Survival from pediatric acute lymphoblastic leukemia (ALL) in a Mexican hospital improved significantly through a close cross-border collaboration with a nearby U.S. center that provided training and improved access.

A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.

Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.

For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.

“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.

The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.

Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.

“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
 

‘Huge survival gap’

“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.

This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.

“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.

Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”

She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”

Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”

Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.

However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.

“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
 

Study details

Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.

In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.

The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.

“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.

This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.

Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.

Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.

Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
 

Impact of the collaboration

To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.

The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.

Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”

Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.

“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.

The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.

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

Survival from pediatric acute lymphoblastic leukemia (ALL) in a Mexican hospital improved significantly through a close cross-border collaboration with a nearby U.S. center that provided training and improved access.

A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.

Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.

For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.

“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.

The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.

Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.

“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
 

‘Huge survival gap’

“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.

This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.

“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.

Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”

She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”

Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”

Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.

However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.

“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
 

Study details

Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.

In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.

The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.

“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.

This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.

Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.

Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.

Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
 

Impact of the collaboration

To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.

The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.

Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”

Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.

“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.

The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.

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

Survival from pediatric acute lymphoblastic leukemia (ALL) in a Mexican hospital improved significantly through a close cross-border collaboration with a nearby U.S. center that provided training and improved access.

A team from a hospital in San Diego combined a previously established training program from the World Health Organization with a new collaboration, which resulted in improvements in care standards and sustainability of care in a center in Tijuana, Mexico, just 23 miles away.

Implementation of the program in 2013 led to a significant 6% improvement in 5-year overall survival for children with ALL.

For patients at standard risk, 5-year overall survival increased from 73% to 100% after implementation of the program.

“This is really remarkable because this survival is the same as we have here in San Diego,” commented Paula Aristizabal, MD, MAS, a pediatric hematologist/oncologist at Rady Children’s Hospital, San Diego, at a press briefing before the annual meeting of the American Society of Clinical Oncology.

The findings show that “sustained improvements in cancer outcomes in low- and middle-income countries [LMICs] are feasible with innovative cross-border programs, particularly in borders that are shared” between a high- and low-income country, she commented. In other words, “it takes a village in both countries” to drive up standards.

Dr. Aristizabal also noted that the partnership will continue with a particularly focus on improving survival among patients with high-risk disease.

“We like to call it ‘twinning,’ because that means we are twins forever,” she said. “This is not a marriage that can be dissolved.”
 

‘Huge survival gap’

“The burden of childhood cancer has increased globally, but unfortunately, survival in low- and middle-income countries has not improved at the same level as in high-income countries,” Dr. Aristizabal commented.

This has resulted in a “huge survival gap” between high-income countries and the LMICs. ALL is now a leading cause of death among children in these countries, she commented.

“This study illustrates collaborative strategies that can be put into place today that could greatly improve outcomes for children with cancer globally,” commented Julie R. Gralow, MD, ASCO chief medical officer and executive vice president.

Speaking at the press conference, she added: “As I’ve heard Princess Dina Mired of Jordan say many times: ‘Your ZIP code should not determine if you survive cancer.’ ”

She said the differences in ALL survival between the United States and Mexico are an “example of children being so close in terms of proximity not having the same advantages.”

Also commenting, ASCO President Eric Winer, MD, from the Yale Cancer Center, New Haven, Conn., asked whether the proximity of the hospitals in San Diego and Tijuana “makes a difference, or do you think this is something that done ... at a distance?”

Dr. Aristizabal said that the proximity between the institutions “has been extremely helpful,” as they can go between hospitals in just 30 minutes.

However, “one of the things that we learned with COVID is that we can do a lot of things remotely,” she answered.

“Some of the projects that we started in Tijuana, through our collaboration with St. Jude Children’s Research Hospital, we have been able to implement in many other centers in Mexico,” she said.
 

Study details

Rady Children’s Hospital partnered with the public sector in Baja California, with the aim of improving outcomes in children’s cancer, she explained.

In 2008, the team collaborated with St. Jude Children’s Research Hospital, Memphis, to establish a training program in the Hospital General Tijuana in Tijuana that shared knowledge, technology, and organizational skills.

The team also consulted on clinical cases and set up education and research programs, all with the aim of building capacity and sustainability in Mexico.

“As the number of leukemia patients increased, we wanted to decrease depending on their international collaborators in the U.S. and ensure long-term sustainability,” Dr. Aristizabal explained.

This led in 2013 to the implementation of the WHO Framework for Action HSS training model, which has several components, including health service delivery.

Combined with the previously established model, the overall goals of the program were to improve health outcomes, systems efficiency, timely access to care, and social and financial risk protection.

Dr. Aristizabal said in an interview that this involved developing highly specific leukemia treatment guidelines, which have now gone through three iterations, as well as guidelines for supportive care.

Working with a local foundation, the team has also “focused on providing psychosocial support, nutritional support, a shelter for families that live 12-14 hours away from the pediatric cancer center, as well as food subsidies, trying to address financial toxicity and food insecurity in these families.”
 

Impact of the collaboration

To assess the impact of the WHO framework, the researchers conducted a study that involved 109 children with ALL who were treated at Hospital General Tijuana over the preimplementation phase in 2008-2012 and the postimplementation phase in 2013-2017.

The mean age of the patients was 7.04 years, and 50.4% were girls. The majority (67%) were classified as having high-risk disease.

Over the entire study period, the 5-year overall survival rate was 65%. Analysis revealed that between the pre- and postimplementation periods, 5-year overall survival increased from 59% to 65%, which Dr. Aristizabal described as “a significant improvement.”

Among high-risk patients, the improvement in 5-year survival between the pre- and postimplementation period went from 48% to 55%.

“This is an area for improvement,” Dr. Aristizabal said, “and we’re working on additional strategies to help improve survival for high-risk patients.

The study was funded by Rady Children’s Hospital, the Mexican Secretary of Health, and the Patronato Foundation. Dr. Aristizabal and coauthors reported no relevant financial relationships. Dr. Gralow reported relationships with Genentech and Roche. Dr. Winer reported relationships with Leap Therapeutics, Jounce Therapeutics, Carrick Therapeutics, and Genentech.

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

CHICAGO – Nearly all patients who were diverted from chemotherapy prior to surgery for HER2-positive early breast cancer survived without cancer recurrence for 3 years, according to new findings from a phase 2 trial.

The secondary primary endpoint results from the PHERgain study, presented at the annual meeting of the American Society of Clinical Oncology, provide more evidence to support a strategy that avoids chemotherapy as long as patients show signs of response to hormone therapy via PET scans. The results revealed that 98.8% (95% confidence interval, 96.3-100.0) of 86 patients who received treatment with trastuzumab and pertuzumab – but no chemotherapy – remained cancer free and alive 3 years after surgery (invasive disease–free survival).

“Only 1 out of 86 patients experience disease recurrence ... in those patients who never received chemotherapy,” said study lead author Javier Cortés, MD, PhD, an oncologist with Ramón y Cajal University Hospital, Madrid, during his presentation at the meeting.

As Dr. Cortés noted, HER2-targeted therapies such as trastuzumab have improved lifespans in women with HER2-positive early breast cancer, sparking interest in whether chemotherapy can be de-escalated. The PHERgain study examines whether it can be avoided entirely.

The primary endpoint results of the multicenter, open-label, noncomparative study were released in The Lancet Oncology in 2021.
 

Study methods and results

At 45 hospitals in Europe, patients with HER2-positive, stage I-IIIA, invasive, operable breast cancer were randomly assigned between 2017 and 2019 to receive chemotherapy prior to surgery (n = 71, group A) or to only receive hormone therapy with trastuzumab and pertuzumab, unless PET scans suggested they needed chemotherapy because they weren’t properly responding (n = 285, group B).

At a median follow-up of 5.7 months, 86 patients in the latter group had a pathological complete response and therefore met the first primary endpoint.

The new analysis tracked patients for 3 years after they underwent surgery (n = 63 and 267 for patients in groups A and B, respectively). As previously noted, at a median follow-up of 43.3 months (range, 2.4-63.0 months), only 1 of 86 patients in group B who didn’t receive chemotherapy had a recurrence of cancer (a locoregional ipsilateral recurrence). The 98.8% invasive disease–free survival rate was higher that what was seen for patients in group B as a whole (95.4% invasive disease–free survival, 95% CI, 92.8%-98.0%, P < .001). The 95.4% met the study’s second primary endpoint.

Treatment-related adverse events were higher in the group that received chemotherapy only (group A) versus group B (experiencing an adverse event grade of at least 3, 61.8% vs. 32.9%, respectively, P < .001; serious adverse events, 27.9% vs. 13.8%, respectively; P = .01). Those in group B who didn’t receive any chemotherapy had very few treatment-related adverse events that were considered being greater than a grade 3 (1.2%) and no treatment-related serious adverse events. The researchers reported that there were no treatment-related deaths.

In an interview, Kevin Kalinsky, MD, MS, an oncologist at Emory University Hospital, Atlanta, and cochair of the session where the study data was presented, said the “intriguing and meaningful [findings] highlight the fact that not everyone may need chemotherapy.” In the big picture, the results reflect a movement toward “individualized, personalized medicine, and moving away from one size fits all.”

Should clinicians embrace the study’s strategy, and what are the costs?

“There may be a need for additional evaluation in a large phase 3 trial,” Dr. Kalinsky said.

There was no discussion about cost during the ASCO presentation. However, Dr. Kalinsky noted that there will be cost savings if patients don’t need chemotherapy. But he added that insurers in the United States don’t always cover the PET scans that are needed to evaluate whether patients are responding to hormone therapy.

The study is funded by Roche and sponsored by MedSIR. Dr. Cortes has multiple disclosures, including stock/other ownership in Leuko, MedSIR, and Nektar and honoraria from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Samsung. Dr. Kalinsky has no disclosures.

CHICAGO – Nearly all patients who were diverted from chemotherapy prior to surgery for HER2-positive early breast cancer survived without cancer recurrence for 3 years, according to new findings from a phase 2 trial.

The secondary primary endpoint results from the PHERgain study, presented at the annual meeting of the American Society of Clinical Oncology, provide more evidence to support a strategy that avoids chemotherapy as long as patients show signs of response to hormone therapy via PET scans. The results revealed that 98.8% (95% confidence interval, 96.3-100.0) of 86 patients who received treatment with trastuzumab and pertuzumab – but no chemotherapy – remained cancer free and alive 3 years after surgery (invasive disease–free survival).

“Only 1 out of 86 patients experience disease recurrence ... in those patients who never received chemotherapy,” said study lead author Javier Cortés, MD, PhD, an oncologist with Ramón y Cajal University Hospital, Madrid, during his presentation at the meeting.

As Dr. Cortés noted, HER2-targeted therapies such as trastuzumab have improved lifespans in women with HER2-positive early breast cancer, sparking interest in whether chemotherapy can be de-escalated. The PHERgain study examines whether it can be avoided entirely.

The primary endpoint results of the multicenter, open-label, noncomparative study were released in The Lancet Oncology in 2021.
 

Study methods and results

At 45 hospitals in Europe, patients with HER2-positive, stage I-IIIA, invasive, operable breast cancer were randomly assigned between 2017 and 2019 to receive chemotherapy prior to surgery (n = 71, group A) or to only receive hormone therapy with trastuzumab and pertuzumab, unless PET scans suggested they needed chemotherapy because they weren’t properly responding (n = 285, group B).

At a median follow-up of 5.7 months, 86 patients in the latter group had a pathological complete response and therefore met the first primary endpoint.

The new analysis tracked patients for 3 years after they underwent surgery (n = 63 and 267 for patients in groups A and B, respectively). As previously noted, at a median follow-up of 43.3 months (range, 2.4-63.0 months), only 1 of 86 patients in group B who didn’t receive chemotherapy had a recurrence of cancer (a locoregional ipsilateral recurrence). The 98.8% invasive disease–free survival rate was higher that what was seen for patients in group B as a whole (95.4% invasive disease–free survival, 95% CI, 92.8%-98.0%, P < .001). The 95.4% met the study’s second primary endpoint.

Treatment-related adverse events were higher in the group that received chemotherapy only (group A) versus group B (experiencing an adverse event grade of at least 3, 61.8% vs. 32.9%, respectively, P < .001; serious adverse events, 27.9% vs. 13.8%, respectively; P = .01). Those in group B who didn’t receive any chemotherapy had very few treatment-related adverse events that were considered being greater than a grade 3 (1.2%) and no treatment-related serious adverse events. The researchers reported that there were no treatment-related deaths.

In an interview, Kevin Kalinsky, MD, MS, an oncologist at Emory University Hospital, Atlanta, and cochair of the session where the study data was presented, said the “intriguing and meaningful [findings] highlight the fact that not everyone may need chemotherapy.” In the big picture, the results reflect a movement toward “individualized, personalized medicine, and moving away from one size fits all.”

Should clinicians embrace the study’s strategy, and what are the costs?

“There may be a need for additional evaluation in a large phase 3 trial,” Dr. Kalinsky said.

There was no discussion about cost during the ASCO presentation. However, Dr. Kalinsky noted that there will be cost savings if patients don’t need chemotherapy. But he added that insurers in the United States don’t always cover the PET scans that are needed to evaluate whether patients are responding to hormone therapy.

The study is funded by Roche and sponsored by MedSIR. Dr. Cortes has multiple disclosures, including stock/other ownership in Leuko, MedSIR, and Nektar and honoraria from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Samsung. Dr. Kalinsky has no disclosures.

CHICAGO – Nearly all patients who were diverted from chemotherapy prior to surgery for HER2-positive early breast cancer survived without cancer recurrence for 3 years, according to new findings from a phase 2 trial.

The secondary primary endpoint results from the PHERgain study, presented at the annual meeting of the American Society of Clinical Oncology, provide more evidence to support a strategy that avoids chemotherapy as long as patients show signs of response to hormone therapy via PET scans. The results revealed that 98.8% (95% confidence interval, 96.3-100.0) of 86 patients who received treatment with trastuzumab and pertuzumab – but no chemotherapy – remained cancer free and alive 3 years after surgery (invasive disease–free survival).

“Only 1 out of 86 patients experience disease recurrence ... in those patients who never received chemotherapy,” said study lead author Javier Cortés, MD, PhD, an oncologist with Ramón y Cajal University Hospital, Madrid, during his presentation at the meeting.

As Dr. Cortés noted, HER2-targeted therapies such as trastuzumab have improved lifespans in women with HER2-positive early breast cancer, sparking interest in whether chemotherapy can be de-escalated. The PHERgain study examines whether it can be avoided entirely.

The primary endpoint results of the multicenter, open-label, noncomparative study were released in The Lancet Oncology in 2021.
 

Study methods and results

At 45 hospitals in Europe, patients with HER2-positive, stage I-IIIA, invasive, operable breast cancer were randomly assigned between 2017 and 2019 to receive chemotherapy prior to surgery (n = 71, group A) or to only receive hormone therapy with trastuzumab and pertuzumab, unless PET scans suggested they needed chemotherapy because they weren’t properly responding (n = 285, group B).

At a median follow-up of 5.7 months, 86 patients in the latter group had a pathological complete response and therefore met the first primary endpoint.

The new analysis tracked patients for 3 years after they underwent surgery (n = 63 and 267 for patients in groups A and B, respectively). As previously noted, at a median follow-up of 43.3 months (range, 2.4-63.0 months), only 1 of 86 patients in group B who didn’t receive chemotherapy had a recurrence of cancer (a locoregional ipsilateral recurrence). The 98.8% invasive disease–free survival rate was higher that what was seen for patients in group B as a whole (95.4% invasive disease–free survival, 95% CI, 92.8%-98.0%, P < .001). The 95.4% met the study’s second primary endpoint.

Treatment-related adverse events were higher in the group that received chemotherapy only (group A) versus group B (experiencing an adverse event grade of at least 3, 61.8% vs. 32.9%, respectively, P < .001; serious adverse events, 27.9% vs. 13.8%, respectively; P = .01). Those in group B who didn’t receive any chemotherapy had very few treatment-related adverse events that were considered being greater than a grade 3 (1.2%) and no treatment-related serious adverse events. The researchers reported that there were no treatment-related deaths.

In an interview, Kevin Kalinsky, MD, MS, an oncologist at Emory University Hospital, Atlanta, and cochair of the session where the study data was presented, said the “intriguing and meaningful [findings] highlight the fact that not everyone may need chemotherapy.” In the big picture, the results reflect a movement toward “individualized, personalized medicine, and moving away from one size fits all.”

Should clinicians embrace the study’s strategy, and what are the costs?

“There may be a need for additional evaluation in a large phase 3 trial,” Dr. Kalinsky said.

There was no discussion about cost during the ASCO presentation. However, Dr. Kalinsky noted that there will be cost savings if patients don’t need chemotherapy. But he added that insurers in the United States don’t always cover the PET scans that are needed to evaluate whether patients are responding to hormone therapy.

The study is funded by Roche and sponsored by MedSIR. Dr. Cortes has multiple disclosures, including stock/other ownership in Leuko, MedSIR, and Nektar and honoraria from AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Samsung. Dr. Kalinsky has no disclosures.

CHICAGO – A new meta-analysis of 25 studies dating back to 1948 provides more evidence linking ovarian suppression/ablation in premenopausal women to less recurrence and more survival in the long term after breast cancer.

Those who didn’t take tamoxifen – a standard treatment today – seemed to gain an especially large benefit.

The randomized studies, which included 14,999 subjects, suggest that ovarian suppression/ablation can provide a “substantial and persistent benefit for premenopausal women,” said study lead author and medical statistician Richard G. Gray, MA, MSc, of the University of Oxford (England), in a presentation at the annual meeting of the American Society of Clinical Oncology.

The study authors sought to better understand the value of ovarian suppression/ablation, which may prevent estrogen from stimulating residual cancer after treatment. According to the study abstract, premenopausal women with estrogen receptor–positive tumors may be at special risk of cancer recurrence because of this phenomenon.

Recently published research has supported hormone therapy targeting the ovaries in this population.

“Ovarian suppression with an aromatase inhibitor should become the preferred initial hormone therapy recommendation for all premenopausal women with high-risk (i.e., grade 3, T2, and age less than 35 years) estrogen receptor–positive breast cancer,” declared a 2022 editorial in the Journal of Clinical Oncology that noted the positive findings of a 13-year follow-up analysis of 2 studies.
 

Study methods and results

For the meta-analysis released at ASCO, researchers examined 25 trials that randomized women with breast cancer who were premenopausal. In some cases, the women went through menopause during the trials, and in some other cases, ovarian suppression/ablation brought on early menopause.

Among women who had received no chemotherapy or remained premenopausal after chemotherapy (n = 7,213), cancer recurred within 15 years in 41% of the controls and 28.9% of the ovarian suppression/ablation group, (relative risk, 0.70; 95% confidence interval, 0.63-0.78; P < .00001).

Among these same women, breast cancer mortality at 20 years was 34.7% in the controls and 23.8% in the ovarian suppression/ablation group (RR, 0.71; 95% CI, 0.62-0.81; P < .00001).

The researchers also looked at the same group of women and divided it into those who didn’t take tamoxifen (2,362) and those who did take tamoxifen (4,851). The drug is now the preferred option “for treatment of breast cancer.”

Among those who did not take tamoxifen, the recurrence rate at 15 years was 56.5% among controls versus 39.0% among those in the ovarian suppression/ablation group (RR, 0.61; 95% CI, 0.52-0.72; P < .00001). The gap shrunk in those who did take tamoxifen: recurrence occurred in 30.3% of the control group and 25.8% of the ovarian suppression/ablation group (RR, 0.80; 95% CI, 0.70-0.93; P = .002).
 

Tamoxifen on its own seems to have powerful positive effect

The findings suggest that tamoxifen on its own has a powerful positive effect, leaving less extra benefit for ovarian suppression/ablation to provide, said Mr. Gray.

The meta-analysis didn’t examine cost or cost-effectiveness.

Kevin Kalinsky, MD, MS, an oncologist at Emory University Hospital, Atlanta, cochair of the session where the meta-analysis data was presented, said in an interview that the new research shows that “patients can really benefit from ovarian function suppression.” Even so, recent trials suggested that the strategy is uncommon, used by less than 20% of high-risk patients.

Dr. Kalinsky noted that suppressing the ovaries with medication or removing the ovaries entirely can cause early menopause and eliminate fertility.

“There can be definitely be side effects like hot flashes and tolerability issues,” he said, “along with an impact on quality of life.”

According to the U.K. organization Breast Cancer Now,“ovarian suppression achieved by hormone therapy or surgery is more likely to cause menopausal symptoms than a natural menopause.” In addition, “research has shown that younger women are more likely to stop taking hormone therapy early if they don’t get help with possible side effects.”

It’s important for patients and providers to have full discussions about possible strategies, Dr. Kalinsky said.

No information about study funding was provided. Dr. Kalinsky and Mr. Gray had no financial conflicts.

CHICAGO – A new meta-analysis of 25 studies dating back to 1948 provides more evidence linking ovarian suppression/ablation in premenopausal women to less recurrence and more survival in the long term after breast cancer.

Those who didn’t take tamoxifen – a standard treatment today – seemed to gain an especially large benefit.

The randomized studies, which included 14,999 subjects, suggest that ovarian suppression/ablation can provide a “substantial and persistent benefit for premenopausal women,” said study lead author and medical statistician Richard G. Gray, MA, MSc, of the University of Oxford (England), in a presentation at the annual meeting of the American Society of Clinical Oncology.

The study authors sought to better understand the value of ovarian suppression/ablation, which may prevent estrogen from stimulating residual cancer after treatment. According to the study abstract, premenopausal women with estrogen receptor–positive tumors may be at special risk of cancer recurrence because of this phenomenon.

Recently published research has supported hormone therapy targeting the ovaries in this population.

“Ovarian suppression with an aromatase inhibitor should become the preferred initial hormone therapy recommendation for all premenopausal women with high-risk (i.e., grade 3, T2, and age less than 35 years) estrogen receptor–positive breast cancer,” declared a 2022 editorial in the Journal of Clinical Oncology that noted the positive findings of a 13-year follow-up analysis of 2 studies.
 

Study methods and results

For the meta-analysis released at ASCO, researchers examined 25 trials that randomized women with breast cancer who were premenopausal. In some cases, the women went through menopause during the trials, and in some other cases, ovarian suppression/ablation brought on early menopause.

Among women who had received no chemotherapy or remained premenopausal after chemotherapy (n = 7,213), cancer recurred within 15 years in 41% of the controls and 28.9% of the ovarian suppression/ablation group, (relative risk, 0.70; 95% confidence interval, 0.63-0.78; P < .00001).

Among these same women, breast cancer mortality at 20 years was 34.7% in the controls and 23.8% in the ovarian suppression/ablation group (RR, 0.71; 95% CI, 0.62-0.81; P < .00001).

The researchers also looked at the same group of women and divided it into those who didn’t take tamoxifen (2,362) and those who did take tamoxifen (4,851). The drug is now the preferred option “for treatment of breast cancer.”

Among those who did not take tamoxifen, the recurrence rate at 15 years was 56.5% among controls versus 39.0% among those in the ovarian suppression/ablation group (RR, 0.61; 95% CI, 0.52-0.72; P < .00001). The gap shrunk in those who did take tamoxifen: recurrence occurred in 30.3% of the control group and 25.8% of the ovarian suppression/ablation group (RR, 0.80; 95% CI, 0.70-0.93; P = .002).
 

Tamoxifen on its own seems to have powerful positive effect

The findings suggest that tamoxifen on its own has a powerful positive effect, leaving less extra benefit for ovarian suppression/ablation to provide, said Mr. Gray.

The meta-analysis didn’t examine cost or cost-effectiveness.

Kevin Kalinsky, MD, MS, an oncologist at Emory University Hospital, Atlanta, cochair of the session where the meta-analysis data was presented, said in an interview that the new research shows that “patients can really benefit from ovarian function suppression.” Even so, recent trials suggested that the strategy is uncommon, used by less than 20% of high-risk patients.

Dr. Kalinsky noted that suppressing the ovaries with medication or removing the ovaries entirely can cause early menopause and eliminate fertility.

“There can be definitely be side effects like hot flashes and tolerability issues,” he said, “along with an impact on quality of life.”

According to the U.K. organization Breast Cancer Now,“ovarian suppression achieved by hormone therapy or surgery is more likely to cause menopausal symptoms than a natural menopause.” In addition, “research has shown that younger women are more likely to stop taking hormone therapy early if they don’t get help with possible side effects.”

It’s important for patients and providers to have full discussions about possible strategies, Dr. Kalinsky said.

No information about study funding was provided. Dr. Kalinsky and Mr. Gray had no financial conflicts.

CHICAGO – A new meta-analysis of 25 studies dating back to 1948 provides more evidence linking ovarian suppression/ablation in premenopausal women to less recurrence and more survival in the long term after breast cancer.

Those who didn’t take tamoxifen – a standard treatment today – seemed to gain an especially large benefit.

The randomized studies, which included 14,999 subjects, suggest that ovarian suppression/ablation can provide a “substantial and persistent benefit for premenopausal women,” said study lead author and medical statistician Richard G. Gray, MA, MSc, of the University of Oxford (England), in a presentation at the annual meeting of the American Society of Clinical Oncology.

The study authors sought to better understand the value of ovarian suppression/ablation, which may prevent estrogen from stimulating residual cancer after treatment. According to the study abstract, premenopausal women with estrogen receptor–positive tumors may be at special risk of cancer recurrence because of this phenomenon.

Recently published research has supported hormone therapy targeting the ovaries in this population.

“Ovarian suppression with an aromatase inhibitor should become the preferred initial hormone therapy recommendation for all premenopausal women with high-risk (i.e., grade 3, T2, and age less than 35 years) estrogen receptor–positive breast cancer,” declared a 2022 editorial in the Journal of Clinical Oncology that noted the positive findings of a 13-year follow-up analysis of 2 studies.
 

Study methods and results

For the meta-analysis released at ASCO, researchers examined 25 trials that randomized women with breast cancer who were premenopausal. In some cases, the women went through menopause during the trials, and in some other cases, ovarian suppression/ablation brought on early menopause.

Among women who had received no chemotherapy or remained premenopausal after chemotherapy (n = 7,213), cancer recurred within 15 years in 41% of the controls and 28.9% of the ovarian suppression/ablation group, (relative risk, 0.70; 95% confidence interval, 0.63-0.78; P < .00001).

Among these same women, breast cancer mortality at 20 years was 34.7% in the controls and 23.8% in the ovarian suppression/ablation group (RR, 0.71; 95% CI, 0.62-0.81; P < .00001).

The researchers also looked at the same group of women and divided it into those who didn’t take tamoxifen (2,362) and those who did take tamoxifen (4,851). The drug is now the preferred option “for treatment of breast cancer.”

Among those who did not take tamoxifen, the recurrence rate at 15 years was 56.5% among controls versus 39.0% among those in the ovarian suppression/ablation group (RR, 0.61; 95% CI, 0.52-0.72; P < .00001). The gap shrunk in those who did take tamoxifen: recurrence occurred in 30.3% of the control group and 25.8% of the ovarian suppression/ablation group (RR, 0.80; 95% CI, 0.70-0.93; P = .002).
 

Tamoxifen on its own seems to have powerful positive effect

The findings suggest that tamoxifen on its own has a powerful positive effect, leaving less extra benefit for ovarian suppression/ablation to provide, said Mr. Gray.

The meta-analysis didn’t examine cost or cost-effectiveness.

Kevin Kalinsky, MD, MS, an oncologist at Emory University Hospital, Atlanta, cochair of the session where the meta-analysis data was presented, said in an interview that the new research shows that “patients can really benefit from ovarian function suppression.” Even so, recent trials suggested that the strategy is uncommon, used by less than 20% of high-risk patients.

Dr. Kalinsky noted that suppressing the ovaries with medication or removing the ovaries entirely can cause early menopause and eliminate fertility.

“There can be definitely be side effects like hot flashes and tolerability issues,” he said, “along with an impact on quality of life.”

According to the U.K. organization Breast Cancer Now,“ovarian suppression achieved by hormone therapy or surgery is more likely to cause menopausal symptoms than a natural menopause.” In addition, “research has shown that younger women are more likely to stop taking hormone therapy early if they don’t get help with possible side effects.”

It’s important for patients and providers to have full discussions about possible strategies, Dr. Kalinsky said.

No information about study funding was provided. Dr. Kalinsky and Mr. Gray had no financial conflicts.

CHICAGO – In a phase 1 small cell lung cancer (SCLC) trial, a bispecific antibody that targets T cells and the inhibitory notch ligand known as delta-like ligand 3 (DLL3) showed a good safety profile and encouraging signs of efficacy, including one response that lasted more than a year.

The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.

SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.
 

A rare SCLC biomarker

“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.

Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.

This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.
 

Study methods and results

The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.

The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.

The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.

At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.

Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.

Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.

“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.
 

Well tolerated, but take efficacy data with a grain of salt

The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.

“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.

Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.

He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.

Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.

CHICAGO – In a phase 1 small cell lung cancer (SCLC) trial, a bispecific antibody that targets T cells and the inhibitory notch ligand known as delta-like ligand 3 (DLL3) showed a good safety profile and encouraging signs of efficacy, including one response that lasted more than a year.

The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.

SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.
 

A rare SCLC biomarker

“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.

Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.

This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.
 

Study methods and results

The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.

The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.

The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.

At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.

Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.

Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.

“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.
 

Well tolerated, but take efficacy data with a grain of salt

The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.

“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.

Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.

He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.

Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.

CHICAGO – In a phase 1 small cell lung cancer (SCLC) trial, a bispecific antibody that targets T cells and the inhibitory notch ligand known as delta-like ligand 3 (DLL3) showed a good safety profile and encouraging signs of efficacy, including one response that lasted more than a year.

The antibody promotes the destruction of tumor cells by T cells by acting as a bridge between T cells and tumors.

SCLC has largely resisted efforts to identify unique surface markers. DLL3 is an exception: It is rarely expressed in normal cells, and it seems to be important to tumor biology, according to Martin Wermke, MD, who presented the study at the annual meeting of the American Society of Clinical Oncology.
 

A rare SCLC biomarker

“The problem, I think, is that small cell [lung cancer] with its high mutational burden is a bunch of many different subentities and you will probably not find a single driver mutation as you do in non–small cell lung cancer. So in that [way] it’s different in its biology,” said Dr. Wermke, professor of experimental tumor therapy at the National Center for Tumor Diseases in Dresden, Germany.

Nevertheless, DLL3 is a sensitive biomarker, with over 90% of SCLC tumors positive for the surface marker, according to Dr. Wermke. “It’s one of the first which proved to be a reliable [SCLC] biomarker for therapeutic approaches,” said Dr. Wermke.

This isn’t the first clinical experience with DLL3. An anti-DLL3 antibody was used as part of an antibody-drug conjugate called Rova-T, which failed a phase 3 trial in SCLC in 2021 and was subsequently canceled by AbbVie, but Dr. Wermke believes that the issue was with the drug and linker (a chemical tag that links the cytotoxic drug to the antibody, which is designed to release the drug in an appropriate environment such as the interior of a tumor cell after an antibody-drug conjugate has been internalized by the tumor cell), not DLL3. DLL3 is also being investigated as a component of chimeric antigen receptor T-cell therapy, though no clinical results have been reported, Dr. Wermke said.
 

Study methods and results

The study included 107 patients. The median age was 60.0 years, and 57% were male. To be included, patients had to have advanced SCLC, large cell neuroendocrine carcinoma, or extrapulmonary neuroendocrine carcinoma, as well as test positive for DLL3 expression.

The drug was well tolerated: 86% of patients experienced at least one treatment-related adverse event: 59% with a grade 1-2 TRAE and 27% with a grade 3-5 TRAE. Cytokine release syndrome (CRS) occurred in 59% of patients, but just 2% were grade 3-5. TRAEs led to discontinuation in 4% of patients. Physicians were able to manage CRS with supportive care, steroids, and anti–interleukin-6 receptor antibodies.

The treatment showed signs of efficacy, with partial responses occurring in 18% of patients, stable disease in 23%, progressive disease in 45%, while 13% were not evaluable.

At doses of 90 mg/kg or above, partial response occurred in 25% of patients, stable disease in 27%, and progressive disease in 31%, while 13% were not evaluable. Similar patterns were seen across three tumor types.

Of 18 responders, 14 continued to be responders at the time of the presentation. The longest response lengths were 13.1 months, 10.7 months, and 9.4 months.

Dr. Wermke said that the responses were encouraging, particularly the duration of some responses.

“Having a small cell [lung cancer] patient responding to something for more than a year is extraordinary. It comes with side effects, which are usually seen during the first [doses]. After that, the drug is pretty well tolerable, and that is also something which distinguishes it from alternative second-line approaches,” he said.
 

Well tolerated, but take efficacy data with a grain of salt

The study was encouraging but should be treated with caution, according to Vamsidhar Velcheti, MD, who moderated the session where the research was presented.

“The toxicity profile is actually very promising and it’s still very early, but there’s certainly a lot of interest in DLL3-targeted [therapies]. We’ve seen some very exciting data with other assets in this category as well,” said Dr. Velcheti, director of thoracic oncology at NYU Langone Health, New York.

Phase 1 efficacy data can be tantalizing but often fails to hold up to further testing, according to Dr. Velcheti. “We’ve seen signals in phase 1 data before, and we’ve been burned. We saw really promising data with Rova-T, and the confirmatory trials were negative, – so we want to be cautiously optimistic,” said Dr. Velcheti.

He also pointed out that patient selection will be important for such studies, considering that SCLC patients often have a lot of comorbidities and the therapy’s potential for causing CRS.

Both Dr. Wermke and Dr. Velcheti have received funding from numerous pharmaceutical companies. Dr. Wermke has consulted with or advised with Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck Therapeutics, Immatics, ISA Pharmaceuticals, Lilly, and Novartis.

CHICAGO – When it comes to preventing pelvic recurrence in low-risk cervical cancer, simple hysterectomy is not inferior to radical hysterectomy, according to results from a phase 3, randomized, controlled trial.

“Following adequate and rigorous preoperative assessment, and that’s key – very careful [patient selection] – simple hysterectomies can now be considered the new standard of care for patients with low-risk early-stage cervical cancer,” said Marie Plante, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. A simple hysterectomy removes the uterus and cervix, while a radical hysterectomy also removes the parametrium and upper vagina.

Cervical cancer incidence has gone down over the past 2 decades as a result of improved screening, and patients tend to be lower in age and are more likely to have low-risk, early-stage disease, according to Dr. Plante. “Although radical surgery is highly effective for the treatment of low-risk disease, women are at risk of suffering survivorship issues related to long-term surgical side effects including compromised bladder, bowel, and sexual function,” said Dr. Plante, who is a professor of obstetrics and gynecology at Laval University and head of clinical research at l’Hôtel-Dieu de Québec, both in Quebec City.

Retrospective studies found that infiltration of the parametrium is quite rare in low-risk cases, “suggesting that less radical surgery may be a safe option associated with decreased morbidity – what we call surgical de-escalation,” said Dr. Plante.

To test that idea more rigorously, the researchers designed the SHAPE trial, which randomized 700 women to a simple hysterectomy or radical hysterectomy. Patients were carefully selected to be low risk, having squamous cell, adenocarcinoma, or adenosquamous carcinoma, stage IA2 or IB2 tumors, fewer than 10 mm of stromal invasion on loop electrosurgical excision procedure or cone biopsy, less than 50% stromal invasion seen in MRI, and a maximum tumor dimension of 20 mm or less. Tumors were grade I-III or not assessable.

Over a median follow-up of 4.5 years, pelvic recurrence was 2.52% in the simple hysterectomy group and 2.17% in the radical hysterectomy group. The difference between the recurrence rate between the two groups was 0.35%, with an upper 95% confidence limit of 2.32%, below the threshold of 4% which had been predetermined as a benchmark for similar outcomes between the two groups. “Therefore, noninferiority of simple hysterectomy to radical hysterectomy could be concluded,” said Dr. Plante.

There were no statistically significant differences in intraoperative complications or mortality between the groups.
 

Surgery-related adverse events greater in radical hysterectomy group

There were some differences between the groups with respect to surgery-related adverse events. Within 4 weeks of surgery, there was a greater incidence of any adverse event in the radical hysterectomy group (50.6% vs. 42.6%; P = .04), as well as greater incidences of urinary incontinence (5.5% vs. 2.4%; P = .048) and urinary retention (11.0% vs. 0.6%; P < .0001). In the 4 weeks following surgery, there was a trend toward more surgery-related adverse events in the radical hysterectomy group (60.5% vs. 53.6%; P = .08) and higher incidences of urinary incontinence (11.0% vs. 4.7%; P = .003) and urinary retention (9.9% vs. 0.6%; P < .0001).

“Urinary incontinence and urinary retention are statistically worse in the radical hysterectomy group – both acutely, as well as [during] the following four weeks after surgery, suggesting that the problem persisted over time,” said Dr. Plante.

Dr. Plante also presented the study at a premeeting virtual press conference, during which Kathleen Moore, MD, provided comments on the study. She expressed enthusiasm about the results.

“Amongst those carefully selected tumors, radical hysterectomy can be converted to a simple hysterectomy, including minimally invasive. You still have to do nodes – that’s an important thing to remember – but you can do this without loss of oncologic control. And importantly, with reduction in surgical complications, postop morbidity, specifically neurologic morbidity. The moment this is presented [at the ASCO conference] this will be the new standard of care, and it represents a huge step forward in the care of women with early-stage cervical cancer,” said Dr. Moore, who is a professor of gynecologic oncology at the University of Oklahoma Health Sciences Center, Oklahoma City.

Also in the press conference, Dr. Plante emphasized the importance of a thorough understanding of the tumor, including size, imaging, and pathology. “The more conservative one wants to be, the more meticulous, the more careful one has to be to make sure that we’re truly dealing with low-risk patients.”

During the question-and-answer session following her presentation at the ASCO session, a moderator asked Dr. Plante if the presence of lymph vascular space invasion (LVSI) should prompt a radical hysterectomy.

Dr. Plante noted that about 13% of both radical and simple hysterectomy groups had LVSI present. “I think the key thing is careful selection, but I’m not sure that we should exclude LVSI [from consideration for simple hysterectomy] de facto,” she said.

Dr. Plante has consulted or advised Merck Serono and has received travel, accommodations, or other expenses from AstraZeneca. Dr. Moore has consulted, advised, and received research funding and travel expenses from numerous pharmaceutical companies.

CHICAGO – When it comes to preventing pelvic recurrence in low-risk cervical cancer, simple hysterectomy is not inferior to radical hysterectomy, according to results from a phase 3, randomized, controlled trial.

“Following adequate and rigorous preoperative assessment, and that’s key – very careful [patient selection] – simple hysterectomies can now be considered the new standard of care for patients with low-risk early-stage cervical cancer,” said Marie Plante, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. A simple hysterectomy removes the uterus and cervix, while a radical hysterectomy also removes the parametrium and upper vagina.

Cervical cancer incidence has gone down over the past 2 decades as a result of improved screening, and patients tend to be lower in age and are more likely to have low-risk, early-stage disease, according to Dr. Plante. “Although radical surgery is highly effective for the treatment of low-risk disease, women are at risk of suffering survivorship issues related to long-term surgical side effects including compromised bladder, bowel, and sexual function,” said Dr. Plante, who is a professor of obstetrics and gynecology at Laval University and head of clinical research at l’Hôtel-Dieu de Québec, both in Quebec City.

Retrospective studies found that infiltration of the parametrium is quite rare in low-risk cases, “suggesting that less radical surgery may be a safe option associated with decreased morbidity – what we call surgical de-escalation,” said Dr. Plante.

To test that idea more rigorously, the researchers designed the SHAPE trial, which randomized 700 women to a simple hysterectomy or radical hysterectomy. Patients were carefully selected to be low risk, having squamous cell, adenocarcinoma, or adenosquamous carcinoma, stage IA2 or IB2 tumors, fewer than 10 mm of stromal invasion on loop electrosurgical excision procedure or cone biopsy, less than 50% stromal invasion seen in MRI, and a maximum tumor dimension of 20 mm or less. Tumors were grade I-III or not assessable.

Over a median follow-up of 4.5 years, pelvic recurrence was 2.52% in the simple hysterectomy group and 2.17% in the radical hysterectomy group. The difference between the recurrence rate between the two groups was 0.35%, with an upper 95% confidence limit of 2.32%, below the threshold of 4% which had been predetermined as a benchmark for similar outcomes between the two groups. “Therefore, noninferiority of simple hysterectomy to radical hysterectomy could be concluded,” said Dr. Plante.

There were no statistically significant differences in intraoperative complications or mortality between the groups.
 

Surgery-related adverse events greater in radical hysterectomy group

There were some differences between the groups with respect to surgery-related adverse events. Within 4 weeks of surgery, there was a greater incidence of any adverse event in the radical hysterectomy group (50.6% vs. 42.6%; P = .04), as well as greater incidences of urinary incontinence (5.5% vs. 2.4%; P = .048) and urinary retention (11.0% vs. 0.6%; P < .0001). In the 4 weeks following surgery, there was a trend toward more surgery-related adverse events in the radical hysterectomy group (60.5% vs. 53.6%; P = .08) and higher incidences of urinary incontinence (11.0% vs. 4.7%; P = .003) and urinary retention (9.9% vs. 0.6%; P < .0001).

“Urinary incontinence and urinary retention are statistically worse in the radical hysterectomy group – both acutely, as well as [during] the following four weeks after surgery, suggesting that the problem persisted over time,” said Dr. Plante.

Dr. Plante also presented the study at a premeeting virtual press conference, during which Kathleen Moore, MD, provided comments on the study. She expressed enthusiasm about the results.

“Amongst those carefully selected tumors, radical hysterectomy can be converted to a simple hysterectomy, including minimally invasive. You still have to do nodes – that’s an important thing to remember – but you can do this without loss of oncologic control. And importantly, with reduction in surgical complications, postop morbidity, specifically neurologic morbidity. The moment this is presented [at the ASCO conference] this will be the new standard of care, and it represents a huge step forward in the care of women with early-stage cervical cancer,” said Dr. Moore, who is a professor of gynecologic oncology at the University of Oklahoma Health Sciences Center, Oklahoma City.

Also in the press conference, Dr. Plante emphasized the importance of a thorough understanding of the tumor, including size, imaging, and pathology. “The more conservative one wants to be, the more meticulous, the more careful one has to be to make sure that we’re truly dealing with low-risk patients.”

During the question-and-answer session following her presentation at the ASCO session, a moderator asked Dr. Plante if the presence of lymph vascular space invasion (LVSI) should prompt a radical hysterectomy.

Dr. Plante noted that about 13% of both radical and simple hysterectomy groups had LVSI present. “I think the key thing is careful selection, but I’m not sure that we should exclude LVSI [from consideration for simple hysterectomy] de facto,” she said.

Dr. Plante has consulted or advised Merck Serono and has received travel, accommodations, or other expenses from AstraZeneca. Dr. Moore has consulted, advised, and received research funding and travel expenses from numerous pharmaceutical companies.

CHICAGO – When it comes to preventing pelvic recurrence in low-risk cervical cancer, simple hysterectomy is not inferior to radical hysterectomy, according to results from a phase 3, randomized, controlled trial.

“Following adequate and rigorous preoperative assessment, and that’s key – very careful [patient selection] – simple hysterectomies can now be considered the new standard of care for patients with low-risk early-stage cervical cancer,” said Marie Plante, MD, during a presentation of the study at the annual meeting of the American Society of Clinical Oncology. A simple hysterectomy removes the uterus and cervix, while a radical hysterectomy also removes the parametrium and upper vagina.

Cervical cancer incidence has gone down over the past 2 decades as a result of improved screening, and patients tend to be lower in age and are more likely to have low-risk, early-stage disease, according to Dr. Plante. “Although radical surgery is highly effective for the treatment of low-risk disease, women are at risk of suffering survivorship issues related to long-term surgical side effects including compromised bladder, bowel, and sexual function,” said Dr. Plante, who is a professor of obstetrics and gynecology at Laval University and head of clinical research at l’Hôtel-Dieu de Québec, both in Quebec City.

Retrospective studies found that infiltration of the parametrium is quite rare in low-risk cases, “suggesting that less radical surgery may be a safe option associated with decreased morbidity – what we call surgical de-escalation,” said Dr. Plante.

To test that idea more rigorously, the researchers designed the SHAPE trial, which randomized 700 women to a simple hysterectomy or radical hysterectomy. Patients were carefully selected to be low risk, having squamous cell, adenocarcinoma, or adenosquamous carcinoma, stage IA2 or IB2 tumors, fewer than 10 mm of stromal invasion on loop electrosurgical excision procedure or cone biopsy, less than 50% stromal invasion seen in MRI, and a maximum tumor dimension of 20 mm or less. Tumors were grade I-III or not assessable.

Over a median follow-up of 4.5 years, pelvic recurrence was 2.52% in the simple hysterectomy group and 2.17% in the radical hysterectomy group. The difference between the recurrence rate between the two groups was 0.35%, with an upper 95% confidence limit of 2.32%, below the threshold of 4% which had been predetermined as a benchmark for similar outcomes between the two groups. “Therefore, noninferiority of simple hysterectomy to radical hysterectomy could be concluded,” said Dr. Plante.

There were no statistically significant differences in intraoperative complications or mortality between the groups.
 

Surgery-related adverse events greater in radical hysterectomy group

There were some differences between the groups with respect to surgery-related adverse events. Within 4 weeks of surgery, there was a greater incidence of any adverse event in the radical hysterectomy group (50.6% vs. 42.6%; P = .04), as well as greater incidences of urinary incontinence (5.5% vs. 2.4%; P = .048) and urinary retention (11.0% vs. 0.6%; P < .0001). In the 4 weeks following surgery, there was a trend toward more surgery-related adverse events in the radical hysterectomy group (60.5% vs. 53.6%; P = .08) and higher incidences of urinary incontinence (11.0% vs. 4.7%; P = .003) and urinary retention (9.9% vs. 0.6%; P < .0001).

“Urinary incontinence and urinary retention are statistically worse in the radical hysterectomy group – both acutely, as well as [during] the following four weeks after surgery, suggesting that the problem persisted over time,” said Dr. Plante.

Dr. Plante also presented the study at a premeeting virtual press conference, during which Kathleen Moore, MD, provided comments on the study. She expressed enthusiasm about the results.

“Amongst those carefully selected tumors, radical hysterectomy can be converted to a simple hysterectomy, including minimally invasive. You still have to do nodes – that’s an important thing to remember – but you can do this without loss of oncologic control. And importantly, with reduction in surgical complications, postop morbidity, specifically neurologic morbidity. The moment this is presented [at the ASCO conference] this will be the new standard of care, and it represents a huge step forward in the care of women with early-stage cervical cancer,” said Dr. Moore, who is a professor of gynecologic oncology at the University of Oklahoma Health Sciences Center, Oklahoma City.

Also in the press conference, Dr. Plante emphasized the importance of a thorough understanding of the tumor, including size, imaging, and pathology. “The more conservative one wants to be, the more meticulous, the more careful one has to be to make sure that we’re truly dealing with low-risk patients.”

During the question-and-answer session following her presentation at the ASCO session, a moderator asked Dr. Plante if the presence of lymph vascular space invasion (LVSI) should prompt a radical hysterectomy.

Dr. Plante noted that about 13% of both radical and simple hysterectomy groups had LVSI present. “I think the key thing is careful selection, but I’m not sure that we should exclude LVSI [from consideration for simple hysterectomy] de facto,” she said.

Dr. Plante has consulted or advised Merck Serono and has received travel, accommodations, or other expenses from AstraZeneca. Dr. Moore has consulted, advised, and received research funding and travel expenses from numerous pharmaceutical companies.

Across patients’ age groups, adding the immune checkpoint inhibitor nivolumab to chemotherapy significantly improves progression-free survival in advanced stage Hodgkin lymphoma while also reducing toxicities, making it a new standard of care, compared with the CD30-targeting drug brentuximab vedotin.

“[SWOG] S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma,” the authors reported in late-breaking research presented at the annual meeting of the American Society of Clinical Oncology.

“Based on the magnitude of the benefit and with nivolumab being better tolerated than brentuximab, we anticipate that these results will be practice changing and nivolumab [and chemotherapy] will become a new standard of care,” lead author Alex Francisco Herrera, MD, an associate professor and chief of the division of lymphoma in the department of hematology and hematopoietic cell transplantation, City of Hope Medical Center, Duarte, Calif., said in an interview.

The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab.

The results are especially important considering that Hodgkin lymphoma disproportionately affects younger patients, including those in their teens, 20s, and 30s, Dr. Herrera noted in an interview.

“We found that treatment with nivolumab reduced the risk of progression by half, and, importantly, the benefit was observed across subgroups,” he said.
 

Relapse/refractory disease common in advanced HL

In general, outcomes are relatively good even for stage III or IV Hodgkin lymphoma; however, about a quarter of patients still have relapses or refractory disease.

While the introduction of novel frontline treatment with brentuximab-AVD was important in improving overall survival, the regimen adds toxicity, particularly among older patients, and many pediatric patients receiving the therapy still require radiation therapy, with its undesirable side effects.

Meanwhile, the progressive death 1 inhibitor nivolumab, approved by the Food and Drug Administration, gained interest as a potentially ideal alternative in light of Hodgkin lymphoma’s status basically as “the poster child for PD-1 blockade,” Dr. Herrera said.

“There are genetic changes in the Hodgkin lymphoma tumor cell that lead to expression of PD-1 ligands on the surface of Hodgkin lymphoma cells, and when we use a drug like nivolumab, we see that even patients with the most treatment-resistant rates of lymphoma have as much as a 70% response rate,” he explained in a press briefing.

To further investigate, the first-of-its-kind collaboration of adult and pediatric cancer teams conducted the S1826 trial to evaluate the treatment across age groups with stage 3 and 4 Hodgkin lymphoma.

For the study, conducted between July 2019 and October 2022, 976 patients were randomized to treatment either with nivolumab (n = 489) or brentuximab (n = 487), each in combination with the AVD regimen.

Of the patients, the median age was 27, with 24% under the age of 18, 10% over 60 and 32% with IPS 4-7. Among them, 56% were male and 76% were White.

For the primary endpoint, at a median follow-up of 12.1 months, the rate of progression-free survival was significantly higher in the nivolumab arm (hazard ratio, 0.48; one-sided P = .0005), with the rate of 1-year survival at 94% in the nivolumab group versus 86% in the brentuximab group, for a 52% reduction in the risk of disease-related death with nivolumab versus brentuximab.

A total of 11 deaths occurred in the brentuximab group, 7 of which were related to adverse events, compared with 4 deaths in the nivolumab group, 3 of which were related to nivolumab.

Importantly, fewer than 1% of patients with nivolumab required radiation therapy.

“That’s a dramatic reduction of the proportion of the very youngest patients receiving radiotherapy,” Dr. Herrera noted.

Grade 3 or higher hematologic adverse events were higher in the nivolumab group, at 48.4%, including 45.1% that were grade 3 or higher neutropenia, compared with 30.5% with brentuximab, including 23.9% with grade 3 or higher neutropenia.

However, rates of any grade of febrile neutropenia were similar with nivolumab and brentuximab (5.6% vs. 6.4%, respectively), as were rates of pneumonitis (2.0% vs. 3.2%), ALT elevation (30.7% vs. 39.8%), and colitis (1% vs. 1.3%).

In addition, rates of hypo- and hyperthyroidism were more frequent after nivolumab (7% and 3% with nivolumab, respectively, vs. fewer than 1% with brentuximab).

But, of note, peripheral neuropathy of any grade was more common after brentuximab (sensory: 28.1% nivolumab vs. 54.2% brentuximab; motor: 4% nivolumab vs. 6.8% brentuximab).

“I can’t emphasize how important neuropathy is as a side effect in these young patients who have the rest of their life ahead of them,” Dr. Herrera explained. “It’s fantastic to be cured of cancer, but tough to not be able to feel your fingers and toes.”

With its broad inclusion of age groups and a diverse population, he added that the study was importantly a “representative” trial, reflecting a “real-world population.”

“Incredibly, a quarter of patients were under the age of 18; 10% were over the age of 60, a quarter of patients were Hispanic and Black, and in fact we had a quite good representation of higher-risk subgroups,” he said.

Looking forward, longer-term follow-up from this study will be important in determining if the improvement observed in disease-related deaths is maintained over time, Dr. Herrera noted.

“Additionally, it is crucial to obtain data on other key outcomes such as overall survival and quality of life from longer-term follow of this study,” he said.
 

‘A huge step forward’

Commenting on the study, Oreofe Odejide, MD, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, said that results were unprecedented.

“Although a majority of patients with advanced stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still end up with relapsed or refractory disease,” she said in an interview. “Therefore, the findings from this study represent a huge step forward in the management of advanced Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”

Dr. Odejide agreed that the findings are potentially practice changing.

“Brentuximab-AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared to ABVD chemotherapy in several years,” she explained.

“The fact that the SWOG1826 trial now shows a significant benefit of nivolumab-AVD over brentuximab and included both pediatric and adult patients unlike prior studies, is highly compelling,” Dr. Odejide added. “This has strong potential to change the standard of care for patients with previously untreated, advanced-stage Hodgkin lymphoma.”

The study received funding from the National Cancer Institute and from Bristol-Myers Squibb. Dr. Herrera reported relationships with Abbvie, ADC Therapeutics, Adicet Bio, AstraZeneca/MedImmune, Bristol-Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Tubulis Gmbh. Dr. Odejide reported no disclosures.

Across patients’ age groups, adding the immune checkpoint inhibitor nivolumab to chemotherapy significantly improves progression-free survival in advanced stage Hodgkin lymphoma while also reducing toxicities, making it a new standard of care, compared with the CD30-targeting drug brentuximab vedotin.

“[SWOG] S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma,” the authors reported in late-breaking research presented at the annual meeting of the American Society of Clinical Oncology.

“Based on the magnitude of the benefit and with nivolumab being better tolerated than brentuximab, we anticipate that these results will be practice changing and nivolumab [and chemotherapy] will become a new standard of care,” lead author Alex Francisco Herrera, MD, an associate professor and chief of the division of lymphoma in the department of hematology and hematopoietic cell transplantation, City of Hope Medical Center, Duarte, Calif., said in an interview.

The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab.

The results are especially important considering that Hodgkin lymphoma disproportionately affects younger patients, including those in their teens, 20s, and 30s, Dr. Herrera noted in an interview.

“We found that treatment with nivolumab reduced the risk of progression by half, and, importantly, the benefit was observed across subgroups,” he said.
 

Relapse/refractory disease common in advanced HL

In general, outcomes are relatively good even for stage III or IV Hodgkin lymphoma; however, about a quarter of patients still have relapses or refractory disease.

While the introduction of novel frontline treatment with brentuximab-AVD was important in improving overall survival, the regimen adds toxicity, particularly among older patients, and many pediatric patients receiving the therapy still require radiation therapy, with its undesirable side effects.

Meanwhile, the progressive death 1 inhibitor nivolumab, approved by the Food and Drug Administration, gained interest as a potentially ideal alternative in light of Hodgkin lymphoma’s status basically as “the poster child for PD-1 blockade,” Dr. Herrera said.

“There are genetic changes in the Hodgkin lymphoma tumor cell that lead to expression of PD-1 ligands on the surface of Hodgkin lymphoma cells, and when we use a drug like nivolumab, we see that even patients with the most treatment-resistant rates of lymphoma have as much as a 70% response rate,” he explained in a press briefing.

To further investigate, the first-of-its-kind collaboration of adult and pediatric cancer teams conducted the S1826 trial to evaluate the treatment across age groups with stage 3 and 4 Hodgkin lymphoma.

For the study, conducted between July 2019 and October 2022, 976 patients were randomized to treatment either with nivolumab (n = 489) or brentuximab (n = 487), each in combination with the AVD regimen.

Of the patients, the median age was 27, with 24% under the age of 18, 10% over 60 and 32% with IPS 4-7. Among them, 56% were male and 76% were White.

For the primary endpoint, at a median follow-up of 12.1 months, the rate of progression-free survival was significantly higher in the nivolumab arm (hazard ratio, 0.48; one-sided P = .0005), with the rate of 1-year survival at 94% in the nivolumab group versus 86% in the brentuximab group, for a 52% reduction in the risk of disease-related death with nivolumab versus brentuximab.

A total of 11 deaths occurred in the brentuximab group, 7 of which were related to adverse events, compared with 4 deaths in the nivolumab group, 3 of which were related to nivolumab.

Importantly, fewer than 1% of patients with nivolumab required radiation therapy.

“That’s a dramatic reduction of the proportion of the very youngest patients receiving radiotherapy,” Dr. Herrera noted.

Grade 3 or higher hematologic adverse events were higher in the nivolumab group, at 48.4%, including 45.1% that were grade 3 or higher neutropenia, compared with 30.5% with brentuximab, including 23.9% with grade 3 or higher neutropenia.

However, rates of any grade of febrile neutropenia were similar with nivolumab and brentuximab (5.6% vs. 6.4%, respectively), as were rates of pneumonitis (2.0% vs. 3.2%), ALT elevation (30.7% vs. 39.8%), and colitis (1% vs. 1.3%).

In addition, rates of hypo- and hyperthyroidism were more frequent after nivolumab (7% and 3% with nivolumab, respectively, vs. fewer than 1% with brentuximab).

But, of note, peripheral neuropathy of any grade was more common after brentuximab (sensory: 28.1% nivolumab vs. 54.2% brentuximab; motor: 4% nivolumab vs. 6.8% brentuximab).

“I can’t emphasize how important neuropathy is as a side effect in these young patients who have the rest of their life ahead of them,” Dr. Herrera explained. “It’s fantastic to be cured of cancer, but tough to not be able to feel your fingers and toes.”

With its broad inclusion of age groups and a diverse population, he added that the study was importantly a “representative” trial, reflecting a “real-world population.”

“Incredibly, a quarter of patients were under the age of 18; 10% were over the age of 60, a quarter of patients were Hispanic and Black, and in fact we had a quite good representation of higher-risk subgroups,” he said.

Looking forward, longer-term follow-up from this study will be important in determining if the improvement observed in disease-related deaths is maintained over time, Dr. Herrera noted.

“Additionally, it is crucial to obtain data on other key outcomes such as overall survival and quality of life from longer-term follow of this study,” he said.
 

‘A huge step forward’

Commenting on the study, Oreofe Odejide, MD, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, said that results were unprecedented.

“Although a majority of patients with advanced stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still end up with relapsed or refractory disease,” she said in an interview. “Therefore, the findings from this study represent a huge step forward in the management of advanced Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”

Dr. Odejide agreed that the findings are potentially practice changing.

“Brentuximab-AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared to ABVD chemotherapy in several years,” she explained.

“The fact that the SWOG1826 trial now shows a significant benefit of nivolumab-AVD over brentuximab and included both pediatric and adult patients unlike prior studies, is highly compelling,” Dr. Odejide added. “This has strong potential to change the standard of care for patients with previously untreated, advanced-stage Hodgkin lymphoma.”

The study received funding from the National Cancer Institute and from Bristol-Myers Squibb. Dr. Herrera reported relationships with Abbvie, ADC Therapeutics, Adicet Bio, AstraZeneca/MedImmune, Bristol-Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Tubulis Gmbh. Dr. Odejide reported no disclosures.

Across patients’ age groups, adding the immune checkpoint inhibitor nivolumab to chemotherapy significantly improves progression-free survival in advanced stage Hodgkin lymphoma while also reducing toxicities, making it a new standard of care, compared with the CD30-targeting drug brentuximab vedotin.

“[SWOG] S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma,” the authors reported in late-breaking research presented at the annual meeting of the American Society of Clinical Oncology.

“Based on the magnitude of the benefit and with nivolumab being better tolerated than brentuximab, we anticipate that these results will be practice changing and nivolumab [and chemotherapy] will become a new standard of care,” lead author Alex Francisco Herrera, MD, an associate professor and chief of the division of lymphoma in the department of hematology and hematopoietic cell transplantation, City of Hope Medical Center, Duarte, Calif., said in an interview.

The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab.

The results are especially important considering that Hodgkin lymphoma disproportionately affects younger patients, including those in their teens, 20s, and 30s, Dr. Herrera noted in an interview.

“We found that treatment with nivolumab reduced the risk of progression by half, and, importantly, the benefit was observed across subgroups,” he said.
 

Relapse/refractory disease common in advanced HL

In general, outcomes are relatively good even for stage III or IV Hodgkin lymphoma; however, about a quarter of patients still have relapses or refractory disease.

While the introduction of novel frontline treatment with brentuximab-AVD was important in improving overall survival, the regimen adds toxicity, particularly among older patients, and many pediatric patients receiving the therapy still require radiation therapy, with its undesirable side effects.

Meanwhile, the progressive death 1 inhibitor nivolumab, approved by the Food and Drug Administration, gained interest as a potentially ideal alternative in light of Hodgkin lymphoma’s status basically as “the poster child for PD-1 blockade,” Dr. Herrera said.

“There are genetic changes in the Hodgkin lymphoma tumor cell that lead to expression of PD-1 ligands on the surface of Hodgkin lymphoma cells, and when we use a drug like nivolumab, we see that even patients with the most treatment-resistant rates of lymphoma have as much as a 70% response rate,” he explained in a press briefing.

To further investigate, the first-of-its-kind collaboration of adult and pediatric cancer teams conducted the S1826 trial to evaluate the treatment across age groups with stage 3 and 4 Hodgkin lymphoma.

For the study, conducted between July 2019 and October 2022, 976 patients were randomized to treatment either with nivolumab (n = 489) or brentuximab (n = 487), each in combination with the AVD regimen.

Of the patients, the median age was 27, with 24% under the age of 18, 10% over 60 and 32% with IPS 4-7. Among them, 56% were male and 76% were White.

For the primary endpoint, at a median follow-up of 12.1 months, the rate of progression-free survival was significantly higher in the nivolumab arm (hazard ratio, 0.48; one-sided P = .0005), with the rate of 1-year survival at 94% in the nivolumab group versus 86% in the brentuximab group, for a 52% reduction in the risk of disease-related death with nivolumab versus brentuximab.

A total of 11 deaths occurred in the brentuximab group, 7 of which were related to adverse events, compared with 4 deaths in the nivolumab group, 3 of which were related to nivolumab.

Importantly, fewer than 1% of patients with nivolumab required radiation therapy.

“That’s a dramatic reduction of the proportion of the very youngest patients receiving radiotherapy,” Dr. Herrera noted.

Grade 3 or higher hematologic adverse events were higher in the nivolumab group, at 48.4%, including 45.1% that were grade 3 or higher neutropenia, compared with 30.5% with brentuximab, including 23.9% with grade 3 or higher neutropenia.

However, rates of any grade of febrile neutropenia were similar with nivolumab and brentuximab (5.6% vs. 6.4%, respectively), as were rates of pneumonitis (2.0% vs. 3.2%), ALT elevation (30.7% vs. 39.8%), and colitis (1% vs. 1.3%).

In addition, rates of hypo- and hyperthyroidism were more frequent after nivolumab (7% and 3% with nivolumab, respectively, vs. fewer than 1% with brentuximab).

But, of note, peripheral neuropathy of any grade was more common after brentuximab (sensory: 28.1% nivolumab vs. 54.2% brentuximab; motor: 4% nivolumab vs. 6.8% brentuximab).

“I can’t emphasize how important neuropathy is as a side effect in these young patients who have the rest of their life ahead of them,” Dr. Herrera explained. “It’s fantastic to be cured of cancer, but tough to not be able to feel your fingers and toes.”

With its broad inclusion of age groups and a diverse population, he added that the study was importantly a “representative” trial, reflecting a “real-world population.”

“Incredibly, a quarter of patients were under the age of 18; 10% were over the age of 60, a quarter of patients were Hispanic and Black, and in fact we had a quite good representation of higher-risk subgroups,” he said.

Looking forward, longer-term follow-up from this study will be important in determining if the improvement observed in disease-related deaths is maintained over time, Dr. Herrera noted.

“Additionally, it is crucial to obtain data on other key outcomes such as overall survival and quality of life from longer-term follow of this study,” he said.
 

‘A huge step forward’

Commenting on the study, Oreofe Odejide, MD, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, said that results were unprecedented.

“Although a majority of patients with advanced stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still end up with relapsed or refractory disease,” she said in an interview. “Therefore, the findings from this study represent a huge step forward in the management of advanced Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”

Dr. Odejide agreed that the findings are potentially practice changing.

“Brentuximab-AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared to ABVD chemotherapy in several years,” she explained.

“The fact that the SWOG1826 trial now shows a significant benefit of nivolumab-AVD over brentuximab and included both pediatric and adult patients unlike prior studies, is highly compelling,” Dr. Odejide added. “This has strong potential to change the standard of care for patients with previously untreated, advanced-stage Hodgkin lymphoma.”

The study received funding from the National Cancer Institute and from Bristol-Myers Squibb. Dr. Herrera reported relationships with Abbvie, ADC Therapeutics, Adicet Bio, AstraZeneca/MedImmune, Bristol-Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Tubulis Gmbh. Dr. Odejide reported no disclosures.

While physicians are getting less of a Medicare pay cut than they thought this year (Congress voted to cut Medicare payments by 2%, which was less than the expected 8.5%), Medicare still pays physicians only 80% of what many third-party insurers pay.

Moreover, those reimbursements are often slow to arrive, and the paperwork is burdensome. In fact, about 65% of doctors won’t accept new Medicare patients, down from 71% just 5 years ago, according to the Medscape Physician Compensation Report 2023.

Worse, inflation makes continuous cuts feel even steeper and trickles down to physicians and their patients as more and more doctors become disenchanted and consider dropping Medicare.
 

Medicare at a glance

Medicare pays physicians about 80% of the “reasonable charge” for covered services. At the same time, private insurers pay nearly double Medicare rates for hospital services.

The Medicare fee schedule is released each year. Physicians who accept Medicare can choose to be a “participating provider” by agreeing to the fee schedule and to not charging more than this amount. “Nonparticipating” providers can charge up to 15% more. Physicians can also opt out of Medicare entirely.

The earliest that physicians receive their payment is 14 days after electronic filing to 28 days after paper filing, but it often can take months.

Physicians lose an estimated 7.3% of Medicare claims to billing problems. With private insurers, an estimated 4.8% is lost.

In 2000, there were 50 million Medicare enrollees; it is projected that by 2050, there will be 87 million enrollees.
 

Why are doctors disenchanted?

“When Medicare started, the concept of the program was good,” said Rahul Gupta, MD, a geriatrician in Westport, Conn., and chief of internal medicine at St. Vincent’s Medical Center, Bridgeport, Conn. “However, over the years, with new developments in medicine and the explosion of the Medicare-eligible population, the program hasn’t kept up with coverages.” In addition, Medicare’s behemoth power as a government-run agency has ramifications that trickle down irrespective of a patient’s insurance carrier.

“Medicare sets the tone on price and reimbursement, and everyone follows suit,” Dr. Gupta said. “It’s a race to the bottom.”

“The program is great for patients when people need hospitalizations, skilled nursing, and physical therapy,” Dr. Gupta said. “But it’s not great about keeping people healthier and maintaining function via preventive treatments.” Many private insurers must become more adept at that too.

For instance, Dr. Gupta laments the lack of coverage for hearing aids, something his patients could greatly benefit from. Thanks to the Build Back Better bill, coverage of hearing aids will begin in 2024. But, again, most private insurers don’t cover hearing aids either. Some Medicare Advantage plans do.

Medicare doesn’t cover eye health (except for eye exams for diabetes patients), which is an issue for Daniel Laroche, MD, a glaucoma specialist and clinical associate professor of ophthalmology at Mount Sinai Medical Center, New York.

“I get paid less for Medicare patients by about 20% because of ‘lesser-of’ payments,” said Dr. Laroche. For example, as per Medicare, after patients meet their Part B deductible, they pay 20% of the Medicare-approved amount for glaucoma testing. “It would be nice to get the full amount for Medicare patients.”

“In addition, getting approvals for testing takes time and exhaustive amounts of paperwork, says Adeeti Gupta, MD, a gynecologist and founder of Walk In GYN Care in New York.

“Medicare only covers gynecologist visits every 2 years after the age of 65,” she said. “Any additional testing requires authorization, and Medicare doesn’t cover hormone replacement at all, which really makes me crazy. They will cover Viagra for men, but they won’t cover HRT, which prolongs life, reduces dementia, and prevents bone loss.”

While these three doctors find Medicare lacking in its coverage of their specialty, and their reimbursements are too low, many physicians also find fault regarding Medicare billing, which can put their patients at risk.
 

The problem with Medicare billing

Because claims are processed by Medicare administrative contractors, it can take about a month for the approval or denial process and for doctors to receive reimbursement.

Prior authorizations, especially with Medicare Advantage plans, are also problematic. For example, one 2022 study found that 18% of payment denials were for services that met coverage and billing rules.

Worse, all of this jockeying for coverage takes time. The average health care provider spends 16.4 hours a week on paperwork and on securing prior authorizations to cover services, according to the American Medical Association.

“A good 40% of my time is exclusively Medicare red tape paperwork,” Rahul Gupta says. “There’s a reason I spend 2-3 hours a night catching up on that stuff.”

Not only does this lead to burnout, but it also means that most physicians must hire an administrator to help with the paperwork.

In comparison, industry averages put the denial rate for all Medicare and private insurance claims at 20%.

“Excessive authorization controls required by health insurers are persistently responsible for serious harm to physician practices and patients when necessary medical care is delayed, denied, or disrupted in an attempt to increase profits,” Dr. Laroche said.

“Our office spends nearly 2 days per week on prior authorizations, creating costly administrative burdens.”

For Adeeti Gupta, the frustrations with Medicare have continued to mount. “We’re just at a dead end,” she said. “Authorizations keep getting denied, and the back-end paperwork is only increasing for us.”
 

Will more doctors opt out of Medicare?

When doctors don’t accept Medicare, it hurts the patients using it, especially patients who have selected either a Medicare Advantage plan or who become eligible for Medicare at age 65 only to find that fewer doctors take the government-sponsored insurance than in the past.

As of 2020, only 1% of nonpediatric physicians had formally opted out, per the Centers for Medicare & Medicaid Services. Psychiatrists account for the largest share of opt-outs (7.2%).

“Unfortunately, most doctors outside of hospital-based practices will reach a point when they can’t deal with Medicare paperwork, so they’ll stop taking it,” Rahul Gupta says.

A coalition of 120 physicians’ groups, including the American Medical Association, disputes that Medicare is paying a fair reimbursement rate to physicians and calls for an overhaul in how they adjust physician pay.

“Nothing much changes no matter how much the AMA shouts,” Rahul Gupta said in an interview.
 

What can doctors do

Prescription prices are another example of the challenges posed by Medicare. When prescriptions are denied because of Medicare’s medigap (or donut hole) program, which puts a cap on medication coverage, which was $4,660 in 2023, Dr. Gupta says she turns to alternative ways to fill them.

“I’ve been telling patients to pay out of pocket and use GoodRx, or we get medications compounded,” she said. “That’s cheaper. For example, for HRT, GoodRx can bring down the cost 40% to 50%.”

The American Medical Association as well as 150 other medical advocacy groups continue to urge Congress to work with the physician community to address the systematic problems within Medicare, especially reimbursement.

Despite the daily challenges, Rahul Gupta says he remains committed to caring for his patients.

“I want to care for the elderly, especially because they already have very few physicians to take care of them, and fortunately, I have a good practice with other coverages,” he said. “I can’t give up.”

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

While physicians are getting less of a Medicare pay cut than they thought this year (Congress voted to cut Medicare payments by 2%, which was less than the expected 8.5%), Medicare still pays physicians only 80% of what many third-party insurers pay.

Moreover, those reimbursements are often slow to arrive, and the paperwork is burdensome. In fact, about 65% of doctors won’t accept new Medicare patients, down from 71% just 5 years ago, according to the Medscape Physician Compensation Report 2023.

Worse, inflation makes continuous cuts feel even steeper and trickles down to physicians and their patients as more and more doctors become disenchanted and consider dropping Medicare.
 

Medicare at a glance

Medicare pays physicians about 80% of the “reasonable charge” for covered services. At the same time, private insurers pay nearly double Medicare rates for hospital services.

The Medicare fee schedule is released each year. Physicians who accept Medicare can choose to be a “participating provider” by agreeing to the fee schedule and to not charging more than this amount. “Nonparticipating” providers can charge up to 15% more. Physicians can also opt out of Medicare entirely.

The earliest that physicians receive their payment is 14 days after electronic filing to 28 days after paper filing, but it often can take months.

Physicians lose an estimated 7.3% of Medicare claims to billing problems. With private insurers, an estimated 4.8% is lost.

In 2000, there were 50 million Medicare enrollees; it is projected that by 2050, there will be 87 million enrollees.
 

Why are doctors disenchanted?

“When Medicare started, the concept of the program was good,” said Rahul Gupta, MD, a geriatrician in Westport, Conn., and chief of internal medicine at St. Vincent’s Medical Center, Bridgeport, Conn. “However, over the years, with new developments in medicine and the explosion of the Medicare-eligible population, the program hasn’t kept up with coverages.” In addition, Medicare’s behemoth power as a government-run agency has ramifications that trickle down irrespective of a patient’s insurance carrier.

“Medicare sets the tone on price and reimbursement, and everyone follows suit,” Dr. Gupta said. “It’s a race to the bottom.”

“The program is great for patients when people need hospitalizations, skilled nursing, and physical therapy,” Dr. Gupta said. “But it’s not great about keeping people healthier and maintaining function via preventive treatments.” Many private insurers must become more adept at that too.

For instance, Dr. Gupta laments the lack of coverage for hearing aids, something his patients could greatly benefit from. Thanks to the Build Back Better bill, coverage of hearing aids will begin in 2024. But, again, most private insurers don’t cover hearing aids either. Some Medicare Advantage plans do.

Medicare doesn’t cover eye health (except for eye exams for diabetes patients), which is an issue for Daniel Laroche, MD, a glaucoma specialist and clinical associate professor of ophthalmology at Mount Sinai Medical Center, New York.

“I get paid less for Medicare patients by about 20% because of ‘lesser-of’ payments,” said Dr. Laroche. For example, as per Medicare, after patients meet their Part B deductible, they pay 20% of the Medicare-approved amount for glaucoma testing. “It would be nice to get the full amount for Medicare patients.”

“In addition, getting approvals for testing takes time and exhaustive amounts of paperwork, says Adeeti Gupta, MD, a gynecologist and founder of Walk In GYN Care in New York.

“Medicare only covers gynecologist visits every 2 years after the age of 65,” she said. “Any additional testing requires authorization, and Medicare doesn’t cover hormone replacement at all, which really makes me crazy. They will cover Viagra for men, but they won’t cover HRT, which prolongs life, reduces dementia, and prevents bone loss.”

While these three doctors find Medicare lacking in its coverage of their specialty, and their reimbursements are too low, many physicians also find fault regarding Medicare billing, which can put their patients at risk.
 

The problem with Medicare billing

Because claims are processed by Medicare administrative contractors, it can take about a month for the approval or denial process and for doctors to receive reimbursement.

Prior authorizations, especially with Medicare Advantage plans, are also problematic. For example, one 2022 study found that 18% of payment denials were for services that met coverage and billing rules.

Worse, all of this jockeying for coverage takes time. The average health care provider spends 16.4 hours a week on paperwork and on securing prior authorizations to cover services, according to the American Medical Association.

“A good 40% of my time is exclusively Medicare red tape paperwork,” Rahul Gupta says. “There’s a reason I spend 2-3 hours a night catching up on that stuff.”

Not only does this lead to burnout, but it also means that most physicians must hire an administrator to help with the paperwork.

In comparison, industry averages put the denial rate for all Medicare and private insurance claims at 20%.

“Excessive authorization controls required by health insurers are persistently responsible for serious harm to physician practices and patients when necessary medical care is delayed, denied, or disrupted in an attempt to increase profits,” Dr. Laroche said.

“Our office spends nearly 2 days per week on prior authorizations, creating costly administrative burdens.”

For Adeeti Gupta, the frustrations with Medicare have continued to mount. “We’re just at a dead end,” she said. “Authorizations keep getting denied, and the back-end paperwork is only increasing for us.”
 

Will more doctors opt out of Medicare?

When doctors don’t accept Medicare, it hurts the patients using it, especially patients who have selected either a Medicare Advantage plan or who become eligible for Medicare at age 65 only to find that fewer doctors take the government-sponsored insurance than in the past.

As of 2020, only 1% of nonpediatric physicians had formally opted out, per the Centers for Medicare & Medicaid Services. Psychiatrists account for the largest share of opt-outs (7.2%).

“Unfortunately, most doctors outside of hospital-based practices will reach a point when they can’t deal with Medicare paperwork, so they’ll stop taking it,” Rahul Gupta says.

A coalition of 120 physicians’ groups, including the American Medical Association, disputes that Medicare is paying a fair reimbursement rate to physicians and calls for an overhaul in how they adjust physician pay.

“Nothing much changes no matter how much the AMA shouts,” Rahul Gupta said in an interview.
 

What can doctors do

Prescription prices are another example of the challenges posed by Medicare. When prescriptions are denied because of Medicare’s medigap (or donut hole) program, which puts a cap on medication coverage, which was $4,660 in 2023, Dr. Gupta says she turns to alternative ways to fill them.

“I’ve been telling patients to pay out of pocket and use GoodRx, or we get medications compounded,” she said. “That’s cheaper. For example, for HRT, GoodRx can bring down the cost 40% to 50%.”

The American Medical Association as well as 150 other medical advocacy groups continue to urge Congress to work with the physician community to address the systematic problems within Medicare, especially reimbursement.

Despite the daily challenges, Rahul Gupta says he remains committed to caring for his patients.

“I want to care for the elderly, especially because they already have very few physicians to take care of them, and fortunately, I have a good practice with other coverages,” he said. “I can’t give up.”

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

While physicians are getting less of a Medicare pay cut than they thought this year (Congress voted to cut Medicare payments by 2%, which was less than the expected 8.5%), Medicare still pays physicians only 80% of what many third-party insurers pay.

Moreover, those reimbursements are often slow to arrive, and the paperwork is burdensome. In fact, about 65% of doctors won’t accept new Medicare patients, down from 71% just 5 years ago, according to the Medscape Physician Compensation Report 2023.

Worse, inflation makes continuous cuts feel even steeper and trickles down to physicians and their patients as more and more doctors become disenchanted and consider dropping Medicare.
 

Medicare at a glance

Medicare pays physicians about 80% of the “reasonable charge” for covered services. At the same time, private insurers pay nearly double Medicare rates for hospital services.

The Medicare fee schedule is released each year. Physicians who accept Medicare can choose to be a “participating provider” by agreeing to the fee schedule and to not charging more than this amount. “Nonparticipating” providers can charge up to 15% more. Physicians can also opt out of Medicare entirely.

The earliest that physicians receive their payment is 14 days after electronic filing to 28 days after paper filing, but it often can take months.

Physicians lose an estimated 7.3% of Medicare claims to billing problems. With private insurers, an estimated 4.8% is lost.

In 2000, there were 50 million Medicare enrollees; it is projected that by 2050, there will be 87 million enrollees.
 

Why are doctors disenchanted?

“When Medicare started, the concept of the program was good,” said Rahul Gupta, MD, a geriatrician in Westport, Conn., and chief of internal medicine at St. Vincent’s Medical Center, Bridgeport, Conn. “However, over the years, with new developments in medicine and the explosion of the Medicare-eligible population, the program hasn’t kept up with coverages.” In addition, Medicare’s behemoth power as a government-run agency has ramifications that trickle down irrespective of a patient’s insurance carrier.

“Medicare sets the tone on price and reimbursement, and everyone follows suit,” Dr. Gupta said. “It’s a race to the bottom.”

“The program is great for patients when people need hospitalizations, skilled nursing, and physical therapy,” Dr. Gupta said. “But it’s not great about keeping people healthier and maintaining function via preventive treatments.” Many private insurers must become more adept at that too.

For instance, Dr. Gupta laments the lack of coverage for hearing aids, something his patients could greatly benefit from. Thanks to the Build Back Better bill, coverage of hearing aids will begin in 2024. But, again, most private insurers don’t cover hearing aids either. Some Medicare Advantage plans do.

Medicare doesn’t cover eye health (except for eye exams for diabetes patients), which is an issue for Daniel Laroche, MD, a glaucoma specialist and clinical associate professor of ophthalmology at Mount Sinai Medical Center, New York.

“I get paid less for Medicare patients by about 20% because of ‘lesser-of’ payments,” said Dr. Laroche. For example, as per Medicare, after patients meet their Part B deductible, they pay 20% of the Medicare-approved amount for glaucoma testing. “It would be nice to get the full amount for Medicare patients.”

“In addition, getting approvals for testing takes time and exhaustive amounts of paperwork, says Adeeti Gupta, MD, a gynecologist and founder of Walk In GYN Care in New York.

“Medicare only covers gynecologist visits every 2 years after the age of 65,” she said. “Any additional testing requires authorization, and Medicare doesn’t cover hormone replacement at all, which really makes me crazy. They will cover Viagra for men, but they won’t cover HRT, which prolongs life, reduces dementia, and prevents bone loss.”

While these three doctors find Medicare lacking in its coverage of their specialty, and their reimbursements are too low, many physicians also find fault regarding Medicare billing, which can put their patients at risk.
 

The problem with Medicare billing

Because claims are processed by Medicare administrative contractors, it can take about a month for the approval or denial process and for doctors to receive reimbursement.

Prior authorizations, especially with Medicare Advantage plans, are also problematic. For example, one 2022 study found that 18% of payment denials were for services that met coverage and billing rules.

Worse, all of this jockeying for coverage takes time. The average health care provider spends 16.4 hours a week on paperwork and on securing prior authorizations to cover services, according to the American Medical Association.

“A good 40% of my time is exclusively Medicare red tape paperwork,” Rahul Gupta says. “There’s a reason I spend 2-3 hours a night catching up on that stuff.”

Not only does this lead to burnout, but it also means that most physicians must hire an administrator to help with the paperwork.

In comparison, industry averages put the denial rate for all Medicare and private insurance claims at 20%.

“Excessive authorization controls required by health insurers are persistently responsible for serious harm to physician practices and patients when necessary medical care is delayed, denied, or disrupted in an attempt to increase profits,” Dr. Laroche said.

“Our office spends nearly 2 days per week on prior authorizations, creating costly administrative burdens.”

For Adeeti Gupta, the frustrations with Medicare have continued to mount. “We’re just at a dead end,” she said. “Authorizations keep getting denied, and the back-end paperwork is only increasing for us.”
 

Will more doctors opt out of Medicare?

When doctors don’t accept Medicare, it hurts the patients using it, especially patients who have selected either a Medicare Advantage plan or who become eligible for Medicare at age 65 only to find that fewer doctors take the government-sponsored insurance than in the past.

As of 2020, only 1% of nonpediatric physicians had formally opted out, per the Centers for Medicare & Medicaid Services. Psychiatrists account for the largest share of opt-outs (7.2%).

“Unfortunately, most doctors outside of hospital-based practices will reach a point when they can’t deal with Medicare paperwork, so they’ll stop taking it,” Rahul Gupta says.

A coalition of 120 physicians’ groups, including the American Medical Association, disputes that Medicare is paying a fair reimbursement rate to physicians and calls for an overhaul in how they adjust physician pay.

“Nothing much changes no matter how much the AMA shouts,” Rahul Gupta said in an interview.
 

What can doctors do

Prescription prices are another example of the challenges posed by Medicare. When prescriptions are denied because of Medicare’s medigap (or donut hole) program, which puts a cap on medication coverage, which was $4,660 in 2023, Dr. Gupta says she turns to alternative ways to fill them.

“I’ve been telling patients to pay out of pocket and use GoodRx, or we get medications compounded,” she said. “That’s cheaper. For example, for HRT, GoodRx can bring down the cost 40% to 50%.”

The American Medical Association as well as 150 other medical advocacy groups continue to urge Congress to work with the physician community to address the systematic problems within Medicare, especially reimbursement.

Despite the daily challenges, Rahul Gupta says he remains committed to caring for his patients.

“I want to care for the elderly, especially because they already have very few physicians to take care of them, and fortunately, I have a good practice with other coverages,” he said. “I can’t give up.”

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

The costs of providing evidence-based interventions in primary care to address social needs far exceed current federal funding streams, say the authors of a new analysis.

A microsimulation analysis by Sanjay Basu, MD, PhD, with Clinical Product Development, Waymark Care, San Francisco, and colleagues found that, as primary care practices are being asked to screen for social needs, the cost of providing evidence-based interventions for these needs averaged $60 per member/person per month (PMPM) (95% confidence interval, $55-$65).

However, less than half ($27) of the $60 cost had existing federal financing in place to pay for it. Of the $60, $5 was for screening and referral.

The study results were published in JAMA Internal Medicine.

The researchers looked at key social needs areas and found major gaps between what interventions cost and what’s covered by federal payers. They demonstrate the gaps in four key areas. Many people in the analysis have more than one need:

• Food insecurity: Cost was $23 PMPM and the proportion borne by existing federal payers was 61.6%.
• Housing insecurity: Cost was $3 PMPM; proportion borne by federal payers was 45.6%.
• Transportation insecurity: Cost was $0.1 PMPM; proportion borne by federal payers was 27.8%.
• Community-based care coordination: Cost was $0.6 PMPM; proportion borne by federal payers is 6.4%.

Gaps varied by type of center

Primary care practices were grouped into federally qualified health centers; non-FQHC urban practices in high-poverty areas; non-FQHC rural practices in high-poverty areas; and practices in lower-poverty areas. Gaps varied among the groups.

While disproportionate funding was available to populations seen at FQHCs, populations seen at non-FQHC practices in high-poverty areas had larger funding gaps.

The study population consisted of 19,225 patients seen in primary care practices; data on social needs were pulled from the National Center for Health Statistics from 2015 to 2018.

Dr. Basu said in an interview with the journal’s deputy editor, Mitchell Katz, MD, that new sustainable revenue streams need to be identified to close the gap. Primary care physicians should not be charged with tasks such as researching the best housing programs and food benefits.

“I can’t imagine fitting this into my primary care appointments,” he said.
 

Is primary care the best setting for addressing these needs?

In an accompanying comment, Jenifer Clapp, MPA, with the Office of Ambulatory Care and Population Health, NYC Health + Hospitals, New York, and colleagues wrote that the study raises the question of whether the health care setting is the right place for addressing social needs. Some aspects have to be addressed in health care, such as asking about the home environment for a patient with environmentally triggered asthma.

“But how involved should health care professionals be in identifying needs unrelated to illness and solving those needs?” Ms. Clapp and colleagues asked.

They wrote that the health care sector in the United States must address these needs because in the United States, unlike in many European countries, “there is an insufficient social service sector to address the basic human needs of children and working-age adults.”
 

Eligible but not enrolled

Importantly, both the study authors and editorialists pointed out, in many cases, intervening doesn’t mean paying for the social services, but helping patients enroll in the services for which they already qualify.

The study authors wrote that among people who had food and housing needs, most met the criteria for federally funded programs, but had low enrollment for reasons including inadequate program capacity.

For example, 78% of people with housing needs were eligible for federal programs but only 24% were enrolled, and 95.6% of people with food needs were eligible for programs but only 70.2% were enrolled in programs like the Supplemental Nutrition and Assistance Program and Women, Infants and Children.

Commentary coauthor Nichola Davis, MD, also with NYC Health + Hospitals, said one thing they’ve done at NYC Health + Hospitals is partner with community-based organizations that provide food navigators so when patients screen positive for food insecurity they can then be seen by a food navigator to pinpoint appropriate programs.

The referral for those who indicate food insecurity is automatically generated by the electronic health system and appears on the after-visit summary.

“At the bare minimum, the patient would leave with a list of resources,” Dr. Davis said.
 

One place primary care providers can make a difference

Dr. Katz said that the $60 cost per person is much lower than that for a service such as an MRI.

“We should be able to achieve that,” he said.

Will Bleser, PhD, MSPH, assistant research director of health care transformation for social needs and health equity at the Duke-Margolis Center for Health Policy, Washington, said it’s exciting to see the per-person cost for social needs quantified.

He pointed to existing revenue options that have been underutilized.

Through Medicare, he noted, if you are part of a Medicare Advantage plan, there is a program implemented in 2020 called Special Supplemental Benefits for the Chronically Ill. “That authorizes Medicare Advantage plans to offer non–primarily health-related services through Medicare Advantage to individuals who meet certain chronic illness conditions.”

Non–primarily health-related services may include meals, transportation, and pest control, for example, the Centers for Medicare & Medicaid Services notes.

Also, within the shared-savings program of traditional Medicare, if an accountable care organization is providing quality care under the cost target and is reaping the savings, “you could use those bonuses to do things that you couldn’t do under the normal Medicare fee schedule like address social needs,” Dr. Bleser said.

Medicaid, he said, offers the most opportunities to address social needs through the health system. One policy mechanism within Medicaid is the Section 1115 Waiver, where states can propose to provide new services as long as they comply with the core rules of Medicaid and meet certain qualifications.
 

Avoiding checking boxes with no benefit to patients

Ms. Clapp and colleagues noted that whether health care professionals agree that social needs can or should be addressed in primary care, CMS will mandate social needs screening and reporting for all hospitalized adults starting in 2024. Additionally, the Joint Commission will require health care systems to gauge social needs and report on resources.

“We need to ensure that these mandates do not become administrative checkboxes that frustrate clinical staff and ratchet up health care costs with no benefit to patients,” they wrote.

Dr. Basu reported receiving personal fees from the University of California, Healthright360, Waymark and Collective Health outside the submitted work; he has a patent issued for a multimodel member outreach system; and a patent pending for operationalizing predicted changes in risk based on interventions. A coauthor reported grants from the North Carolina Department of Health and Human Services, Blue Cross Blue Shield of North Carolina, and personal fees from several nonprofit organizations outside the submitted work. Another coauthor reported personal fees from ZealCare outside the submitted work.

The costs of providing evidence-based interventions in primary care to address social needs far exceed current federal funding streams, say the authors of a new analysis.

A microsimulation analysis by Sanjay Basu, MD, PhD, with Clinical Product Development, Waymark Care, San Francisco, and colleagues found that, as primary care practices are being asked to screen for social needs, the cost of providing evidence-based interventions for these needs averaged $60 per member/person per month (PMPM) (95% confidence interval, $55-$65).

However, less than half ($27) of the $60 cost had existing federal financing in place to pay for it. Of the $60, $5 was for screening and referral.

The study results were published in JAMA Internal Medicine.

The researchers looked at key social needs areas and found major gaps between what interventions cost and what’s covered by federal payers. They demonstrate the gaps in four key areas. Many people in the analysis have more than one need:

• Food insecurity: Cost was $23 PMPM and the proportion borne by existing federal payers was 61.6%.
• Housing insecurity: Cost was $3 PMPM; proportion borne by federal payers was 45.6%.
• Transportation insecurity: Cost was $0.1 PMPM; proportion borne by federal payers was 27.8%.
• Community-based care coordination: Cost was $0.6 PMPM; proportion borne by federal payers is 6.4%.

Gaps varied by type of center

Primary care practices were grouped into federally qualified health centers; non-FQHC urban practices in high-poverty areas; non-FQHC rural practices in high-poverty areas; and practices in lower-poverty areas. Gaps varied among the groups.

While disproportionate funding was available to populations seen at FQHCs, populations seen at non-FQHC practices in high-poverty areas had larger funding gaps.

The study population consisted of 19,225 patients seen in primary care practices; data on social needs were pulled from the National Center for Health Statistics from 2015 to 2018.

Dr. Basu said in an interview with the journal’s deputy editor, Mitchell Katz, MD, that new sustainable revenue streams need to be identified to close the gap. Primary care physicians should not be charged with tasks such as researching the best housing programs and food benefits.

“I can’t imagine fitting this into my primary care appointments,” he said.
 

Is primary care the best setting for addressing these needs?

In an accompanying comment, Jenifer Clapp, MPA, with the Office of Ambulatory Care and Population Health, NYC Health + Hospitals, New York, and colleagues wrote that the study raises the question of whether the health care setting is the right place for addressing social needs. Some aspects have to be addressed in health care, such as asking about the home environment for a patient with environmentally triggered asthma.

“But how involved should health care professionals be in identifying needs unrelated to illness and solving those needs?” Ms. Clapp and colleagues asked.

They wrote that the health care sector in the United States must address these needs because in the United States, unlike in many European countries, “there is an insufficient social service sector to address the basic human needs of children and working-age adults.”
 

Eligible but not enrolled

Importantly, both the study authors and editorialists pointed out, in many cases, intervening doesn’t mean paying for the social services, but helping patients enroll in the services for which they already qualify.

The study authors wrote that among people who had food and housing needs, most met the criteria for federally funded programs, but had low enrollment for reasons including inadequate program capacity.

For example, 78% of people with housing needs were eligible for federal programs but only 24% were enrolled, and 95.6% of people with food needs were eligible for programs but only 70.2% were enrolled in programs like the Supplemental Nutrition and Assistance Program and Women, Infants and Children.

Commentary coauthor Nichola Davis, MD, also with NYC Health + Hospitals, said one thing they’ve done at NYC Health + Hospitals is partner with community-based organizations that provide food navigators so when patients screen positive for food insecurity they can then be seen by a food navigator to pinpoint appropriate programs.

The referral for those who indicate food insecurity is automatically generated by the electronic health system and appears on the after-visit summary.

“At the bare minimum, the patient would leave with a list of resources,” Dr. Davis said.
 

One place primary care providers can make a difference

Dr. Katz said that the $60 cost per person is much lower than that for a service such as an MRI.

“We should be able to achieve that,” he said.

Will Bleser, PhD, MSPH, assistant research director of health care transformation for social needs and health equity at the Duke-Margolis Center for Health Policy, Washington, said it’s exciting to see the per-person cost for social needs quantified.

He pointed to existing revenue options that have been underutilized.

Through Medicare, he noted, if you are part of a Medicare Advantage plan, there is a program implemented in 2020 called Special Supplemental Benefits for the Chronically Ill. “That authorizes Medicare Advantage plans to offer non–primarily health-related services through Medicare Advantage to individuals who meet certain chronic illness conditions.”

Non–primarily health-related services may include meals, transportation, and pest control, for example, the Centers for Medicare & Medicaid Services notes.

Also, within the shared-savings program of traditional Medicare, if an accountable care organization is providing quality care under the cost target and is reaping the savings, “you could use those bonuses to do things that you couldn’t do under the normal Medicare fee schedule like address social needs,” Dr. Bleser said.

Medicaid, he said, offers the most opportunities to address social needs through the health system. One policy mechanism within Medicaid is the Section 1115 Waiver, where states can propose to provide new services as long as they comply with the core rules of Medicaid and meet certain qualifications.
 

Avoiding checking boxes with no benefit to patients

Ms. Clapp and colleagues noted that whether health care professionals agree that social needs can or should be addressed in primary care, CMS will mandate social needs screening and reporting for all hospitalized adults starting in 2024. Additionally, the Joint Commission will require health care systems to gauge social needs and report on resources.

“We need to ensure that these mandates do not become administrative checkboxes that frustrate clinical staff and ratchet up health care costs with no benefit to patients,” they wrote.

Dr. Basu reported receiving personal fees from the University of California, Healthright360, Waymark and Collective Health outside the submitted work; he has a patent issued for a multimodel member outreach system; and a patent pending for operationalizing predicted changes in risk based on interventions. A coauthor reported grants from the North Carolina Department of Health and Human Services, Blue Cross Blue Shield of North Carolina, and personal fees from several nonprofit organizations outside the submitted work. Another coauthor reported personal fees from ZealCare outside the submitted work.

The costs of providing evidence-based interventions in primary care to address social needs far exceed current federal funding streams, say the authors of a new analysis.

A microsimulation analysis by Sanjay Basu, MD, PhD, with Clinical Product Development, Waymark Care, San Francisco, and colleagues found that, as primary care practices are being asked to screen for social needs, the cost of providing evidence-based interventions for these needs averaged $60 per member/person per month (PMPM) (95% confidence interval, $55-$65).

However, less than half ($27) of the $60 cost had existing federal financing in place to pay for it. Of the $60, $5 was for screening and referral.

The study results were published in JAMA Internal Medicine.

The researchers looked at key social needs areas and found major gaps between what interventions cost and what’s covered by federal payers. They demonstrate the gaps in four key areas. Many people in the analysis have more than one need:

• Food insecurity: Cost was $23 PMPM and the proportion borne by existing federal payers was 61.6%.
• Housing insecurity: Cost was $3 PMPM; proportion borne by federal payers was 45.6%.
• Transportation insecurity: Cost was $0.1 PMPM; proportion borne by federal payers was 27.8%.
• Community-based care coordination: Cost was $0.6 PMPM; proportion borne by federal payers is 6.4%.

Gaps varied by type of center

Primary care practices were grouped into federally qualified health centers; non-FQHC urban practices in high-poverty areas; non-FQHC rural practices in high-poverty areas; and practices in lower-poverty areas. Gaps varied among the groups.

While disproportionate funding was available to populations seen at FQHCs, populations seen at non-FQHC practices in high-poverty areas had larger funding gaps.

The study population consisted of 19,225 patients seen in primary care practices; data on social needs were pulled from the National Center for Health Statistics from 2015 to 2018.

Dr. Basu said in an interview with the journal’s deputy editor, Mitchell Katz, MD, that new sustainable revenue streams need to be identified to close the gap. Primary care physicians should not be charged with tasks such as researching the best housing programs and food benefits.

“I can’t imagine fitting this into my primary care appointments,” he said.
 

Is primary care the best setting for addressing these needs?

In an accompanying comment, Jenifer Clapp, MPA, with the Office of Ambulatory Care and Population Health, NYC Health + Hospitals, New York, and colleagues wrote that the study raises the question of whether the health care setting is the right place for addressing social needs. Some aspects have to be addressed in health care, such as asking about the home environment for a patient with environmentally triggered asthma.

“But how involved should health care professionals be in identifying needs unrelated to illness and solving those needs?” Ms. Clapp and colleagues asked.

They wrote that the health care sector in the United States must address these needs because in the United States, unlike in many European countries, “there is an insufficient social service sector to address the basic human needs of children and working-age adults.”
 

Eligible but not enrolled

Importantly, both the study authors and editorialists pointed out, in many cases, intervening doesn’t mean paying for the social services, but helping patients enroll in the services for which they already qualify.

The study authors wrote that among people who had food and housing needs, most met the criteria for federally funded programs, but had low enrollment for reasons including inadequate program capacity.

For example, 78% of people with housing needs were eligible for federal programs but only 24% were enrolled, and 95.6% of people with food needs were eligible for programs but only 70.2% were enrolled in programs like the Supplemental Nutrition and Assistance Program and Women, Infants and Children.

Commentary coauthor Nichola Davis, MD, also with NYC Health + Hospitals, said one thing they’ve done at NYC Health + Hospitals is partner with community-based organizations that provide food navigators so when patients screen positive for food insecurity they can then be seen by a food navigator to pinpoint appropriate programs.

The referral for those who indicate food insecurity is automatically generated by the electronic health system and appears on the after-visit summary.

“At the bare minimum, the patient would leave with a list of resources,” Dr. Davis said.
 

One place primary care providers can make a difference

Dr. Katz said that the $60 cost per person is much lower than that for a service such as an MRI.

“We should be able to achieve that,” he said.

Will Bleser, PhD, MSPH, assistant research director of health care transformation for social needs and health equity at the Duke-Margolis Center for Health Policy, Washington, said it’s exciting to see the per-person cost for social needs quantified.

He pointed to existing revenue options that have been underutilized.

Through Medicare, he noted, if you are part of a Medicare Advantage plan, there is a program implemented in 2020 called Special Supplemental Benefits for the Chronically Ill. “That authorizes Medicare Advantage plans to offer non–primarily health-related services through Medicare Advantage to individuals who meet certain chronic illness conditions.”

Non–primarily health-related services may include meals, transportation, and pest control, for example, the Centers for Medicare & Medicaid Services notes.

Also, within the shared-savings program of traditional Medicare, if an accountable care organization is providing quality care under the cost target and is reaping the savings, “you could use those bonuses to do things that you couldn’t do under the normal Medicare fee schedule like address social needs,” Dr. Bleser said.

Medicaid, he said, offers the most opportunities to address social needs through the health system. One policy mechanism within Medicaid is the Section 1115 Waiver, where states can propose to provide new services as long as they comply with the core rules of Medicaid and meet certain qualifications.
 

Avoiding checking boxes with no benefit to patients

Ms. Clapp and colleagues noted that whether health care professionals agree that social needs can or should be addressed in primary care, CMS will mandate social needs screening and reporting for all hospitalized adults starting in 2024. Additionally, the Joint Commission will require health care systems to gauge social needs and report on resources.

“We need to ensure that these mandates do not become administrative checkboxes that frustrate clinical staff and ratchet up health care costs with no benefit to patients,” they wrote.

Dr. Basu reported receiving personal fees from the University of California, Healthright360, Waymark and Collective Health outside the submitted work; he has a patent issued for a multimodel member outreach system; and a patent pending for operationalizing predicted changes in risk based on interventions. A coauthor reported grants from the North Carolina Department of Health and Human Services, Blue Cross Blue Shield of North Carolina, and personal fees from several nonprofit organizations outside the submitted work. Another coauthor reported personal fees from ZealCare outside the submitted work.

More than 600,000 Americans have lost Medicaid coverage since pandemic protections ended on April 1. And a KFF Health News analysis of state data shows the vast majority were removed from state rolls for not completing paperwork.

Under normal circumstances, states review their Medicaid enrollment lists regularly to ensure every recipient qualifies for coverage. But because of a nationwide pause in those reviews during the pandemic, the health insurance program for low-income and disabled Americans kept people covered even if they no longer qualified.

Now, in what’s known as the Medicaid unwinding, states are combing through rolls and deciding who stays and who goes. People who are no longer eligible or don’t complete paperwork in time will be dropped.

The overwhelming majority of people who have lost coverage in most states were dropped because of technicalities, not because state officials determined they no longer meet Medicaid income limits. Four out of every five people dropped so far either never returned the paperwork or omitted required documents, according to a KFF Health News analysis of data from 11 states that provided details on recent cancellations. Now, lawmakers and advocates are expressing alarm over the volume of people losing coverage and, in some states, calling to pause the process.

KFF Health News sought data from the 19 states that started cancellations by May 1. Based on records from 14 states that provided detailed numbers, either in response to a public records request or by posting online, 36% of people whose eligibility was reviewed have been disenrolled.

In Indiana, 53,000 residents lost coverage in the first month of the unwinding, 89% for procedural reasons like not returning renewal forms. State Rep. Ed Clere, a Republican, expressed dismay at those “staggering numbers” in a May 24 Medicaid advisory group meeting, repeatedly questioning state officials about forms mailed to out-of-date addresses and urging them to give people more than 2 weeks’ notice before canceling their coverage.

Rep. Clere warned that the cancellations set in motion an avoidable revolving door. Some people dropped from Medicaid will have to forgo filling prescriptions and cancel doctor visits because they can’t afford care. Months down the line, after untreated chronic illnesses spiral out of control, they’ll end up in the emergency room where social workers will need to again help them join the program, he said.

Before the unwinding, more than one in four Americans – 93 million – were covered by Medicaid or CHIP, the Children’s Health Insurance Program, according to KFF Health News’ analysis of the latest enrollment data. Half of all kids are covered by the programs.

About 15 million people will be dropped over the next year as states review participants’ eligibility in monthly tranches.

Most people will find health coverage through new jobs or qualify for subsidized plans through the Affordable Care Act. But millions of others, including many children, will become uninsured and unable to afford basic prescriptions or preventive care. The uninsured rate among those under 65 is projected to rise from a historical low of 8.3% today to 9.3% next year, according to the Congressional Budget Office.

Because each state is handling the unwinding differently, the share of enrollees dropped in the first weeks varies widely.

Several states are first reviewing people officials believe are no longer eligible or who haven’t recently used their insurance. High cancellation rates in those states should level out as the agencies move on to people who likely still qualify.

In Utah, nearly 56% of people included in early reviews were dropped. In New Hampshire, 44% received cancellation letters within the first 2 months – almost all for procedural reasons, like not returning paperwork.

But New Hampshire officials found that thousands of people who didn’t fill out the forms indeed earn too much to qualify, according to Henry Lipman, the state’s Medicaid director. They would have been denied anyway. Even so, more people than he expected are not returning renewal forms. “That tells us that we need to change up our strategy,” said Mr. Lipman.

In other states, like Virginia and Nebraska, which aren’t prioritizing renewals by likely eligibility, about 90% have been renewed.

Because of the 3-year pause in renewals, many people on Medicaid have never been through the process or aren’t aware they may need to fill out long verification forms, as a recent KFF poll found. Some people moved and didn’t update their contact information.

And while agencies are required to assist enrollees who don’t speak English well, many are sending the forms in only a few common languages.

Tens of thousands of children are losing coverage, as researchers have warned, even though some may still qualify for Medicaid or CHIP. In its first month of reviews, South Dakota ended coverage for 10% of all Medicaid and CHIP enrollees in the state. More than half of them were children. In Arkansas, about 40% were kids.

Many parents don’t know that limits on household income are significantly higher for children than adults. Parents should fill out renewal forms even if they don’t qualify themselves, said Joan Alker, executive director of the Georgetown University Center for Children and Families, Washington.

New Hampshire has moved most families with children to the end of the review process. Mr. Lipman said his biggest worry is that a child will end up uninsured. Florida also planned to push kids with serious health conditions and other vulnerable groups to the end of the review line.

But according to Miriam Harmatz, advocacy director and founder of the Florida Health Justice Project, state officials sent cancellation letters to several clients with disabled children who probably still qualify. She’s helping those families appeal.

Nearly 250,000 Floridians reviewed in the first month of the unwinding lost coverage, 82% of them for reasons like incomplete paperwork, the state reported to federal authorities. House Democrats from the state petitioned Republican Gov. Ron DeSantis to pause the unwinding.

Advocacy coalitions in both Florida and Arkansas also have called for investigations into the review process and a pause on cancellations.

The state is contacting enrollees by phone, email, and text, and continues to process late applications, said Tori Cuddy, a spokesperson for the Florida Department of Children and Families. Ms. Cuddy did not respond to questions about issues raised in the petitions.

Federal officials are investigating those complaints and any other problems that emerge, said Dan Tsai, director of the Center for Medicaid & CHIP Services. “If we find that the rules are not being followed, we will take action.”

His agency has directed states to automatically reenroll residents using data from other government programs like unemployment and food assistance when possible. Anyone who can’t be approved through that process must act quickly.

“For the past 3 years, people have been told to ignore the mail around this, that the renewal was not going to lead to a termination.” Suddenly that mail matters, he said.

Federal law requires states to tell people why they’re losing Medicaid coverage and how to appeal the decision.

Ms. Harmatz said some cancellation notices in Florida are vague and could violate due process rules. Letters that she’s seen say “your Medicaid for this period is ending” rather than providing a specific reason for disenrollment, like having too high an income or incomplete paperwork.
If a person requests a hearing before their cancellation takes effect, they can stay covered during the appeals process. Even after being disenrolled, many still have a 90-day window to restore coverage.

In New Hampshire, 13% of people deemed ineligible in the first month have asked for extra time to provide the necessary records. “If you’re eligible for Medicaid, we don’t want you to lose it,” said Mr. Lipman.

Rep. Clere pushed Indiana’s Medicaid officials during the May meeting to immediately make changes to avoid people unnecessarily becoming uninsured. One official responded that they’ll learn and improve over time.

“I’m just concerned that we’re going to be ‘learning’ as a result of people losing coverage,” Rep. Clere replied. “So I don’t want to learn at their expense.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

More than 600,000 Americans have lost Medicaid coverage since pandemic protections ended on April 1. And a KFF Health News analysis of state data shows the vast majority were removed from state rolls for not completing paperwork.

Under normal circumstances, states review their Medicaid enrollment lists regularly to ensure every recipient qualifies for coverage. But because of a nationwide pause in those reviews during the pandemic, the health insurance program for low-income and disabled Americans kept people covered even if they no longer qualified.

Now, in what’s known as the Medicaid unwinding, states are combing through rolls and deciding who stays and who goes. People who are no longer eligible or don’t complete paperwork in time will be dropped.

The overwhelming majority of people who have lost coverage in most states were dropped because of technicalities, not because state officials determined they no longer meet Medicaid income limits. Four out of every five people dropped so far either never returned the paperwork or omitted required documents, according to a KFF Health News analysis of data from 11 states that provided details on recent cancellations. Now, lawmakers and advocates are expressing alarm over the volume of people losing coverage and, in some states, calling to pause the process.

KFF Health News sought data from the 19 states that started cancellations by May 1. Based on records from 14 states that provided detailed numbers, either in response to a public records request or by posting online, 36% of people whose eligibility was reviewed have been disenrolled.

In Indiana, 53,000 residents lost coverage in the first month of the unwinding, 89% for procedural reasons like not returning renewal forms. State Rep. Ed Clere, a Republican, expressed dismay at those “staggering numbers” in a May 24 Medicaid advisory group meeting, repeatedly questioning state officials about forms mailed to out-of-date addresses and urging them to give people more than 2 weeks’ notice before canceling their coverage.

Rep. Clere warned that the cancellations set in motion an avoidable revolving door. Some people dropped from Medicaid will have to forgo filling prescriptions and cancel doctor visits because they can’t afford care. Months down the line, after untreated chronic illnesses spiral out of control, they’ll end up in the emergency room where social workers will need to again help them join the program, he said.

Before the unwinding, more than one in four Americans – 93 million – were covered by Medicaid or CHIP, the Children’s Health Insurance Program, according to KFF Health News’ analysis of the latest enrollment data. Half of all kids are covered by the programs.

About 15 million people will be dropped over the next year as states review participants’ eligibility in monthly tranches.

Most people will find health coverage through new jobs or qualify for subsidized plans through the Affordable Care Act. But millions of others, including many children, will become uninsured and unable to afford basic prescriptions or preventive care. The uninsured rate among those under 65 is projected to rise from a historical low of 8.3% today to 9.3% next year, according to the Congressional Budget Office.

Because each state is handling the unwinding differently, the share of enrollees dropped in the first weeks varies widely.

Several states are first reviewing people officials believe are no longer eligible or who haven’t recently used their insurance. High cancellation rates in those states should level out as the agencies move on to people who likely still qualify.

In Utah, nearly 56% of people included in early reviews were dropped. In New Hampshire, 44% received cancellation letters within the first 2 months – almost all for procedural reasons, like not returning paperwork.

But New Hampshire officials found that thousands of people who didn’t fill out the forms indeed earn too much to qualify, according to Henry Lipman, the state’s Medicaid director. They would have been denied anyway. Even so, more people than he expected are not returning renewal forms. “That tells us that we need to change up our strategy,” said Mr. Lipman.

In other states, like Virginia and Nebraska, which aren’t prioritizing renewals by likely eligibility, about 90% have been renewed.

Because of the 3-year pause in renewals, many people on Medicaid have never been through the process or aren’t aware they may need to fill out long verification forms, as a recent KFF poll found. Some people moved and didn’t update their contact information.

And while agencies are required to assist enrollees who don’t speak English well, many are sending the forms in only a few common languages.

Tens of thousands of children are losing coverage, as researchers have warned, even though some may still qualify for Medicaid or CHIP. In its first month of reviews, South Dakota ended coverage for 10% of all Medicaid and CHIP enrollees in the state. More than half of them were children. In Arkansas, about 40% were kids.

Many parents don’t know that limits on household income are significantly higher for children than adults. Parents should fill out renewal forms even if they don’t qualify themselves, said Joan Alker, executive director of the Georgetown University Center for Children and Families, Washington.

New Hampshire has moved most families with children to the end of the review process. Mr. Lipman said his biggest worry is that a child will end up uninsured. Florida also planned to push kids with serious health conditions and other vulnerable groups to the end of the review line.

But according to Miriam Harmatz, advocacy director and founder of the Florida Health Justice Project, state officials sent cancellation letters to several clients with disabled children who probably still qualify. She’s helping those families appeal.

Nearly 250,000 Floridians reviewed in the first month of the unwinding lost coverage, 82% of them for reasons like incomplete paperwork, the state reported to federal authorities. House Democrats from the state petitioned Republican Gov. Ron DeSantis to pause the unwinding.

Advocacy coalitions in both Florida and Arkansas also have called for investigations into the review process and a pause on cancellations.

The state is contacting enrollees by phone, email, and text, and continues to process late applications, said Tori Cuddy, a spokesperson for the Florida Department of Children and Families. Ms. Cuddy did not respond to questions about issues raised in the petitions.

Federal officials are investigating those complaints and any other problems that emerge, said Dan Tsai, director of the Center for Medicaid & CHIP Services. “If we find that the rules are not being followed, we will take action.”

His agency has directed states to automatically reenroll residents using data from other government programs like unemployment and food assistance when possible. Anyone who can’t be approved through that process must act quickly.

“For the past 3 years, people have been told to ignore the mail around this, that the renewal was not going to lead to a termination.” Suddenly that mail matters, he said.

Federal law requires states to tell people why they’re losing Medicaid coverage and how to appeal the decision.

Ms. Harmatz said some cancellation notices in Florida are vague and could violate due process rules. Letters that she’s seen say “your Medicaid for this period is ending” rather than providing a specific reason for disenrollment, like having too high an income or incomplete paperwork.
If a person requests a hearing before their cancellation takes effect, they can stay covered during the appeals process. Even after being disenrolled, many still have a 90-day window to restore coverage.

In New Hampshire, 13% of people deemed ineligible in the first month have asked for extra time to provide the necessary records. “If you’re eligible for Medicaid, we don’t want you to lose it,” said Mr. Lipman.

Rep. Clere pushed Indiana’s Medicaid officials during the May meeting to immediately make changes to avoid people unnecessarily becoming uninsured. One official responded that they’ll learn and improve over time.

“I’m just concerned that we’re going to be ‘learning’ as a result of people losing coverage,” Rep. Clere replied. “So I don’t want to learn at their expense.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

More than 600,000 Americans have lost Medicaid coverage since pandemic protections ended on April 1. And a KFF Health News analysis of state data shows the vast majority were removed from state rolls for not completing paperwork.

Under normal circumstances, states review their Medicaid enrollment lists regularly to ensure every recipient qualifies for coverage. But because of a nationwide pause in those reviews during the pandemic, the health insurance program for low-income and disabled Americans kept people covered even if they no longer qualified.

Now, in what’s known as the Medicaid unwinding, states are combing through rolls and deciding who stays and who goes. People who are no longer eligible or don’t complete paperwork in time will be dropped.

The overwhelming majority of people who have lost coverage in most states were dropped because of technicalities, not because state officials determined they no longer meet Medicaid income limits. Four out of every five people dropped so far either never returned the paperwork or omitted required documents, according to a KFF Health News analysis of data from 11 states that provided details on recent cancellations. Now, lawmakers and advocates are expressing alarm over the volume of people losing coverage and, in some states, calling to pause the process.

KFF Health News sought data from the 19 states that started cancellations by May 1. Based on records from 14 states that provided detailed numbers, either in response to a public records request or by posting online, 36% of people whose eligibility was reviewed have been disenrolled.

In Indiana, 53,000 residents lost coverage in the first month of the unwinding, 89% for procedural reasons like not returning renewal forms. State Rep. Ed Clere, a Republican, expressed dismay at those “staggering numbers” in a May 24 Medicaid advisory group meeting, repeatedly questioning state officials about forms mailed to out-of-date addresses and urging them to give people more than 2 weeks’ notice before canceling their coverage.

Rep. Clere warned that the cancellations set in motion an avoidable revolving door. Some people dropped from Medicaid will have to forgo filling prescriptions and cancel doctor visits because they can’t afford care. Months down the line, after untreated chronic illnesses spiral out of control, they’ll end up in the emergency room where social workers will need to again help them join the program, he said.

Before the unwinding, more than one in four Americans – 93 million – were covered by Medicaid or CHIP, the Children’s Health Insurance Program, according to KFF Health News’ analysis of the latest enrollment data. Half of all kids are covered by the programs.

About 15 million people will be dropped over the next year as states review participants’ eligibility in monthly tranches.

Most people will find health coverage through new jobs or qualify for subsidized plans through the Affordable Care Act. But millions of others, including many children, will become uninsured and unable to afford basic prescriptions or preventive care. The uninsured rate among those under 65 is projected to rise from a historical low of 8.3% today to 9.3% next year, according to the Congressional Budget Office.

Because each state is handling the unwinding differently, the share of enrollees dropped in the first weeks varies widely.

Several states are first reviewing people officials believe are no longer eligible or who haven’t recently used their insurance. High cancellation rates in those states should level out as the agencies move on to people who likely still qualify.

In Utah, nearly 56% of people included in early reviews were dropped. In New Hampshire, 44% received cancellation letters within the first 2 months – almost all for procedural reasons, like not returning paperwork.

But New Hampshire officials found that thousands of people who didn’t fill out the forms indeed earn too much to qualify, according to Henry Lipman, the state’s Medicaid director. They would have been denied anyway. Even so, more people than he expected are not returning renewal forms. “That tells us that we need to change up our strategy,” said Mr. Lipman.

In other states, like Virginia and Nebraska, which aren’t prioritizing renewals by likely eligibility, about 90% have been renewed.

Because of the 3-year pause in renewals, many people on Medicaid have never been through the process or aren’t aware they may need to fill out long verification forms, as a recent KFF poll found. Some people moved and didn’t update their contact information.

And while agencies are required to assist enrollees who don’t speak English well, many are sending the forms in only a few common languages.

Tens of thousands of children are losing coverage, as researchers have warned, even though some may still qualify for Medicaid or CHIP. In its first month of reviews, South Dakota ended coverage for 10% of all Medicaid and CHIP enrollees in the state. More than half of them were children. In Arkansas, about 40% were kids.

Many parents don’t know that limits on household income are significantly higher for children than adults. Parents should fill out renewal forms even if they don’t qualify themselves, said Joan Alker, executive director of the Georgetown University Center for Children and Families, Washington.

New Hampshire has moved most families with children to the end of the review process. Mr. Lipman said his biggest worry is that a child will end up uninsured. Florida also planned to push kids with serious health conditions and other vulnerable groups to the end of the review line.

But according to Miriam Harmatz, advocacy director and founder of the Florida Health Justice Project, state officials sent cancellation letters to several clients with disabled children who probably still qualify. She’s helping those families appeal.

Nearly 250,000 Floridians reviewed in the first month of the unwinding lost coverage, 82% of them for reasons like incomplete paperwork, the state reported to federal authorities. House Democrats from the state petitioned Republican Gov. Ron DeSantis to pause the unwinding.

Advocacy coalitions in both Florida and Arkansas also have called for investigations into the review process and a pause on cancellations.

The state is contacting enrollees by phone, email, and text, and continues to process late applications, said Tori Cuddy, a spokesperson for the Florida Department of Children and Families. Ms. Cuddy did not respond to questions about issues raised in the petitions.

Federal officials are investigating those complaints and any other problems that emerge, said Dan Tsai, director of the Center for Medicaid & CHIP Services. “If we find that the rules are not being followed, we will take action.”

His agency has directed states to automatically reenroll residents using data from other government programs like unemployment and food assistance when possible. Anyone who can’t be approved through that process must act quickly.

“For the past 3 years, people have been told to ignore the mail around this, that the renewal was not going to lead to a termination.” Suddenly that mail matters, he said.

Federal law requires states to tell people why they’re losing Medicaid coverage and how to appeal the decision.

Ms. Harmatz said some cancellation notices in Florida are vague and could violate due process rules. Letters that she’s seen say “your Medicaid for this period is ending” rather than providing a specific reason for disenrollment, like having too high an income or incomplete paperwork.
If a person requests a hearing before their cancellation takes effect, they can stay covered during the appeals process. Even after being disenrolled, many still have a 90-day window to restore coverage.

In New Hampshire, 13% of people deemed ineligible in the first month have asked for extra time to provide the necessary records. “If you’re eligible for Medicaid, we don’t want you to lose it,” said Mr. Lipman.

Rep. Clere pushed Indiana’s Medicaid officials during the May meeting to immediately make changes to avoid people unnecessarily becoming uninsured. One official responded that they’ll learn and improve over time.

“I’m just concerned that we’re going to be ‘learning’ as a result of people losing coverage,” Rep. Clere replied. “So I don’t want to learn at their expense.”

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Taking a daily flavanol supplement improves hippocampal-dependent memory in older adults who have a relatively poor diet, results of a large new study suggest.

There’s increasing evidence that certain nutrients are important for the aging body and brain, study investigator Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, told this news organization.

“With this new study, I think we can begin to say flavanols might be the first one that really is a nutrient for the aging brain.”

These findings, said Dr. Small, represent “the beginning of a new era” that will eventually lead to formal recommendations” related to ideal intake of flavanols to reduce cognitive aging.

The findings were published online in the Proceedings of the National Academy of Science.
 

Better cognitive aging

Cognitive aging refers to the decline in cognitive abilities that are not thought to be caused by neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Cognitive aging targets two areas of the brain: the hippocampus, which is related to memory function, and the prefrontal cortex, which is related to attention and executive function.

Previous research has linked flavanols, which are found in foods like apples, pears, berries, and cocoa beans, to improved cognitive aging. The evidence shows that consuming these nutrients might be associated with the hippocampal-dependent memory component of cognitive aging.

The new study, known as COcoa Supplement and Multivitamin Outcomes Study-Web (COSMOS-Web), included 3,562 generally healthy men and women, mean age 71 years, who were mostly well-educated and non-Hispanic/non-Latinx White individuals.

Participants were randomly assigned to receive oral flavanol-containing cocoa extract (500 mg of cocoa flavanols, including 80 mg of epicatechin) or a placebo daily.

The primary endpoint was hippocampal-dependent memory at year 1 as assessed with the ModRey, a neuropsychological test designed to measure hippocampal function.

Results showed participants in both groups had a typical learning (practice) effect, with similar improvements (d = 0.025; P = .42).

Researchers used other tests to measure cognition: the Color/Directional Flanker Task, a measure of prefrontal cortex function, and the ModBent, a measure that’s sensitive to dentate gyrus function. The flavanol intervention did not affect ModBent results or performance on the Flanker test after 1 year.

However, it was a different story for those with a poor diet at baseline. Researchers stratified participants into tertiles on the basis of diet quality as measured by the Healthy Eating Index (HEI) scores. Those in the lowest tertile had poorer baseline hippocampal-dependent memory performance but not memory related to the prefrontal cortex.

The flavanol intervention improved performance on the ModRey test, compared with placebo in participants in the low HEI tertile (overall effect: d = 0.086; P = .011) but not among those with a medium or high HEI at baseline.

“We confirmed that the flavanol intervention only benefits people who are relatively deficient at baseline,” said Dr. Small.

The correlation with hippocampal-dependent memory was confirmed in a subset of 1,361 study participants who provided a urine sample. Researchers measured urinary 5-(3′,4′-dihydroxyphenyl)-gamma-valerolactone metabolite (gVLM) concentrations, a validated biomarker of flavanol consumption.

After stratifying these results into tertiles, researchers found performance on the ModRey was significantly improved with the dietary flavanol intervention (overall effect: d = 0.141; P = .006) in the lowest gVLM tertile.
 

Memory restored

When participants in the lowest tertile consumed the supplement, “their flavanol levels went back to normal, and when that happened, their memory was restored,” said Dr. Small.

It appears that there is a sort of ceiling effect to the flavanol benefits. “It seems what you need to do is normalize your flavanol levels; if you go above normal, there was no evidence that your memory keeps on getting better,” said Dr. Small.

The study included only older adults, so it’s unclear what the impact of flavanol supplementation is in younger adults. But cognitive aging “begins its slippery side” in the 40s, said Dr. Small. “If this is truly a nutrient that is taken to prevent that slide from happening, it might be beneficial to start in our 40s.”

He recognized that the effect size is not large but said this is “very dependent” on baseline factors and most study participants had a rather healthy diet. “None of our participants were really highly deficient” in flavanols, he said.

“To see a stronger effect size, we need to do another study where we recruit people who are very low, truly deficient, in flavanols, and then see what happens.”

Showing that flavanols are linked to the hippocampal and not to the prefrontal component of cognitive aging “speaks to the mechanism,” said Dr. Small.

Though the exact mechanism linking flavanols with enhanced memory isn’t clear, there are some clues; for example, research suggests cognitive aging affects the dentate gyrus, a subregion of the hippocampus.

The flavanol supplements were well tolerated. “I can say with close to certainty that this is very safe,” said Dr. Small, adding the flavanols have now been used in numerous studies.

The findings suggest flavanol consumption might be part of future dietary guidelines. “I suspect that once there is sufficient evidence, flavanols will be part of the dietary recommendations for healthy aging,” said Dr. Small.
 

A word of caution

Heather M. Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, said that though science suggests a balanced diet is good for overall brain health, no single food, beverage, ingredient, vitamin, or supplement has yet been proven to prevent dementia, treat or cure Alzheimer’s, or benefit cognitive function or brain health.

Experts agree the best source of vitamins and other nutrients is from whole foods as part of a balanced diet. “We recognize that, for a variety of reasons, this may not always be possible,” said Dr. Snyder.

However, she noted, dietary supplements are not subject to the same rigorous review and regulation process as medications.

“The Alzheimer’s Association strongly encourages individuals to have conversations with their physicians about all medications and dietary supplements they are currently taking or interested in starting.” 

COSMOS is supported by an investigator-initiated grant from Mars Edge, a segment of Mars, company engaged in flavanol research and flavanol-related commercial activities, which included infrastructure support and the donation of study pills and packaging. Small reports receiving an unrestricted research grant from Mars.

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

Taking a daily flavanol supplement improves hippocampal-dependent memory in older adults who have a relatively poor diet, results of a large new study suggest.

There’s increasing evidence that certain nutrients are important for the aging body and brain, study investigator Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, told this news organization.

“With this new study, I think we can begin to say flavanols might be the first one that really is a nutrient for the aging brain.”

These findings, said Dr. Small, represent “the beginning of a new era” that will eventually lead to formal recommendations” related to ideal intake of flavanols to reduce cognitive aging.

The findings were published online in the Proceedings of the National Academy of Science.
 

Better cognitive aging

Cognitive aging refers to the decline in cognitive abilities that are not thought to be caused by neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Cognitive aging targets two areas of the brain: the hippocampus, which is related to memory function, and the prefrontal cortex, which is related to attention and executive function.

Previous research has linked flavanols, which are found in foods like apples, pears, berries, and cocoa beans, to improved cognitive aging. The evidence shows that consuming these nutrients might be associated with the hippocampal-dependent memory component of cognitive aging.

The new study, known as COcoa Supplement and Multivitamin Outcomes Study-Web (COSMOS-Web), included 3,562 generally healthy men and women, mean age 71 years, who were mostly well-educated and non-Hispanic/non-Latinx White individuals.

Participants were randomly assigned to receive oral flavanol-containing cocoa extract (500 mg of cocoa flavanols, including 80 mg of epicatechin) or a placebo daily.

The primary endpoint was hippocampal-dependent memory at year 1 as assessed with the ModRey, a neuropsychological test designed to measure hippocampal function.

Results showed participants in both groups had a typical learning (practice) effect, with similar improvements (d = 0.025; P = .42).

Researchers used other tests to measure cognition: the Color/Directional Flanker Task, a measure of prefrontal cortex function, and the ModBent, a measure that’s sensitive to dentate gyrus function. The flavanol intervention did not affect ModBent results or performance on the Flanker test after 1 year.

However, it was a different story for those with a poor diet at baseline. Researchers stratified participants into tertiles on the basis of diet quality as measured by the Healthy Eating Index (HEI) scores. Those in the lowest tertile had poorer baseline hippocampal-dependent memory performance but not memory related to the prefrontal cortex.

The flavanol intervention improved performance on the ModRey test, compared with placebo in participants in the low HEI tertile (overall effect: d = 0.086; P = .011) but not among those with a medium or high HEI at baseline.

“We confirmed that the flavanol intervention only benefits people who are relatively deficient at baseline,” said Dr. Small.

The correlation with hippocampal-dependent memory was confirmed in a subset of 1,361 study participants who provided a urine sample. Researchers measured urinary 5-(3′,4′-dihydroxyphenyl)-gamma-valerolactone metabolite (gVLM) concentrations, a validated biomarker of flavanol consumption.

After stratifying these results into tertiles, researchers found performance on the ModRey was significantly improved with the dietary flavanol intervention (overall effect: d = 0.141; P = .006) in the lowest gVLM tertile.
 

Memory restored

When participants in the lowest tertile consumed the supplement, “their flavanol levels went back to normal, and when that happened, their memory was restored,” said Dr. Small.

It appears that there is a sort of ceiling effect to the flavanol benefits. “It seems what you need to do is normalize your flavanol levels; if you go above normal, there was no evidence that your memory keeps on getting better,” said Dr. Small.

The study included only older adults, so it’s unclear what the impact of flavanol supplementation is in younger adults. But cognitive aging “begins its slippery side” in the 40s, said Dr. Small. “If this is truly a nutrient that is taken to prevent that slide from happening, it might be beneficial to start in our 40s.”

He recognized that the effect size is not large but said this is “very dependent” on baseline factors and most study participants had a rather healthy diet. “None of our participants were really highly deficient” in flavanols, he said.

“To see a stronger effect size, we need to do another study where we recruit people who are very low, truly deficient, in flavanols, and then see what happens.”

Showing that flavanols are linked to the hippocampal and not to the prefrontal component of cognitive aging “speaks to the mechanism,” said Dr. Small.

Though the exact mechanism linking flavanols with enhanced memory isn’t clear, there are some clues; for example, research suggests cognitive aging affects the dentate gyrus, a subregion of the hippocampus.

The flavanol supplements were well tolerated. “I can say with close to certainty that this is very safe,” said Dr. Small, adding the flavanols have now been used in numerous studies.

The findings suggest flavanol consumption might be part of future dietary guidelines. “I suspect that once there is sufficient evidence, flavanols will be part of the dietary recommendations for healthy aging,” said Dr. Small.
 

A word of caution

Heather M. Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, said that though science suggests a balanced diet is good for overall brain health, no single food, beverage, ingredient, vitamin, or supplement has yet been proven to prevent dementia, treat or cure Alzheimer’s, or benefit cognitive function or brain health.

Experts agree the best source of vitamins and other nutrients is from whole foods as part of a balanced diet. “We recognize that, for a variety of reasons, this may not always be possible,” said Dr. Snyder.

However, she noted, dietary supplements are not subject to the same rigorous review and regulation process as medications.

“The Alzheimer’s Association strongly encourages individuals to have conversations with their physicians about all medications and dietary supplements they are currently taking or interested in starting.” 

COSMOS is supported by an investigator-initiated grant from Mars Edge, a segment of Mars, company engaged in flavanol research and flavanol-related commercial activities, which included infrastructure support and the donation of study pills and packaging. Small reports receiving an unrestricted research grant from Mars.

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

Taking a daily flavanol supplement improves hippocampal-dependent memory in older adults who have a relatively poor diet, results of a large new study suggest.

There’s increasing evidence that certain nutrients are important for the aging body and brain, study investigator Scott Small, MD, the Boris and Rose Katz Professor of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, told this news organization.

“With this new study, I think we can begin to say flavanols might be the first one that really is a nutrient for the aging brain.”

These findings, said Dr. Small, represent “the beginning of a new era” that will eventually lead to formal recommendations” related to ideal intake of flavanols to reduce cognitive aging.

The findings were published online in the Proceedings of the National Academy of Science.
 

Better cognitive aging

Cognitive aging refers to the decline in cognitive abilities that are not thought to be caused by neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Cognitive aging targets two areas of the brain: the hippocampus, which is related to memory function, and the prefrontal cortex, which is related to attention and executive function.

Previous research has linked flavanols, which are found in foods like apples, pears, berries, and cocoa beans, to improved cognitive aging. The evidence shows that consuming these nutrients might be associated with the hippocampal-dependent memory component of cognitive aging.

The new study, known as COcoa Supplement and Multivitamin Outcomes Study-Web (COSMOS-Web), included 3,562 generally healthy men and women, mean age 71 years, who were mostly well-educated and non-Hispanic/non-Latinx White individuals.

Participants were randomly assigned to receive oral flavanol-containing cocoa extract (500 mg of cocoa flavanols, including 80 mg of epicatechin) or a placebo daily.

The primary endpoint was hippocampal-dependent memory at year 1 as assessed with the ModRey, a neuropsychological test designed to measure hippocampal function.

Results showed participants in both groups had a typical learning (practice) effect, with similar improvements (d = 0.025; P = .42).

Researchers used other tests to measure cognition: the Color/Directional Flanker Task, a measure of prefrontal cortex function, and the ModBent, a measure that’s sensitive to dentate gyrus function. The flavanol intervention did not affect ModBent results or performance on the Flanker test after 1 year.

However, it was a different story for those with a poor diet at baseline. Researchers stratified participants into tertiles on the basis of diet quality as measured by the Healthy Eating Index (HEI) scores. Those in the lowest tertile had poorer baseline hippocampal-dependent memory performance but not memory related to the prefrontal cortex.

The flavanol intervention improved performance on the ModRey test, compared with placebo in participants in the low HEI tertile (overall effect: d = 0.086; P = .011) but not among those with a medium or high HEI at baseline.

“We confirmed that the flavanol intervention only benefits people who are relatively deficient at baseline,” said Dr. Small.

The correlation with hippocampal-dependent memory was confirmed in a subset of 1,361 study participants who provided a urine sample. Researchers measured urinary 5-(3′,4′-dihydroxyphenyl)-gamma-valerolactone metabolite (gVLM) concentrations, a validated biomarker of flavanol consumption.

After stratifying these results into tertiles, researchers found performance on the ModRey was significantly improved with the dietary flavanol intervention (overall effect: d = 0.141; P = .006) in the lowest gVLM tertile.
 

Memory restored

When participants in the lowest tertile consumed the supplement, “their flavanol levels went back to normal, and when that happened, their memory was restored,” said Dr. Small.

It appears that there is a sort of ceiling effect to the flavanol benefits. “It seems what you need to do is normalize your flavanol levels; if you go above normal, there was no evidence that your memory keeps on getting better,” said Dr. Small.

The study included only older adults, so it’s unclear what the impact of flavanol supplementation is in younger adults. But cognitive aging “begins its slippery side” in the 40s, said Dr. Small. “If this is truly a nutrient that is taken to prevent that slide from happening, it might be beneficial to start in our 40s.”

He recognized that the effect size is not large but said this is “very dependent” on baseline factors and most study participants had a rather healthy diet. “None of our participants were really highly deficient” in flavanols, he said.

“To see a stronger effect size, we need to do another study where we recruit people who are very low, truly deficient, in flavanols, and then see what happens.”

Showing that flavanols are linked to the hippocampal and not to the prefrontal component of cognitive aging “speaks to the mechanism,” said Dr. Small.

Though the exact mechanism linking flavanols with enhanced memory isn’t clear, there are some clues; for example, research suggests cognitive aging affects the dentate gyrus, a subregion of the hippocampus.

The flavanol supplements were well tolerated. “I can say with close to certainty that this is very safe,” said Dr. Small, adding the flavanols have now been used in numerous studies.

The findings suggest flavanol consumption might be part of future dietary guidelines. “I suspect that once there is sufficient evidence, flavanols will be part of the dietary recommendations for healthy aging,” said Dr. Small.
 

A word of caution

Heather M. Snyder, PhD, vice president of medical and scientific relations, Alzheimer’s Association, said that though science suggests a balanced diet is good for overall brain health, no single food, beverage, ingredient, vitamin, or supplement has yet been proven to prevent dementia, treat or cure Alzheimer’s, or benefit cognitive function or brain health.

Experts agree the best source of vitamins and other nutrients is from whole foods as part of a balanced diet. “We recognize that, for a variety of reasons, this may not always be possible,” said Dr. Snyder.

However, she noted, dietary supplements are not subject to the same rigorous review and regulation process as medications.

“The Alzheimer’s Association strongly encourages individuals to have conversations with their physicians about all medications and dietary supplements they are currently taking or interested in starting.” 

COSMOS is supported by an investigator-initiated grant from Mars Edge, a segment of Mars, company engaged in flavanol research and flavanol-related commercial activities, which included infrastructure support and the donation of study pills and packaging. Small reports receiving an unrestricted research grant from Mars.

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