).

To date, only one RSV vaccine (Abrysvo, Pfizer) has been approved for use during pregnancy to protect infants from RSV-associated lower respiratory tract infection.

“It was a very big deal that this trial was stopped, and the new candidate won’t get approval.” said Aaron E. Glatt, MD, chair of the Department of Medicine and chief of Infectious Diseases and Hospital Epidemiologist at Mount Sinai South Nassau in Oceanside, New York.
 

Only One RSV Vaccine Approved in Pregnancy

Dr. Glatt pointed out the GSK vaccine is like the maternal vaccine that did get approved. “The data clearly show that there was a slight but increased risk in preterm labor,” Dr. Glatt said, “and while not as clearly shown, there was an increase in neonatal death in the group of very small numbers, but any neonatal death is of concern.”

The implications were disturbing, he added, “You’re giving this vaccine to prevent neonatal death.” Though the Pfizer vaccine that was granted approval had a very slight increase in premature birth, the risk wasn’t statistically significant, he pointed out, “and it showed similar benefits in preventing neonatal illness, which can be fatal.”

Dr. Glatt said that there is still a lingering concern with the approved vaccine, and he explained that most clinicians will give it closer to the end of the recommended time window of 34 weeks. “This way, even if there is a slight increase in premature term labor, you’re probably not going to have a serious outcome because the baby will be far enough along.”

A difference in the incidence of preterm birth between the experimental vaccine and placebo groups was predominantly found in low- and middle-income countries, according to Dieussaert’s team, “where approximately 50% of the trial population was enrolled and where the medical need for maternal RSV vaccines is the greatest.”

The RR was 1.56 (95% CI, 1.17-2.10) for low- and middle-income countries and 1.04 (95% CI, 0.68-1.58) for high-income countries. 

“If a smaller percentage of participants from low- and middle-income countries had been enrolled in our trial, the RR for preterm birth in the vaccine group as compared with the placebo group might have been reduced in the overall trial population,” they reported.

The authors explained that the data do not reveal the cause of the higher risk for preterm birth in the vaccine group.

“We do not know what caused the signal,” the company’s spokesperson added. “GSK completed all the necessary steps of product development including preclinical toxicology studies and clinical studies in nonpregnant women prior to starting the studies in pregnant women. There were no safety signals identified in any of the earlier parts of the clinical testing. There have been no safety signals identified in the other phase 3 trials for this vaccine candidate.”

Researchers did not find a correlation between preterm births in the treatment vs control groups with gestational age at the time of vaccination or with particular vaccine clinical trial material lots, race, ethnicity, maternal smoking, alcohol consumption, body mass index, or time between study vaccination and delivery, the GSK spokesperson said.

The spokesperson noted that the halted vaccine is different from GSK’s currently approved adjuvanted RSV vaccine (Arexvy) for adults aged 60 years or older.

What’s Next for Other Vaccines

Maternal vaccines have been effective in preventing other diseases in infants, such as tetanus, influenza, and pertussis, but RSV is a very hard virus to make a vaccine for, Dr. Glatt shared.

The need is great to have more than one option for a maternal RSV vaccine, he added, to address any potential supply concerns.

“People have to realize how serious RSV can be in infants,” he said. “It can be a fatal disease. This can be a serious illness even in healthy children.”

A version of this article appeared on Medscape.com.

A phase 3 trial of a maternal vaccine candidate for respiratory syncytial virus (RSV) has been stopped early because the risk for preterm births is higher in the candidate vaccine group than in the placebo group.

By the time enrollment was stopped on February 25, 2022 because of the safety signal of preterm birth, 5328 pregnant women had been vaccinated, about half of the intended 10,000 enrollees. Of these, 3557 received the candidate vaccine RSV prefusion F protein–based maternal vaccine, and another 1771 received a placebo.

Data from the trial, sponsored by GSK, were immediately made available when recruitment and vaccination were stopped, and investigation of the preterm birth risk followed. Results of that analysis, led by Ilse Dieussaert, IR, vice president for vaccine development at GSK in Wavre, Belgium, are published online on March 13 in The New England Journal of Medicine. 

“We have discontinued our work on this RSV maternal candidate vaccine, and we are closing out all ongoing trials with the exception of the MAT-015 follow-on study to monitor subsequent pregnancies,” a GSK spokesperson said in an interview.

The trial was conducted in pregnant women aged 18-49 years to assess the efficacy and safety of the vaccine. The women were randomly assigned 2:1 to receive the candidate vaccine or placebo between 24 and 34 weeks’ gestation.
 

Preterm Births

The primary outcomes were any or severe medically assessed RSV-associated lower respiratory tract infection in infants from birth to 6 months and safety in infants from birth to 12 months.

According to the data, preterm birth occurred in 6.8% of the infants in the vaccine group and in 4.9% of those in the placebo group (relative risk [RR], 1.37; 95% CI, 1.08-1.74; P = .01). Neonatal death occurred in 0.4% in the vaccine group and 0.2% in the placebo group (RR, 2.16; 95% CI, 0.62-7.56; P = .23).

To date, only one RSV vaccine (Abrysvo, Pfizer) has been approved for use during pregnancy to protect infants from RSV-associated lower respiratory tract infection.

“It was a very big deal that this trial was stopped, and the new candidate won’t get approval.” said Aaron E. Glatt, MD, chair of the Department of Medicine and chief of Infectious Diseases and Hospital Epidemiologist at Mount Sinai South Nassau in Oceanside, New York.
 

Only One RSV Vaccine Approved in Pregnancy

Dr. Glatt pointed out the GSK vaccine is like the maternal vaccine that did get approved. “The data clearly show that there was a slight but increased risk in preterm labor,” Dr. Glatt said, “and while not as clearly shown, there was an increase in neonatal death in the group of very small numbers, but any neonatal death is of concern.”

The implications were disturbing, he added, “You’re giving this vaccine to prevent neonatal death.” Though the Pfizer vaccine that was granted approval had a very slight increase in premature birth, the risk wasn’t statistically significant, he pointed out, “and it showed similar benefits in preventing neonatal illness, which can be fatal.”

Dr. Glatt said that there is still a lingering concern with the approved vaccine, and he explained that most clinicians will give it closer to the end of the recommended time window of 34 weeks. “This way, even if there is a slight increase in premature term labor, you’re probably not going to have a serious outcome because the baby will be far enough along.”

A difference in the incidence of preterm birth between the experimental vaccine and placebo groups was predominantly found in low- and middle-income countries, according to Dieussaert’s team, “where approximately 50% of the trial population was enrolled and where the medical need for maternal RSV vaccines is the greatest.”

The RR was 1.56 (95% CI, 1.17-2.10) for low- and middle-income countries and 1.04 (95% CI, 0.68-1.58) for high-income countries. 

“If a smaller percentage of participants from low- and middle-income countries had been enrolled in our trial, the RR for preterm birth in the vaccine group as compared with the placebo group might have been reduced in the overall trial population,” they reported.

The authors explained that the data do not reveal the cause of the higher risk for preterm birth in the vaccine group.

“We do not know what caused the signal,” the company’s spokesperson added. “GSK completed all the necessary steps of product development including preclinical toxicology studies and clinical studies in nonpregnant women prior to starting the studies in pregnant women. There were no safety signals identified in any of the earlier parts of the clinical testing. There have been no safety signals identified in the other phase 3 trials for this vaccine candidate.”

Researchers did not find a correlation between preterm births in the treatment vs control groups with gestational age at the time of vaccination or with particular vaccine clinical trial material lots, race, ethnicity, maternal smoking, alcohol consumption, body mass index, or time between study vaccination and delivery, the GSK spokesperson said.

The spokesperson noted that the halted vaccine is different from GSK’s currently approved adjuvanted RSV vaccine (Arexvy) for adults aged 60 years or older.

What’s Next for Other Vaccines

Maternal vaccines have been effective in preventing other diseases in infants, such as tetanus, influenza, and pertussis, but RSV is a very hard virus to make a vaccine for, Dr. Glatt shared.