Feature

The presence of any aberration in the SMAD4 gene and decreased messenger RNA sequencing expression of SMAD4 were both associated with worse overall survival in patients with resected pancreatic adenocarcinoma.

These were the main findings of a new study of more than 300 individuals.

Previous studies have shown an association between widespread disease and loss of SMAD4 immunolabeling, according to the paper. Biomarkers to predict which pancreatic adenocarcinoma patients may benefit from more aggressive therapy are lacking, wrote Emily J. Anstadt, MD, of the University of Pennsylvania, Philadelphia, and colleagues, in their paper published in Cancer.

The human transcription factor and tumor suppressor, mothers against decapentaplegic homolog 4 (SMAD4), “may be a promising biomarker for predicting the likelihood of experiencing distant failure in patients with pancreatic cancer,” the researchers wrote.

“For patients with pancreatic cancer, improving treatments and overall outcomes remains invaluable,” Dr. Anstadt said in an interview. However, the disparate clinical courses make studies of this patient population challenging.

“As with much of medicine and oncology at this time, we feel the key to better outcomes lies in personalizing treatment strategies and relying on tumor genetics to predict tumor behavior and guide us towards individualized optimal treatments,” she added.
 

Study Methods and Results

The researchers identified 322 patients with resected stage I–III pancreatic adenocarcinoma from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). The study population included 165 patients from the TCGA who served as the training set and 157 patients from the ICGC who served as the validation set.

The primary outcomes were overall survival (OS) and distant metastasis-free survival (DMFS).

A total of 50 patients in the TCGA group (30%) had at least one of the three identified SMAD4 genomic aberrations.

Using the TCGA group, the researchers conducted a regression analysis on the survival outcomes as a function of either the presence of an SMAD4 genomic aberration or the expression of messenger RNA sequencing (RNA-seq). They then used the ICGC to validate whether SMAD4 RNA-seq expression improved risk stratification for OS and DMFS in a separate group of patients.

In the TCGA group, 3-year OS for patients with any SMAD4 aberrations vs no SMAD4 aberrations was 18% vs 36% (hazard ratio, 1.55; P = .048). However, the 3-year DMFS for patients with and without SMAD4 aberrations was 14% vs 23%, a nonsignificant difference (HR, 1.33; P = .19).

In a multivariate analysis, SMAD4 aberrations also were associated with increased risk of stage III disease (HR, 1.89; P = .003). The researchers noted that adjuvant radiotherapy and adjuvant chemotherapy were significantly associated with a decreased risk of death in these patients (HR, 0.53 and HR, 0.28, respectively).

In addition, low SMAD4 RNA-seq expression was associated with worse OS and DMFS, (HR, 1.83 and HR, 1.70, respectively) in the TCGA group.

In the ICGC validation group, increased SMAD4 RNA‐seq expression correlated with improved OS (area under the curve .92) and DMFS (AUC, .84).

Dr. Anstadt said she and her colleagues were not surprised by any of their findings, given earlier research’s suggestions of SMAD4 loss having been associated with poor outcomes for pancreatic cancer.

“Prior studies determined SMAD4 status based on immunohistochemistry and different investigators used different scoring systems,” Dr. Anstadt noted, in an interview. “The results of those studies were conflicting, and consequently SMAD4 has not been adopted clinically as part of the work-up or to aid in treatment decisions.”

“It is essential to find robust, reliable, and cost-effective methods for implementing this in the clinic. As such, we were happy to find that expression of SMAD4 by mRNA sequencing may be that method,” she added.

Not Quite Clinic-Ready

“While we are hopeful that this tool will be a reliable method for use in the clinic, it has yet to be validated in a prospective manner,” Dr. Anstadt said in an interview. “In addition, this study showed that [genetic] expression levels are correlated with worse outcomes and can be of prognostic use; however, we have not directly studied whether expression levels can be predictive of treatment response,” she said.

“Practicing oncologists often have to make difficult decisions in situations where there are no clear answers,” Dr. Anstadt continued. “When considering gray-zone treatment recommendations, we often integrate multiple factors to form an opinion. The reality of cancer medicine is that not all those factors we consider have been validated in prospective studies, but together they produce a picture that is clinically useful. We would submit that SMAD4 status should be one of those factors taken into consideration in forming a comprehensive opinion about suitability for resection or radiotherapy.”

In practice, “if this test is prospectively validated in a future study and will impact clinical decision-making, then this cost will be similar to other genetic tests that have been adopted and have been practice-changing in other oncologic fields,” said Dr. Anstadt. “Being able to individualize treatment can also save overall cost; for instance, predicting which patients would not benefit from local radiation or surgery could decrease use and cost in that population,” she said.

Limitations of the current study included the inability to examine interactions between SMAD4 and radiotherapy because of the sample size and the potential for selection bias, the researchers wrote.
 

Potential Predictive Value

“A major challenge in the management of patients with pancreatic cancer is the difficulty in predicting which patients will develop metastasis early,” said Jatin Roper, MD, a gastroenterologist at Duke University, Durham, North Carolina, in an interview.

“SMAD4 has previously been evaluated as a prognostic marker in pancreatic cancer, but the association between SMAD4 gene expression, gene mutations, and cancer metastasis has not yet been systematically evaluated in patients, said Dr. Roper, who was not involved in the study.

The new study’s main findings that SMAD4 genomic alterations are associated with worse overall survival, but not distant metastasis-free survival, and that increased SMAD4 expression is associated with improved overall survival and distant metastasis-free survival, suggest that SMAD4 gene expression may be a useful marker in predicting clinical outcomes in pancreatic cancer, Dr. Roper said.

In the future the current study may prompt prospective research to determine a potential association between clinical assessment of SMAD4 gene expression at the time of surgical cancer resection and worse overall survival and distant metastasis-free survival, he said.

The study received no outside funding. Dr. Anstadt and Dr. Roper had no financial conflicts to disclose.

The presence of any aberration in the SMAD4 gene and decreased messenger RNA sequencing expression of SMAD4 were both associated with worse overall survival in patients with resected pancreatic adenocarcinoma.

These were the main findings of a new study of more than 300 individuals.

Previous studies have shown an association between widespread disease and loss of SMAD4 immunolabeling, according to the paper. Biomarkers to predict which pancreatic adenocarcinoma patients may benefit from more aggressive therapy are lacking, wrote Emily J. Anstadt, MD, of the University of Pennsylvania, Philadelphia, and colleagues, in their paper published in Cancer.

The human transcription factor and tumor suppressor, mothers against decapentaplegic homolog 4 (SMAD4), “may be a promising biomarker for predicting the likelihood of experiencing distant failure in patients with pancreatic cancer,” the researchers wrote.

“For patients with pancreatic cancer, improving treatments and overall outcomes remains invaluable,” Dr. Anstadt said in an interview. However, the disparate clinical courses make studies of this patient population challenging.

“As with much of medicine and oncology at this time, we feel the key to better outcomes lies in personalizing treatment strategies and relying on tumor genetics to predict tumor behavior and guide us towards individualized optimal treatments,” she added.
 

Study Methods and Results

The researchers identified 322 patients with resected stage I–III pancreatic adenocarcinoma from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). The study population included 165 patients from the TCGA who served as the training set and 157 patients from the ICGC who served as the validation set.

The primary outcomes were overall survival (OS) and distant metastasis-free survival (DMFS).

A total of 50 patients in the TCGA group (30%) had at least one of the three identified SMAD4 genomic aberrations.

Using the TCGA group, the researchers conducted a regression analysis on the survival outcomes as a function of either the presence of an SMAD4 genomic aberration or the expression of messenger RNA sequencing (RNA-seq). They then used the ICGC to validate whether SMAD4 RNA-seq expression improved risk stratification for OS and DMFS in a separate group of patients.

In the TCGA group, 3-year OS for patients with any SMAD4 aberrations vs no SMAD4 aberrations was 18% vs 36% (hazard ratio, 1.55; P = .048). However, the 3-year DMFS for patients with and without SMAD4 aberrations was 14% vs 23%, a nonsignificant difference (HR, 1.33; P = .19).

In a multivariate analysis, SMAD4 aberrations also were associated with increased risk of stage III disease (HR, 1.89; P = .003). The researchers noted that adjuvant radiotherapy and adjuvant chemotherapy were significantly associated with a decreased risk of death in these patients (HR, 0.53 and HR, 0.28, respectively).

In addition, low SMAD4 RNA-seq expression was associated with worse OS and DMFS, (HR, 1.83 and HR, 1.70, respectively) in the TCGA group.

In the ICGC validation group, increased SMAD4 RNA‐seq expression correlated with improved OS (area under the curve .92) and DMFS (AUC, .84).

Dr. Anstadt said she and her colleagues were not surprised by any of their findings, given earlier research’s suggestions of SMAD4 loss having been associated with poor outcomes for pancreatic cancer.

“Prior studies determined SMAD4 status based on immunohistochemistry and different investigators used different scoring systems,” Dr. Anstadt noted, in an interview. “The results of those studies were conflicting, and consequently SMAD4 has not been adopted clinically as part of the work-up or to aid in treatment decisions.”

“It is essential to find robust, reliable, and cost-effective methods for implementing this in the clinic. As such, we were happy to find that expression of SMAD4 by mRNA sequencing may be that method,” she added.

Not Quite Clinic-Ready

“While we are hopeful that this tool will be a reliable method for use in the clinic, it has yet to be validated in a prospective manner,” Dr. Anstadt said in an interview. “In addition, this study showed that [genetic] expression levels are correlated with worse outcomes and can be of prognostic use; however, we have not directly studied whether expression levels can be predictive of treatment response,” she said.

“Practicing oncologists often have to make difficult decisions in situations where there are no clear answers,” Dr. Anstadt continued. “When considering gray-zone treatment recommendations, we often integrate multiple factors to form an opinion. The reality of cancer medicine is that not all those factors we consider have been validated in prospective studies, but together they produce a picture that is clinically useful. We would submit that SMAD4 status should be one of those factors taken into consideration in forming a comprehensive opinion about suitability for resection or radiotherapy.”

In practice, “if this test is prospectively validated in a future study and will impact clinical decision-making, then this cost will be similar to other genetic tests that have been adopted and have been practice-changing in other oncologic fields,” said Dr. Anstadt. “Being able to individualize treatment can also save overall cost; for instance, predicting which patients would not benefit from local radiation or surgery could decrease use and cost in that population,” she said.

Limitations of the current study included the inability to examine interactions between SMAD4 and radiotherapy because of the sample size and the potential for selection bias, the researchers wrote.
 

Potential Predictive Value

“A major challenge in the management of patients with pancreatic cancer is the difficulty in predicting which patients will develop metastasis early,” said Jatin Roper, MD, a gastroenterologist at Duke University, Durham, North Carolina, in an interview.

“SMAD4 has previously been evaluated as a prognostic marker in pancreatic cancer, but the association between SMAD4 gene expression, gene mutations, and cancer metastasis has not yet been systematically evaluated in patients, said Dr. Roper, who was not involved in the study.

The new study’s main findings that SMAD4 genomic alterations are associated with worse overall survival, but not distant metastasis-free survival, and that increased SMAD4 expression is associated with improved overall survival and distant metastasis-free survival, suggest that SMAD4 gene expression may be a useful marker in predicting clinical outcomes in pancreatic cancer, Dr. Roper said.

In the future the current study may prompt prospective research to determine a potential association between clinical assessment of SMAD4 gene expression at the time of surgical cancer resection and worse overall survival and distant metastasis-free survival, he said.

The study received no outside funding. Dr. Anstadt and Dr. Roper had no financial conflicts to disclose.

The presence of any aberration in the SMAD4 gene and decreased messenger RNA sequencing expression of SMAD4 were both associated with worse overall survival in patients with resected pancreatic adenocarcinoma.

These were the main findings of a new study of more than 300 individuals.

Previous studies have shown an association between widespread disease and loss of SMAD4 immunolabeling, according to the paper. Biomarkers to predict which pancreatic adenocarcinoma patients may benefit from more aggressive therapy are lacking, wrote Emily J. Anstadt, MD, of the University of Pennsylvania, Philadelphia, and colleagues, in their paper published in Cancer.

The human transcription factor and tumor suppressor, mothers against decapentaplegic homolog 4 (SMAD4), “may be a promising biomarker for predicting the likelihood of experiencing distant failure in patients with pancreatic cancer,” the researchers wrote.

“For patients with pancreatic cancer, improving treatments and overall outcomes remains invaluable,” Dr. Anstadt said in an interview. However, the disparate clinical courses make studies of this patient population challenging.

“As with much of medicine and oncology at this time, we feel the key to better outcomes lies in personalizing treatment strategies and relying on tumor genetics to predict tumor behavior and guide us towards individualized optimal treatments,” she added.
 

Study Methods and Results

The researchers identified 322 patients with resected stage I–III pancreatic adenocarcinoma from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). The study population included 165 patients from the TCGA who served as the training set and 157 patients from the ICGC who served as the validation set.

The primary outcomes were overall survival (OS) and distant metastasis-free survival (DMFS).

A total of 50 patients in the TCGA group (30%) had at least one of the three identified SMAD4 genomic aberrations.

Using the TCGA group, the researchers conducted a regression analysis on the survival outcomes as a function of either the presence of an SMAD4 genomic aberration or the expression of messenger RNA sequencing (RNA-seq). They then used the ICGC to validate whether SMAD4 RNA-seq expression improved risk stratification for OS and DMFS in a separate group of patients.

In the TCGA group, 3-year OS for patients with any SMAD4 aberrations vs no SMAD4 aberrations was 18% vs 36% (hazard ratio, 1.55; P = .048). However, the 3-year DMFS for patients with and without SMAD4 aberrations was 14% vs 23%, a nonsignificant difference (HR, 1.33; P = .19).

In a multivariate analysis, SMAD4 aberrations also were associated with increased risk of stage III disease (HR, 1.89; P = .003). The researchers noted that adjuvant radiotherapy and adjuvant chemotherapy were significantly associated with a decreased risk of death in these patients (HR, 0.53 and HR, 0.28, respectively).

In addition, low SMAD4 RNA-seq expression was associated with worse OS and DMFS, (HR, 1.83 and HR, 1.70, respectively) in the TCGA group.

In the ICGC validation group, increased SMAD4 RNA‐seq expression correlated with improved OS (area under the curve .92) and DMFS (AUC, .84).

Dr. Anstadt said she and her colleagues were not surprised by any of their findings, given earlier research’s suggestions of SMAD4 loss having been associated with poor outcomes for pancreatic cancer.

“Prior studies determined SMAD4 status based on immunohistochemistry and different investigators used different scoring systems,” Dr. Anstadt noted, in an interview. “The results of those studies were conflicting, and consequently SMAD4 has not been adopted clinically as part of the work-up or to aid in treatment decisions.”

“It is essential to find robust, reliable, and cost-effective methods for implementing this in the clinic. As such, we were happy to find that expression of SMAD4 by mRNA sequencing may be that method,” she added.

Not Quite Clinic-Ready

“While we are hopeful that this tool will be a reliable method for use in the clinic, it has yet to be validated in a prospective manner,” Dr. Anstadt said in an interview. “In addition, this study showed that [genetic] expression levels are correlated with worse outcomes and can be of prognostic use; however, we have not directly studied whether expression levels can be predictive of treatment response,” she said.

“Practicing oncologists often have to make difficult decisions in situations where there are no clear answers,” Dr. Anstadt continued. “When considering gray-zone treatment recommendations, we often integrate multiple factors to form an opinion. The reality of cancer medicine is that not all those factors we consider have been validated in prospective studies, but together they produce a picture that is clinically useful. We would submit that SMAD4 status should be one of those factors taken into consideration in forming a comprehensive opinion about suitability for resection or radiotherapy.”

In practice, “if this test is prospectively validated in a future study and will impact clinical decision-making, then this cost will be similar to other genetic tests that have been adopted and have been practice-changing in other oncologic fields,” said Dr. Anstadt. “Being able to individualize treatment can also save overall cost; for instance, predicting which patients would not benefit from local radiation or surgery could decrease use and cost in that population,” she said.

Limitations of the current study included the inability to examine interactions between SMAD4 and radiotherapy because of the sample size and the potential for selection bias, the researchers wrote.
 

Potential Predictive Value

“A major challenge in the management of patients with pancreatic cancer is the difficulty in predicting which patients will develop metastasis early,” said Jatin Roper, MD, a gastroenterologist at Duke University, Durham, North Carolina, in an interview.

“SMAD4 has previously been evaluated as a prognostic marker in pancreatic cancer, but the association between SMAD4 gene expression, gene mutations, and cancer metastasis has not yet been systematically evaluated in patients, said Dr. Roper, who was not involved in the study.

The new study’s main findings that SMAD4 genomic alterations are associated with worse overall survival, but not distant metastasis-free survival, and that increased SMAD4 expression is associated with improved overall survival and distant metastasis-free survival, suggest that SMAD4 gene expression may be a useful marker in predicting clinical outcomes in pancreatic cancer, Dr. Roper said.

In the future the current study may prompt prospective research to determine a potential association between clinical assessment of SMAD4 gene expression at the time of surgical cancer resection and worse overall survival and distant metastasis-free survival, he said.

The study received no outside funding. Dr. Anstadt and Dr. Roper had no financial conflicts to disclose.

Circulating tumor cells (CTCs), the cells shed from a solid tumor into the bloodstream, may help doctors avoid having to do repeat needle biopsies on patients with unresectable non–small cell lung cancer.

Challenges to using CTCs clinically are that they are not abundant in the blood and have been difficult to isolate in patients with this type of cancer with commercially available assays.

New research published in Cell Reports may bring doctors closer to using CTCs as a biomarker for patients with non–small cell lung cancer (NSCLC) in clinic. In their paper, the authors show that an experimental nanotechnology can effectively isolate and measure CTCs in patients with stage 3 NSCLC. They also found that a precipitous drop in CTCs during chemoradiation treatment predicted significantly longer progression-free survival in those patients.
 

Study Results and Methods

For their research, study coauthors Shruti Jolly, MD, and Sunitha Nagrath, PhD, used a novel graphene oxide technology called the GO chip, developed more than a decade ago by Dr. Nagrath and her colleagues, to isolate CTCs from patients with stage 3 NSCLC. While a different technology, which is approved by the US Food and Drug Administration (FDA), uses a single antibody to pick up CTCs, the GO chip uses a cocktail of three antibodies to CTC proteins, making it more sensitive.

The 26 patients in the study (mean age 67, 27% female) all received radiation treatment for 6 weeks, plus weekly carboplatin and paclitaxel chemotherapy. Sixteen of the patients afterward went on to have immunotherapy with durvalumab. Blood was drawn at six fixed time points: before treatment, and at weeks 1, 4, 10, 18, and 30. CTCs were measured and analyzed with every draw.

Previous studies showed that absolute number of CTCs did not correlate with either tumor volume or progression-free survival in NSCLC.

Dr. Jolly and Dr. Nagrath sought to measure change in CTCs from baseline for each patient, having the patient serve as his or her own control. They found that patients whose individual CTC counts dropped by 75% or more between pretreatment and week 4 of chemoradiation saw a mean 21 months of progression-free survival compared with 7 months for patients whose CTCs dropped by less than 75% in the same period (P = .0076).

Dr. Jolly and Dr. Nagrath also aimed to determine, as an exploratory outcome of their study, whether other information collected from the CTCs could predict response to treatment with durvalumab immunotherapy. They found that having more than 50% of CTCs positive for the protein PD-L1 correlated to shorter progression-free survival among the 16 patients receiving durvalumab (P = .04).

“Every person’s tumor is unique in terms of its response to treatment,” said Dr. Jolly, a radiation oncologist and professor and associate chair of community practices in the Department of Radiation Oncology at the University of Michigan, Ann Arbor.

“Two people with a three-centimeter lung tumor will not necessarily shed the same amount of tumor cells into circulation. CTCs are reflective of disease burden; however, this is not related to the absolute numbers. That’s why we decided to use individualized baselines and look at the percentage of decrease,” she said.

Dr. Nagrath, professor of chemical and biomedical engineering at the University of Michigan, noted, in the same interview, that the findings argue for CTCs as a biomarker in stage 3 NSCLC.

“A lot of researchers who do lung cancer studies struggle with isolating lung cancer CTCs,” Dr. Nagrath said. “We showed, with repeated blood draws during treatment, what is changing at a molecular level and that you can see it with a simple blood draw. It also gives the proof of concept that if these cells are present, this is a good way to monitor and see if a treatment is working, even early in the treatment.” Moreover, she added, “many studies in lung cancer are in stage 4.”

Our study is unique as it followed patients with locally advanced tumors from their being treatment naive to all the way through immunotherapy,” she continued.

The University of Michigan has a patent on the GO chip technology, but thus far no company has made efforts to license it and submit it for approval. While “liquid biopsy” is an important emerging concept in lung cancer, there is little consensus yet as to which blood biomarkers — whether CTCs, circulating tumor DNA (ctDNA), or extracellular vesicles (EVs) — are most clinically relevant, Dr. Nagrath said.

The study’s small size is one of its weaknesses, according to the authors.
 

Findings are ‘Particularly Intriguing’

Majid Ebrahimi Warkiani, PhD, who was not involved in the study, described the new findings as “particularly intriguing [and] highlighting the efficacy of liquid biopsy using CTCs for predicting treatment outcomes.”

A challenge within the realm of CTCs lies in the community’s ongoing struggle to define and classify these cells accurately, Dr. Warkiani said in an interview.

“While surface protein markers offer valuable insights, emerging layers of analysis, such as metabolomics, are increasingly entering the scene to bolster the identification of putative cancer cells, alongside molecular tests like fluorescence in situ hybridization (FISH),” said Dr. Warkiani of the University of Technology Sydney in Australia. “The amalgamation of these approaches simultaneously presents a significant challenge, particularly in terms of standardization for patient care, unlike ctDNA, which faces fewer bottlenecks.

“The robustness of the research in this study is commendable. However, further clinical testing and randomized trials are imperative,” Dr. Warkiani continued. “Companies like Epic Sciences are actively engaged in advancing research and standardization in this field.”

The study by Dr. Jolly and Dr. Nagrath was funded by the National Institutes of Health. None of the study authors reported financial conflicts of interest. Dr. Warkiani reported no conflicts of interest related to his comment.

Circulating tumor cells (CTCs), the cells shed from a solid tumor into the bloodstream, may help doctors avoid having to do repeat needle biopsies on patients with unresectable non–small cell lung cancer.

Challenges to using CTCs clinically are that they are not abundant in the blood and have been difficult to isolate in patients with this type of cancer with commercially available assays.

New research published in Cell Reports may bring doctors closer to using CTCs as a biomarker for patients with non–small cell lung cancer (NSCLC) in clinic. In their paper, the authors show that an experimental nanotechnology can effectively isolate and measure CTCs in patients with stage 3 NSCLC. They also found that a precipitous drop in CTCs during chemoradiation treatment predicted significantly longer progression-free survival in those patients.
 

Study Results and Methods

For their research, study coauthors Shruti Jolly, MD, and Sunitha Nagrath, PhD, used a novel graphene oxide technology called the GO chip, developed more than a decade ago by Dr. Nagrath and her colleagues, to isolate CTCs from patients with stage 3 NSCLC. While a different technology, which is approved by the US Food and Drug Administration (FDA), uses a single antibody to pick up CTCs, the GO chip uses a cocktail of three antibodies to CTC proteins, making it more sensitive.

The 26 patients in the study (mean age 67, 27% female) all received radiation treatment for 6 weeks, plus weekly carboplatin and paclitaxel chemotherapy. Sixteen of the patients afterward went on to have immunotherapy with durvalumab. Blood was drawn at six fixed time points: before treatment, and at weeks 1, 4, 10, 18, and 30. CTCs were measured and analyzed with every draw.

Previous studies showed that absolute number of CTCs did not correlate with either tumor volume or progression-free survival in NSCLC.

Dr. Jolly and Dr. Nagrath sought to measure change in CTCs from baseline for each patient, having the patient serve as his or her own control. They found that patients whose individual CTC counts dropped by 75% or more between pretreatment and week 4 of chemoradiation saw a mean 21 months of progression-free survival compared with 7 months for patients whose CTCs dropped by less than 75% in the same period (P = .0076).

Dr. Jolly and Dr. Nagrath also aimed to determine, as an exploratory outcome of their study, whether other information collected from the CTCs could predict response to treatment with durvalumab immunotherapy. They found that having more than 50% of CTCs positive for the protein PD-L1 correlated to shorter progression-free survival among the 16 patients receiving durvalumab (P = .04).

“Every person’s tumor is unique in terms of its response to treatment,” said Dr. Jolly, a radiation oncologist and professor and associate chair of community practices in the Department of Radiation Oncology at the University of Michigan, Ann Arbor.

“Two people with a three-centimeter lung tumor will not necessarily shed the same amount of tumor cells into circulation. CTCs are reflective of disease burden; however, this is not related to the absolute numbers. That’s why we decided to use individualized baselines and look at the percentage of decrease,” she said.

Dr. Nagrath, professor of chemical and biomedical engineering at the University of Michigan, noted, in the same interview, that the findings argue for CTCs as a biomarker in stage 3 NSCLC.

“A lot of researchers who do lung cancer studies struggle with isolating lung cancer CTCs,” Dr. Nagrath said. “We showed, with repeated blood draws during treatment, what is changing at a molecular level and that you can see it with a simple blood draw. It also gives the proof of concept that if these cells are present, this is a good way to monitor and see if a treatment is working, even early in the treatment.” Moreover, she added, “many studies in lung cancer are in stage 4.”

Our study is unique as it followed patients with locally advanced tumors from their being treatment naive to all the way through immunotherapy,” she continued.

The University of Michigan has a patent on the GO chip technology, but thus far no company has made efforts to license it and submit it for approval. While “liquid biopsy” is an important emerging concept in lung cancer, there is little consensus yet as to which blood biomarkers — whether CTCs, circulating tumor DNA (ctDNA), or extracellular vesicles (EVs) — are most clinically relevant, Dr. Nagrath said.

The study’s small size is one of its weaknesses, according to the authors.
 

Findings are ‘Particularly Intriguing’

Majid Ebrahimi Warkiani, PhD, who was not involved in the study, described the new findings as “particularly intriguing [and] highlighting the efficacy of liquid biopsy using CTCs for predicting treatment outcomes.”

A challenge within the realm of CTCs lies in the community’s ongoing struggle to define and classify these cells accurately, Dr. Warkiani said in an interview.

“While surface protein markers offer valuable insights, emerging layers of analysis, such as metabolomics, are increasingly entering the scene to bolster the identification of putative cancer cells, alongside molecular tests like fluorescence in situ hybridization (FISH),” said Dr. Warkiani of the University of Technology Sydney in Australia. “The amalgamation of these approaches simultaneously presents a significant challenge, particularly in terms of standardization for patient care, unlike ctDNA, which faces fewer bottlenecks.

“The robustness of the research in this study is commendable. However, further clinical testing and randomized trials are imperative,” Dr. Warkiani continued. “Companies like Epic Sciences are actively engaged in advancing research and standardization in this field.”

The study by Dr. Jolly and Dr. Nagrath was funded by the National Institutes of Health. None of the study authors reported financial conflicts of interest. Dr. Warkiani reported no conflicts of interest related to his comment.

Circulating tumor cells (CTCs), the cells shed from a solid tumor into the bloodstream, may help doctors avoid having to do repeat needle biopsies on patients with unresectable non–small cell lung cancer.

Challenges to using CTCs clinically are that they are not abundant in the blood and have been difficult to isolate in patients with this type of cancer with commercially available assays.

New research published in Cell Reports may bring doctors closer to using CTCs as a biomarker for patients with non–small cell lung cancer (NSCLC) in clinic. In their paper, the authors show that an experimental nanotechnology can effectively isolate and measure CTCs in patients with stage 3 NSCLC. They also found that a precipitous drop in CTCs during chemoradiation treatment predicted significantly longer progression-free survival in those patients.
 

Study Results and Methods

For their research, study coauthors Shruti Jolly, MD, and Sunitha Nagrath, PhD, used a novel graphene oxide technology called the GO chip, developed more than a decade ago by Dr. Nagrath and her colleagues, to isolate CTCs from patients with stage 3 NSCLC. While a different technology, which is approved by the US Food and Drug Administration (FDA), uses a single antibody to pick up CTCs, the GO chip uses a cocktail of three antibodies to CTC proteins, making it more sensitive.

The 26 patients in the study (mean age 67, 27% female) all received radiation treatment for 6 weeks, plus weekly carboplatin and paclitaxel chemotherapy. Sixteen of the patients afterward went on to have immunotherapy with durvalumab. Blood was drawn at six fixed time points: before treatment, and at weeks 1, 4, 10, 18, and 30. CTCs were measured and analyzed with every draw.

Previous studies showed that absolute number of CTCs did not correlate with either tumor volume or progression-free survival in NSCLC.

Dr. Jolly and Dr. Nagrath sought to measure change in CTCs from baseline for each patient, having the patient serve as his or her own control. They found that patients whose individual CTC counts dropped by 75% or more between pretreatment and week 4 of chemoradiation saw a mean 21 months of progression-free survival compared with 7 months for patients whose CTCs dropped by less than 75% in the same period (P = .0076).

Dr. Jolly and Dr. Nagrath also aimed to determine, as an exploratory outcome of their study, whether other information collected from the CTCs could predict response to treatment with durvalumab immunotherapy. They found that having more than 50% of CTCs positive for the protein PD-L1 correlated to shorter progression-free survival among the 16 patients receiving durvalumab (P = .04).

“Every person’s tumor is unique in terms of its response to treatment,” said Dr. Jolly, a radiation oncologist and professor and associate chair of community practices in the Department of Radiation Oncology at the University of Michigan, Ann Arbor.

“Two people with a three-centimeter lung tumor will not necessarily shed the same amount of tumor cells into circulation. CTCs are reflective of disease burden; however, this is not related to the absolute numbers. That’s why we decided to use individualized baselines and look at the percentage of decrease,” she said.

Dr. Nagrath, professor of chemical and biomedical engineering at the University of Michigan, noted, in the same interview, that the findings argue for CTCs as a biomarker in stage 3 NSCLC.

“A lot of researchers who do lung cancer studies struggle with isolating lung cancer CTCs,” Dr. Nagrath said. “We showed, with repeated blood draws during treatment, what is changing at a molecular level and that you can see it with a simple blood draw. It also gives the proof of concept that if these cells are present, this is a good way to monitor and see if a treatment is working, even early in the treatment.” Moreover, she added, “many studies in lung cancer are in stage 4.”

Our study is unique as it followed patients with locally advanced tumors from their being treatment naive to all the way through immunotherapy,” she continued.

The University of Michigan has a patent on the GO chip technology, but thus far no company has made efforts to license it and submit it for approval. While “liquid biopsy” is an important emerging concept in lung cancer, there is little consensus yet as to which blood biomarkers — whether CTCs, circulating tumor DNA (ctDNA), or extracellular vesicles (EVs) — are most clinically relevant, Dr. Nagrath said.

The study’s small size is one of its weaknesses, according to the authors.
 

Findings are ‘Particularly Intriguing’

Majid Ebrahimi Warkiani, PhD, who was not involved in the study, described the new findings as “particularly intriguing [and] highlighting the efficacy of liquid biopsy using CTCs for predicting treatment outcomes.”

A challenge within the realm of CTCs lies in the community’s ongoing struggle to define and classify these cells accurately, Dr. Warkiani said in an interview.

“While surface protein markers offer valuable insights, emerging layers of analysis, such as metabolomics, are increasingly entering the scene to bolster the identification of putative cancer cells, alongside molecular tests like fluorescence in situ hybridization (FISH),” said Dr. Warkiani of the University of Technology Sydney in Australia. “The amalgamation of these approaches simultaneously presents a significant challenge, particularly in terms of standardization for patient care, unlike ctDNA, which faces fewer bottlenecks.

“The robustness of the research in this study is commendable. However, further clinical testing and randomized trials are imperative,” Dr. Warkiani continued. “Companies like Epic Sciences are actively engaged in advancing research and standardization in this field.”

The study by Dr. Jolly and Dr. Nagrath was funded by the National Institutes of Health. None of the study authors reported financial conflicts of interest. Dr. Warkiani reported no conflicts of interest related to his comment.

A study from the University of Texas demonstrates the feasibility of using robotic single-port laparoscopy in nipple-sparing mastectomy (NSM), a type of conservative mastectomy preserving the skin and nipple-areola complex. The new findings potentially expand the application of robotic surgery to a larger patient population but doubts about the safety of this approach linger.

Robotic Mastectomy

The first surgeries involving the Da Vinci robotic surgeon for breast removal date to 2015. Multiport robotic surgery faces significant obstacles in this field, however. Feasibility studies have primarily focused on women with small breasts, corresponding to cup size C or smaller.

In the study that was published in JAMA Surgery, surgeons used the more cost-effective single-port platform for bilateral NSM procedures. Among the 20 patients included in the analysis (age, 29-63 years), 11 underwent prophylactic mastectomy (for a high risk for cancer) and 9 had mastectomy for breast tumors. Breast sizes ranged from A cup to D cup.

The duration of the procedure, from skin incision to suture for both breasts, ranged from 205 to 351 minutes (median, 277 minutes). No immediate operative complications (eg, hematoma) occurred, and there was no need for conversion to open surgery in any case. Over the 36-month follow-up, there were no recurrences. About 95% of patients retained skin sensitivity and 55% retained nipple sensitivity.
 

Unanswered Questions

In an accompanying article, Monica Morrow, MD, director of surgical breast oncology at the Memorial Sloan-Kettering Cancer Center in New York, acknowledged that the new evidence confirms the surgical approach’s feasibility but deems it insufficient to adopt it lightly. “At this point, the issue is not whether robotic mastectomy can be done but whether there is sufficient information about its oncologic safety that it should be done,” she wrote.

In a 2019 statement that was updated in 2021, the US Food and Drug Administration stated, “The safety and effectiveness of using robotically assisted surgical devices in mastectomy procedures or in the prevention or treatment of breast cancer have not been established.” The significance of this caution is underscored by the experience with laparoscopic and robotic radical hysterectomies. These procedures were widely adopted until a randomized prospective study demonstrated lower disease-free and overall survival for the minimally invasive approach compared with open surgery.

The University of Texas surgeons stated that acceptable safety and oncological outcomes for robotic NSM compared with conventional NSM had been demonstrated. They cited two trials with 238 cases and a median follow-up of less than 3 years. Dr. Morrow wrote, “While these reports provide reassurance that gross residual tumor is not being left behind, they do not address the issue of failure to remove all of the breast tissue due to thick skin flaps, with the potential for development of late recurrence or new cancers.” It is worth noting that even with the traditional surgical approach, the 5-year local recurrence rate after NSM is approximately double when observed with shorter follow-ups.

According to Dr. Morrow, the high rate of sensory preservation observed with robotic surgery, a desirable outcome for patients, is also a cause for concern. “While this may be due to incision placement or minimal skin flap retraction, as suggested by the authors, it is equally plausible that this could be due to thick skin flaps with preservation of the terminal branches of the fourth intercostal nerve.”

Therefore, more information on long-term oncological outcomes in a large number of patients will be necessary to confirm the safety of the procedure. In addition, measuring patient-reported outcomes will be useful in demonstrating that the benefits of the procedure outweigh increased operating times and costs. 

This article was translated from Univadis Italy, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.

A study from the University of Texas demonstrates the feasibility of using robotic single-port laparoscopy in nipple-sparing mastectomy (NSM), a type of conservative mastectomy preserving the skin and nipple-areola complex. The new findings potentially expand the application of robotic surgery to a larger patient population but doubts about the safety of this approach linger.

Robotic Mastectomy

The first surgeries involving the Da Vinci robotic surgeon for breast removal date to 2015. Multiport robotic surgery faces significant obstacles in this field, however. Feasibility studies have primarily focused on women with small breasts, corresponding to cup size C or smaller.

In the study that was published in JAMA Surgery, surgeons used the more cost-effective single-port platform for bilateral NSM procedures. Among the 20 patients included in the analysis (age, 29-63 years), 11 underwent prophylactic mastectomy (for a high risk for cancer) and 9 had mastectomy for breast tumors. Breast sizes ranged from A cup to D cup.

The duration of the procedure, from skin incision to suture for both breasts, ranged from 205 to 351 minutes (median, 277 minutes). No immediate operative complications (eg, hematoma) occurred, and there was no need for conversion to open surgery in any case. Over the 36-month follow-up, there were no recurrences. About 95% of patients retained skin sensitivity and 55% retained nipple sensitivity.
 

Unanswered Questions

In an accompanying article, Monica Morrow, MD, director of surgical breast oncology at the Memorial Sloan-Kettering Cancer Center in New York, acknowledged that the new evidence confirms the surgical approach’s feasibility but deems it insufficient to adopt it lightly. “At this point, the issue is not whether robotic mastectomy can be done but whether there is sufficient information about its oncologic safety that it should be done,” she wrote.

In a 2019 statement that was updated in 2021, the US Food and Drug Administration stated, “The safety and effectiveness of using robotically assisted surgical devices in mastectomy procedures or in the prevention or treatment of breast cancer have not been established.” The significance of this caution is underscored by the experience with laparoscopic and robotic radical hysterectomies. These procedures were widely adopted until a randomized prospective study demonstrated lower disease-free and overall survival for the minimally invasive approach compared with open surgery.

The University of Texas surgeons stated that acceptable safety and oncological outcomes for robotic NSM compared with conventional NSM had been demonstrated. They cited two trials with 238 cases and a median follow-up of less than 3 years. Dr. Morrow wrote, “While these reports provide reassurance that gross residual tumor is not being left behind, they do not address the issue of failure to remove all of the breast tissue due to thick skin flaps, with the potential for development of late recurrence or new cancers.” It is worth noting that even with the traditional surgical approach, the 5-year local recurrence rate after NSM is approximately double when observed with shorter follow-ups.

According to Dr. Morrow, the high rate of sensory preservation observed with robotic surgery, a desirable outcome for patients, is also a cause for concern. “While this may be due to incision placement or minimal skin flap retraction, as suggested by the authors, it is equally plausible that this could be due to thick skin flaps with preservation of the terminal branches of the fourth intercostal nerve.”

Therefore, more information on long-term oncological outcomes in a large number of patients will be necessary to confirm the safety of the procedure. In addition, measuring patient-reported outcomes will be useful in demonstrating that the benefits of the procedure outweigh increased operating times and costs. 

This article was translated from Univadis Italy, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.

A study from the University of Texas demonstrates the feasibility of using robotic single-port laparoscopy in nipple-sparing mastectomy (NSM), a type of conservative mastectomy preserving the skin and nipple-areola complex. The new findings potentially expand the application of robotic surgery to a larger patient population but doubts about the safety of this approach linger.

Robotic Mastectomy

The first surgeries involving the Da Vinci robotic surgeon for breast removal date to 2015. Multiport robotic surgery faces significant obstacles in this field, however. Feasibility studies have primarily focused on women with small breasts, corresponding to cup size C or smaller.

In the study that was published in JAMA Surgery, surgeons used the more cost-effective single-port platform for bilateral NSM procedures. Among the 20 patients included in the analysis (age, 29-63 years), 11 underwent prophylactic mastectomy (for a high risk for cancer) and 9 had mastectomy for breast tumors. Breast sizes ranged from A cup to D cup.

The duration of the procedure, from skin incision to suture for both breasts, ranged from 205 to 351 minutes (median, 277 minutes). No immediate operative complications (eg, hematoma) occurred, and there was no need for conversion to open surgery in any case. Over the 36-month follow-up, there were no recurrences. About 95% of patients retained skin sensitivity and 55% retained nipple sensitivity.
 

Unanswered Questions

In an accompanying article, Monica Morrow, MD, director of surgical breast oncology at the Memorial Sloan-Kettering Cancer Center in New York, acknowledged that the new evidence confirms the surgical approach’s feasibility but deems it insufficient to adopt it lightly. “At this point, the issue is not whether robotic mastectomy can be done but whether there is sufficient information about its oncologic safety that it should be done,” she wrote.

In a 2019 statement that was updated in 2021, the US Food and Drug Administration stated, “The safety and effectiveness of using robotically assisted surgical devices in mastectomy procedures or in the prevention or treatment of breast cancer have not been established.” The significance of this caution is underscored by the experience with laparoscopic and robotic radical hysterectomies. These procedures were widely adopted until a randomized prospective study demonstrated lower disease-free and overall survival for the minimally invasive approach compared with open surgery.

The University of Texas surgeons stated that acceptable safety and oncological outcomes for robotic NSM compared with conventional NSM had been demonstrated. They cited two trials with 238 cases and a median follow-up of less than 3 years. Dr. Morrow wrote, “While these reports provide reassurance that gross residual tumor is not being left behind, they do not address the issue of failure to remove all of the breast tissue due to thick skin flaps, with the potential for development of late recurrence or new cancers.” It is worth noting that even with the traditional surgical approach, the 5-year local recurrence rate after NSM is approximately double when observed with shorter follow-ups.

According to Dr. Morrow, the high rate of sensory preservation observed with robotic surgery, a desirable outcome for patients, is also a cause for concern. “While this may be due to incision placement or minimal skin flap retraction, as suggested by the authors, it is equally plausible that this could be due to thick skin flaps with preservation of the terminal branches of the fourth intercostal nerve.”

Therefore, more information on long-term oncological outcomes in a large number of patients will be necessary to confirm the safety of the procedure. In addition, measuring patient-reported outcomes will be useful in demonstrating that the benefits of the procedure outweigh increased operating times and costs. 

This article was translated from Univadis Italy, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.

The arrival of GLP-1 receptor agonists has revolutionized treatment options for people with obesity and medical practice.

This news organization recently hosted a panel of experts across specialties — including endocrinology, gastroenterology, and obesity medicine — to discuss these potentially life-changing medications and to answer questions from the audience.

Because of the flood of queries from our audience, we asked our panelists to address some of the questions that didn’t make the recording. Their answers are below.

Beverly Tchang, MD, endocrinologist, Weill Cornell Medicine, New York City

Audience member: Can you initiate glucagon-like peptide-1 agonists (GLP-1 RAs) as a primary drug in a patient with obesity and newly diagnosed type 2 diabetes?

BT: We often prescribe GLP-1 RAs to individuals with type 2 diabetes as a first-line medication. Guidelines from the American Diabetes Association are really emphasizing a patient-centered approach, and metformin may not be the best first-line medication anymore.

Audience member: What should clinicians know about dose titration of GLP-1 RAs in diabetic patients with renal disease, especially those in stages IV and V chronic kidney disease?

BT: GLP-1 RAs do not need to be renally dosed, but I still recommend conferring with the patient’s nephrologist because the glomerular filtration rate might decrease in the setting of dehydration. Because GLP1s suppress the thirst, not just appetite, patients can go all day without drinking water and not feel thirsty.

Michael Camilleri, MD, gastroenterologist, Mayo Clinic, Rochester, Minnesota

Audience member: Should GLP-1 RAs be held for 1 week or 4 weeks prior to surgery to reduce the patient’s risk for aspiration? And is tapering required?

MC: For a patient taking liraglutide, I would hold the drug for 1 week prior to surgery. For patients taking other GLP-1 RAs, including extended exenatide, I advise holding for between 2 and 3 weeks before the procedure. It’s also important to make sure the patient’s diabetes is well-controlled with other medications — not GLP-1 RAs — during this period.

After surgery, you can restart GLP-1 RA therapy once there is recovery of oral food intake and normal bowel function.

Audience member: Is treatment with GLP-1 RAs appropriate for a patient with a family history of colon cancer but an otherwise unremarkable medical and family history?

MC: I have not seen a contraindication to receiving GLP-1 RAs based on a family history of colorectal cancer or other malignancies. An analysis of the French national healthcare insurance system database has suggested 1-3 years use of GLP-1 RAs (exenatide, liraglutide, and dulaglutide) may be linked with increased occurrence of thyroid cancer. Data from 37 randomized controlled trials and 19 real-world studies having 16,839 patients in placebo control group, 16,550 patients in active control group, and 13,330 patients in real-world studies were analyzed in a 2023 systematic review and meta-analysis. Compared to placebo or active control treatments, occurrence of pancreatic cancer, thyroid cancer, and all neoplasms — benign, malignant, and otherwise unspecified — were similar in the semaglutide group.

Toshi Iroku-Malize, MD, MPH, MBA, FAAFP, family physician, Zucker School of Medicine, Hempstead, New York

Audience member: What do you do about elevated liver functions after starting treatment with GLP-1 RAs, and what do you do when a patient has reached their weight loss goal?

TI-M: I recommend monitoring the liver function tests, evaluating for underlying causes, such as viral hepatitis, alcohol-related damage, or problems with other medications, and consulting a gastroenterologist or liver specialist if necessary. It’s also important to discuss the risk-benefit of continuing on the GP-1 RA for that particular patient.

Audience member: What effects will GLP-1 RAs have on sleep-disordered breathing/obstructive sleep apnea (OSA)? Are you aware of any ongoing trials addressing this subject?

TI-M: GLP-1 RAs may have beneficial effects on sleep-disordered breathing and OSA through weight loss, which can lead to a reduction in excess adipose tissue, and improvements in metabolic parameters. In terms of studies, a 2023 paper addressed this question, but more research is needed.

Audience member: Is it within a psychiatric provider’s scope of practice to prescribe GLP-1 agents for the reduction of weight gain associated with psychiatric medications?

TI-M: Obesity medicine is an interdisciplinary process. Numerous medications prescribed for mental health can contribute to obesity, and psychiatrists can play a role in collaborating with a patient’s primary care provider and/or obesity medicine specialist to determine which medications can be adjusted or replaced. It is important to remember that obesity management is not just about medications. It requires managing nutrition and activity in addition to behavioral health issues and social determinants of health. If the clinician has had the training to manage these pillars and is comfortable managing this chronic illness — similar to diabetes, hypertension, and other conditions — then this is a possibility. Otherwise, team-based care is appropriate.

Holly Lofton, MD, obesity medicine, NYU Langone Health, New York City

Audience member: Can we safely use them on patients who have had bariatric surgery and regularly develop dumping syndrome?

HL: These medications can be used after bariatric surgery in patients who meet the criteria for pharmacologic treatment. If a patient is having postoperative symptoms of dumping syndrome or excessive gastrointestinal losses from vomiting or diarrhea, dietary adjustments and other methods of managing the dumping syndrome in gastric bypass patients should be initiated before considering GLP-1 RAs because these patients do not have a functioning pylorus in their alimentary tract and these drugs are not indicated to treat dumping syndrome. The first-line approach typically involves reducing the patient’s intake of simple carbohydrates but can also include medications or surgical intervention when appropriate.

Audience member: Would teaching a patient to fast intermittently while they’re on GLP-1 RAs help them preserve weight loss if they choose to wean off the medication?

HL: Personally, I feel it is best to use the titration period and the time in which the patient is actively losing weight when on GLP-1 RAs. These are the best periods to help develop an individualized treatment plan, one that includes nutrition, activity, behavior modification, and resistance training. The patient’s lifestyle plan will likely change based on their environment and other factors. Intermittent fasting can be a part of such a plan. There is no consensus as to exactly which eating pattern will help patients maintain weight once they lose the physiologic benefit of the weight loss medications. However, studies have been published that demonstrate an average weight regain of 66% or greater when patients go from taking the maximum dose of a GLP-1 RA to taking none at all. Thus, patients should still be followed closely for weight regain when they discontinue a GLP-1 RA.

A version of this article appeared on Medscape.com.

The arrival of GLP-1 receptor agonists has revolutionized treatment options for people with obesity and medical practice.

This news organization recently hosted a panel of experts across specialties — including endocrinology, gastroenterology, and obesity medicine — to discuss these potentially life-changing medications and to answer questions from the audience.

Because of the flood of queries from our audience, we asked our panelists to address some of the questions that didn’t make the recording. Their answers are below.

Beverly Tchang, MD, endocrinologist, Weill Cornell Medicine, New York City

Audience member: Can you initiate glucagon-like peptide-1 agonists (GLP-1 RAs) as a primary drug in a patient with obesity and newly diagnosed type 2 diabetes?

BT: We often prescribe GLP-1 RAs to individuals with type 2 diabetes as a first-line medication. Guidelines from the American Diabetes Association are really emphasizing a patient-centered approach, and metformin may not be the best first-line medication anymore.

Audience member: What should clinicians know about dose titration of GLP-1 RAs in diabetic patients with renal disease, especially those in stages IV and V chronic kidney disease?

BT: GLP-1 RAs do not need to be renally dosed, but I still recommend conferring with the patient’s nephrologist because the glomerular filtration rate might decrease in the setting of dehydration. Because GLP1s suppress the thirst, not just appetite, patients can go all day without drinking water and not feel thirsty.

Michael Camilleri, MD, gastroenterologist, Mayo Clinic, Rochester, Minnesota

Audience member: Should GLP-1 RAs be held for 1 week or 4 weeks prior to surgery to reduce the patient’s risk for aspiration? And is tapering required?

MC: For a patient taking liraglutide, I would hold the drug for 1 week prior to surgery. For patients taking other GLP-1 RAs, including extended exenatide, I advise holding for between 2 and 3 weeks before the procedure. It’s also important to make sure the patient’s diabetes is well-controlled with other medications — not GLP-1 RAs — during this period.

After surgery, you can restart GLP-1 RA therapy once there is recovery of oral food intake and normal bowel function.

Audience member: Is treatment with GLP-1 RAs appropriate for a patient with a family history of colon cancer but an otherwise unremarkable medical and family history?

MC: I have not seen a contraindication to receiving GLP-1 RAs based on a family history of colorectal cancer or other malignancies. An analysis of the French national healthcare insurance system database has suggested 1-3 years use of GLP-1 RAs (exenatide, liraglutide, and dulaglutide) may be linked with increased occurrence of thyroid cancer. Data from 37 randomized controlled trials and 19 real-world studies having 16,839 patients in placebo control group, 16,550 patients in active control group, and 13,330 patients in real-world studies were analyzed in a 2023 systematic review and meta-analysis. Compared to placebo or active control treatments, occurrence of pancreatic cancer, thyroid cancer, and all neoplasms — benign, malignant, and otherwise unspecified — were similar in the semaglutide group.

Toshi Iroku-Malize, MD, MPH, MBA, FAAFP, family physician, Zucker School of Medicine, Hempstead, New York

Audience member: What do you do about elevated liver functions after starting treatment with GLP-1 RAs, and what do you do when a patient has reached their weight loss goal?

TI-M: I recommend monitoring the liver function tests, evaluating for underlying causes, such as viral hepatitis, alcohol-related damage, or problems with other medications, and consulting a gastroenterologist or liver specialist if necessary. It’s also important to discuss the risk-benefit of continuing on the GP-1 RA for that particular patient.

Audience member: What effects will GLP-1 RAs have on sleep-disordered breathing/obstructive sleep apnea (OSA)? Are you aware of any ongoing trials addressing this subject?

TI-M: GLP-1 RAs may have beneficial effects on sleep-disordered breathing and OSA through weight loss, which can lead to a reduction in excess adipose tissue, and improvements in metabolic parameters. In terms of studies, a 2023 paper addressed this question, but more research is needed.

Audience member: Is it within a psychiatric provider’s scope of practice to prescribe GLP-1 agents for the reduction of weight gain associated with psychiatric medications?

TI-M: Obesity medicine is an interdisciplinary process. Numerous medications prescribed for mental health can contribute to obesity, and psychiatrists can play a role in collaborating with a patient’s primary care provider and/or obesity medicine specialist to determine which medications can be adjusted or replaced. It is important to remember that obesity management is not just about medications. It requires managing nutrition and activity in addition to behavioral health issues and social determinants of health. If the clinician has had the training to manage these pillars and is comfortable managing this chronic illness — similar to diabetes, hypertension, and other conditions — then this is a possibility. Otherwise, team-based care is appropriate.

Holly Lofton, MD, obesity medicine, NYU Langone Health, New York City

Audience member: Can we safely use them on patients who have had bariatric surgery and regularly develop dumping syndrome?

HL: These medications can be used after bariatric surgery in patients who meet the criteria for pharmacologic treatment. If a patient is having postoperative symptoms of dumping syndrome or excessive gastrointestinal losses from vomiting or diarrhea, dietary adjustments and other methods of managing the dumping syndrome in gastric bypass patients should be initiated before considering GLP-1 RAs because these patients do not have a functioning pylorus in their alimentary tract and these drugs are not indicated to treat dumping syndrome. The first-line approach typically involves reducing the patient’s intake of simple carbohydrates but can also include medications or surgical intervention when appropriate.

Audience member: Would teaching a patient to fast intermittently while they’re on GLP-1 RAs help them preserve weight loss if they choose to wean off the medication?

HL: Personally, I feel it is best to use the titration period and the time in which the patient is actively losing weight when on GLP-1 RAs. These are the best periods to help develop an individualized treatment plan, one that includes nutrition, activity, behavior modification, and resistance training. The patient’s lifestyle plan will likely change based on their environment and other factors. Intermittent fasting can be a part of such a plan. There is no consensus as to exactly which eating pattern will help patients maintain weight once they lose the physiologic benefit of the weight loss medications. However, studies have been published that demonstrate an average weight regain of 66% or greater when patients go from taking the maximum dose of a GLP-1 RA to taking none at all. Thus, patients should still be followed closely for weight regain when they discontinue a GLP-1 RA.

A version of this article appeared on Medscape.com.

The arrival of GLP-1 receptor agonists has revolutionized treatment options for people with obesity and medical practice.

This news organization recently hosted a panel of experts across specialties — including endocrinology, gastroenterology, and obesity medicine — to discuss these potentially life-changing medications and to answer questions from the audience.

Because of the flood of queries from our audience, we asked our panelists to address some of the questions that didn’t make the recording. Their answers are below.

Beverly Tchang, MD, endocrinologist, Weill Cornell Medicine, New York City

Audience member: Can you initiate glucagon-like peptide-1 agonists (GLP-1 RAs) as a primary drug in a patient with obesity and newly diagnosed type 2 diabetes?

BT: We often prescribe GLP-1 RAs to individuals with type 2 diabetes as a first-line medication. Guidelines from the American Diabetes Association are really emphasizing a patient-centered approach, and metformin may not be the best first-line medication anymore.

Audience member: What should clinicians know about dose titration of GLP-1 RAs in diabetic patients with renal disease, especially those in stages IV and V chronic kidney disease?

BT: GLP-1 RAs do not need to be renally dosed, but I still recommend conferring with the patient’s nephrologist because the glomerular filtration rate might decrease in the setting of dehydration. Because GLP1s suppress the thirst, not just appetite, patients can go all day without drinking water and not feel thirsty.

Michael Camilleri, MD, gastroenterologist, Mayo Clinic, Rochester, Minnesota

Audience member: Should GLP-1 RAs be held for 1 week or 4 weeks prior to surgery to reduce the patient’s risk for aspiration? And is tapering required?

MC: For a patient taking liraglutide, I would hold the drug for 1 week prior to surgery. For patients taking other GLP-1 RAs, including extended exenatide, I advise holding for between 2 and 3 weeks before the procedure. It’s also important to make sure the patient’s diabetes is well-controlled with other medications — not GLP-1 RAs — during this period.

After surgery, you can restart GLP-1 RA therapy once there is recovery of oral food intake and normal bowel function.

Audience member: Is treatment with GLP-1 RAs appropriate for a patient with a family history of colon cancer but an otherwise unremarkable medical and family history?

MC: I have not seen a contraindication to receiving GLP-1 RAs based on a family history of colorectal cancer or other malignancies. An analysis of the French national healthcare insurance system database has suggested 1-3 years use of GLP-1 RAs (exenatide, liraglutide, and dulaglutide) may be linked with increased occurrence of thyroid cancer. Data from 37 randomized controlled trials and 19 real-world studies having 16,839 patients in placebo control group, 16,550 patients in active control group, and 13,330 patients in real-world studies were analyzed in a 2023 systematic review and meta-analysis. Compared to placebo or active control treatments, occurrence of pancreatic cancer, thyroid cancer, and all neoplasms — benign, malignant, and otherwise unspecified — were similar in the semaglutide group.

Toshi Iroku-Malize, MD, MPH, MBA, FAAFP, family physician, Zucker School of Medicine, Hempstead, New York

Audience member: What do you do about elevated liver functions after starting treatment with GLP-1 RAs, and what do you do when a patient has reached their weight loss goal?

TI-M: I recommend monitoring the liver function tests, evaluating for underlying causes, such as viral hepatitis, alcohol-related damage, or problems with other medications, and consulting a gastroenterologist or liver specialist if necessary. It’s also important to discuss the risk-benefit of continuing on the GP-1 RA for that particular patient.

Audience member: What effects will GLP-1 RAs have on sleep-disordered breathing/obstructive sleep apnea (OSA)? Are you aware of any ongoing trials addressing this subject?

TI-M: GLP-1 RAs may have beneficial effects on sleep-disordered breathing and OSA through weight loss, which can lead to a reduction in excess adipose tissue, and improvements in metabolic parameters. In terms of studies, a 2023 paper addressed this question, but more research is needed.

Audience member: Is it within a psychiatric provider’s scope of practice to prescribe GLP-1 agents for the reduction of weight gain associated with psychiatric medications?

TI-M: Obesity medicine is an interdisciplinary process. Numerous medications prescribed for mental health can contribute to obesity, and psychiatrists can play a role in collaborating with a patient’s primary care provider and/or obesity medicine specialist to determine which medications can be adjusted or replaced. It is important to remember that obesity management is not just about medications. It requires managing nutrition and activity in addition to behavioral health issues and social determinants of health. If the clinician has had the training to manage these pillars and is comfortable managing this chronic illness — similar to diabetes, hypertension, and other conditions — then this is a possibility. Otherwise, team-based care is appropriate.

Holly Lofton, MD, obesity medicine, NYU Langone Health, New York City

Audience member: Can we safely use them on patients who have had bariatric surgery and regularly develop dumping syndrome?

HL: These medications can be used after bariatric surgery in patients who meet the criteria for pharmacologic treatment. If a patient is having postoperative symptoms of dumping syndrome or excessive gastrointestinal losses from vomiting or diarrhea, dietary adjustments and other methods of managing the dumping syndrome in gastric bypass patients should be initiated before considering GLP-1 RAs because these patients do not have a functioning pylorus in their alimentary tract and these drugs are not indicated to treat dumping syndrome. The first-line approach typically involves reducing the patient’s intake of simple carbohydrates but can also include medications or surgical intervention when appropriate.

Audience member: Would teaching a patient to fast intermittently while they’re on GLP-1 RAs help them preserve weight loss if they choose to wean off the medication?

HL: Personally, I feel it is best to use the titration period and the time in which the patient is actively losing weight when on GLP-1 RAs. These are the best periods to help develop an individualized treatment plan, one that includes nutrition, activity, behavior modification, and resistance training. The patient’s lifestyle plan will likely change based on their environment and other factors. Intermittent fasting can be a part of such a plan. There is no consensus as to exactly which eating pattern will help patients maintain weight once they lose the physiologic benefit of the weight loss medications. However, studies have been published that demonstrate an average weight regain of 66% or greater when patients go from taking the maximum dose of a GLP-1 RA to taking none at all. Thus, patients should still be followed closely for weight regain when they discontinue a GLP-1 RA.

A version of this article appeared on Medscape.com.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

The patient had an advanced cutaneous squamous cell carcinoma (cSCC) on the face that seemed to be affecting the facial nerve, ruling out aggressive surgery. When Mohs surgery failed to clear the tumor, radiation was ordered. But the best option — an immune checkpoint inhibitor — could not be administered because the patient was a lung transplant recipient.

Although approved for metastatic cSCC, immune checkpoint inhibitors are associated with a higher potential for rejection of an organ transplant.

“The feeling is that the risk of rejection is just too great if we were to try to give an immune checkpoint inhibitor,” said Sean Christensen, MD, PhD, director of dermatologic surgery at Yale Dermatology–Branford, in Connecticut, who was treating the patient. Dr. Christensen consulted with the transplant team, and together they decided to switch the patient to sirolimus, an immunosuppressant that has been shown to have less risk of promoting skin cancer in those who take the medication. Sirolimus, however, is not as well tolerated as the usual first-line immunosuppressant, tacrolimus.

Dr. Christensen

Dr. Bottomley

Reducing Risk Factors

Dr. Bottomley said that there’s also been renewed effort to identify how to reduce cSCC risk in transplant recipients through recently developed consensus guidelines and a proposed decision framework developed by Dr. Bottomley and colleagues. The evidence will help clinicians have “greater confidence in making early interventions,” he said.

Currently, solid organ transplant patients are told to reduce sun exposure, in part because the majority of cSCCs occur in sun-exposed areas, such as the head and neck, and ultraviolet radiation leads to mutations. “Sun protection is critical,” Dr. Christensen said. That’s especially true in younger transplant recipients, who may have decades of sun exposure, he said.

The immunosuppressive medications also increase cancer risk, for a variety of reasons. One of the more-commonly used immunosuppressants in the past, azathioprine, is itself carcinogenic. Other antirejection medications, such as tacrolimus and mycophenolate, may also induce mutagenic changes that give rise to malignancies, according to the paper by Dr. Bibee, assistant professor of dermatology at Johns Hopkins, Baltimore.

Both Dr. Bibee, in her paper, and Dr. Arron, in an interview, noted that voriconazole, an antifungal used to prevent Aspergillus infection after lung transplant, has been associated with an increase in cSCC in lung transplant recipients.

Dr. Arron

In addition, immunosuppression essentially “blocks the body’s immune system from recognizing that there are abnormal cancerous cells present,” Dr. Arron, a dermatologist in private practice in Burlingame, California, told this news organization.

Previously, while at the High-Risk Skin Cancer Program at University of California, San Francisco (UCSF), Dr. Arron and others studied whether human papillomavirus (HPV) might play a role in spurring the development of cSCC formation in the immunocompromised. HPV is highly prevalent on the skin, but the virus found on the skin tends to be composed of lower-risk strains.

“In our research, we did not find any biologic mechanism by which this virus might be driving these cancers,” said Dr. Arron, although she said that some researchers “feel very strongly that HPV must be in some way a driver.”

Dr. Bottomley believes that HPV’s role has not been completely determined. The excess incidence of cSCC suggests a virus might be involved, as has been seen with excess risk of lymphoma in patients with Epstein-Barr virus, he said.

Some of his research is focusing on whether advanced immune aging is an independent risk factor for subsequent cSCC development in solid organ transplant recipients. The immune system undergoes changes as people age, and the speed of this process varies from patient to patient, which means immune age can be different from chronological age, said Dr. Bottomley. “We’re still exploring why immune aging should predispose you to cSCC,” he said.
 

When to Intervene?

Transplant patients are followed by dermatologists at regular intervals. But guidelines are not consistent on the recommended timing of those intervals.

Dr. Arron and colleagues in 2019 created a risk prediction module that recommended frequency of follow-up based on low, medium, high, or very high risk. The tool is available to clinicians in an app called SUNTRAC, or the Skin and Ultraviolet Neoplasia Transplant Risk Assessment Calculator.

A question that Dr. Arron said dermatologists and transplant specialists have wrangled with: How early can they intervene to prevent further lesions?

In the 2022 decision framework paper in Transplant International, Dr. Bottomley and dermatology colleagues from around the world attempted to better delineate when and how clinicians should intervene when a cSCC is first detected. That first cSCC “should be regarded as a ‘red flag’ heralding an increased risk of further skin cancers and possibly internal malignancies,” the authors wrote. That moment is “a key opportunity to proactively consider secondary preventive strategies,” they wrote, but noted that the best interventions and “their sequencing remain unclear,” indicating the need for further research.
 

Coordinating With the Transplant Team

A key strategy to help prevent cSCC development — suggested in Dr. Bottomley’s paper, and by Dr. Arron and Dr. Christensen — is to consult with the transplant team on potentially changing a patient’s immunosuppressive medication or reducing the dose.

Dr. Arron said that a decade ago, it was somewhat of a novel concept, requiring data-sharing and making personal connections with the transplant team to forge trusting relationships. By the time she left UCSF a few years ago, she said, “the transplant program was very much on board with preventing and treating skin cancer and oftentimes they were making changes even before I would suggest them.”

Suggesting a change or dose reduction is not undertaken lightly. “Our transplant physician colleagues are balancing multiple problems in very sick patients, of which skin cancer might be one, but not the most pressing one in the setting of other transplant complications,” said Dr. Arron.

Dr. Bottomley said that “as transplant physicians, we very much respect and value the input of our dermatology colleagues,” but agreed that many factors “outside malignancy risk” must be weighed when considering changing an immunosuppressive regimen.

In a Delphi Consensus Statement on prevention of cSCC in organ transplant recipients, published in 2021 in JAMA Dermatology, the authors recommended having discussions about immunosuppression with transplant specialists, but did not make a recommendation on what strategy to use. The consensus panel said it preferred “to defer this decision to transplant physicians.”

Acitretin a Go, Nicotinamide Not So Much

Outside of changing an immunosuppressive regimen, among the interventions for secondary prevention are acitretin, the systemic retinoid, and nicotinamide, a form of niacin.

Dr. Christensen conducted a small retrospective investigation evaluating the effectiveness of acitretin in reducing cSCC in both immunocompromised and immunocompetent patients who had received care at Yale, which was recently published in the Journal of the American Academy of Dermatology. Acitretin reduced invasive cSCC by about 75% in both patient groups — a surprising result for the immunocompetent group, but well-established in patients who have had a solid organ transplant. But acitretin had no effect on cSCC in situ or basal cell carcinoma. “The benefit of acitretin is primarily in preventing the invasive SCC,” said Dr. Christensen, which is why he tends to reserve it for patients who have already had several cSCCs.

“It’s not a completely benign medication,” he said, noting the need for monitoring for cholesterol and liver function.

Several years ago, a study in immunocompetent patients, published in the New England Journal of Medicine, found that nicotinamide (also known as niacinamide) reduced the rate of nonmelonoma skin cancer by 23%, giving clinicians hope that it might also be a low-risk, low-cost cancer preventive for solid organ transplant patients. But enthusiasm has dampened since a 2023 study in the New England Journal of Medicine found that the vitamin did not reduce cSCCs in transplant recipients.

Dr. Christensen said he believes the most-recent study wasn’t powered to detect a 25% reduction in cancers. “It’s certainly possible that it still works exactly the same way in transplant patients that it does in immunocompetent patients,” he said. “There’s very little risk of recommending it to patients for general prevention. But it probably has a very modest effect in many,” he said.

Dr. Arron agreed, saying, “it may be that we simply need bigger studies to achieve that statistical significance.” Even so, she said she would not use the therapy “until there is more evidence supporting the use of nicotinamide in transplant recipients.”

Immune checkpoint inhibitors such as cemiplimab and pembrolizumab have been approved by the US Food and Drug Administration for advanced cSCC; nivolumab is another drug in the same class that has not yet been approved for cSCC. But “there’s always been a fear — and a legitimate fear — that if you gave those to organ transplant recipients they would reject their organ,” said Dr. Christensen.

Patients who take the checkpoint inhibitors may first have to stop taking their antirejection drugs, leaving them at risk. It also appears that the checkpoint inhibitors themselves contribute to organ rejection. Recent studies suggest that “the rate of organ rejection is only about 30% to 40%,” with the checkpoint inhibitors, said Dr. Christensen. “Obviously that’s still not an ideal outcome,” he said, but noted that with patients who have inoperable metastatic cSCC, “immune therapy can be a good option.”

Dr. Christensen reported no disclosures. Dr. Bottomley has previously received speaker fees and an educational grant from Astellas. Dr. Arron disclosed ties with Regeneron, Castle Biosciences, and Enspectra Health, not specific to transplantation.

A new Senate bill would require Medicare to test two tools routinely used by credit card companies to prevent fraud: Artificial intelligence (AI)-trained algorithms to detect suspicious activity and a system to quickly alert Medicare patients on whose behalf payment is being sought.

Senator Mike Braun (R-IN) recently introduced the Medicare Transaction Fraud Prevention Act, which calls for a 2-year test of this approach.

The experiment, targeted to start in 2025, would focus on durable medical equipment and clinical diagnostic laboratory tests and cover Medicare beneficiaries who receive electronic notices about claims.

The legislation would direct the Center for Medicare and Medicaid Services (CMS) to test the use of predictive risk-scoring algorithms in finding fraud. The program would be modeled on the systems that credit card companies already use. Transactions could be scored from 1 (least risky) to 99 (most risky).

CMS would then check directly by email or phone call with selected Medicare enrollees about transactions considered to present a high risk for fraud.

Many consumers have benefited from this approach when used to check for fraud on their credit cards, Braun noted during a November hearing of the Senate Special Committee on Aging. Credit card companies often can intervene before a fraudulent transaction is cleared.

“There’s no reason we wouldn’t want to minimally at least mimic that,” Braun said at the hearing.

Asking Medicare enrollees to verify certain purchases could give CMS increased access to vital predictive data, test proof of concept, and save hundreds of millions of dollars, Braun said.

Concerns Raised

So far, Braun has only one cosponsor for the bill, Senator Bill Cassidy, MD (R-LA), and the bill has drawn some criticism.

Brett Meeks, executive director of the Health Innovation Alliance, a trade group representing technology companies, insurers, and consumer organizations, objected to requiring Medicare enrollees to verify flagged orders. CMS should internally root out fraud through technology, not burden seniors, Meeks told this news organization.

Meeks said he has been following the discussion about the use of AI in addressing Medicare fraud. Had a bill broadly targeted Medicare fraud through AI, his alliance might have backed it, he said. But the current proposed legislation has a narrower focus.

Focusing on durable medical equipment, for example, could have unintended consequences like denying power wheelchairs to people with debilitating conditions like multiple sclerosis, Meeks said.

But Braun’s bill won a quick nod of approval from a researcher who studies the use of AI to detect Medicare fraud. Taghi M. Khoshgoftaar, PhD, director of the Data Mining and Machine Learning Lab at Florida Atlantic University, Boca Raton, Florida, said he sees an advantage to Braun’s approach of involving Medicare enrollees in the protection of their benefits.

The bill does not authorize funding for the pilot project, and it’s unclear what it would cost.

Detecting Medicare Fraud

The federal government has stepped up Medicare fraud investigations in recent years, and more doctors are getting caught.

A study published in 2018 examined cases of physicians excluded from Medicare using data from the US Office of Inspector General (OIG) at the Department of Health and Human Services.

The OIG has the right to exclude clinicians from Medicare for fraud or other reasons. Chen and coauthors looked at Medicare physician exclusions from 2007 to 2017. They found that exclusions due to fraud increased an estimated 14% per year on average from a base level of 139 exclusions in 2007.

In 2019, CMS sought feedback on new ways to use AI to detect fraud. In a public request for information, the agency said Medicare scrutinizes fewer claims for payment than commercial insurers do.

About 99.7% of Medicare fee-for-service claims are processed and paid within 17 days without any medical review, CMS said at the time.

A version of this article appeared on Medscape.com .

A new Senate bill would require Medicare to test two tools routinely used by credit card companies to prevent fraud: Artificial intelligence (AI)-trained algorithms to detect suspicious activity and a system to quickly alert Medicare patients on whose behalf payment is being sought.

Senator Mike Braun (R-IN) recently introduced the Medicare Transaction Fraud Prevention Act, which calls for a 2-year test of this approach.

The experiment, targeted to start in 2025, would focus on durable medical equipment and clinical diagnostic laboratory tests and cover Medicare beneficiaries who receive electronic notices about claims.

The legislation would direct the Center for Medicare and Medicaid Services (CMS) to test the use of predictive risk-scoring algorithms in finding fraud. The program would be modeled on the systems that credit card companies already use. Transactions could be scored from 1 (least risky) to 99 (most risky).

CMS would then check directly by email or phone call with selected Medicare enrollees about transactions considered to present a high risk for fraud.

Many consumers have benefited from this approach when used to check for fraud on their credit cards, Braun noted during a November hearing of the Senate Special Committee on Aging. Credit card companies often can intervene before a fraudulent transaction is cleared.

“There’s no reason we wouldn’t want to minimally at least mimic that,” Braun said at the hearing.

Asking Medicare enrollees to verify certain purchases could give CMS increased access to vital predictive data, test proof of concept, and save hundreds of millions of dollars, Braun said.

Concerns Raised

So far, Braun has only one cosponsor for the bill, Senator Bill Cassidy, MD (R-LA), and the bill has drawn some criticism.

Brett Meeks, executive director of the Health Innovation Alliance, a trade group representing technology companies, insurers, and consumer organizations, objected to requiring Medicare enrollees to verify flagged orders. CMS should internally root out fraud through technology, not burden seniors, Meeks told this news organization.

Meeks said he has been following the discussion about the use of AI in addressing Medicare fraud. Had a bill broadly targeted Medicare fraud through AI, his alliance might have backed it, he said. But the current proposed legislation has a narrower focus.

Focusing on durable medical equipment, for example, could have unintended consequences like denying power wheelchairs to people with debilitating conditions like multiple sclerosis, Meeks said.

But Braun’s bill won a quick nod of approval from a researcher who studies the use of AI to detect Medicare fraud. Taghi M. Khoshgoftaar, PhD, director of the Data Mining and Machine Learning Lab at Florida Atlantic University, Boca Raton, Florida, said he sees an advantage to Braun’s approach of involving Medicare enrollees in the protection of their benefits.

The bill does not authorize funding for the pilot project, and it’s unclear what it would cost.

Detecting Medicare Fraud

The federal government has stepped up Medicare fraud investigations in recent years, and more doctors are getting caught.

A study published in 2018 examined cases of physicians excluded from Medicare using data from the US Office of Inspector General (OIG) at the Department of Health and Human Services.

The OIG has the right to exclude clinicians from Medicare for fraud or other reasons. Chen and coauthors looked at Medicare physician exclusions from 2007 to 2017. They found that exclusions due to fraud increased an estimated 14% per year on average from a base level of 139 exclusions in 2007.

In 2019, CMS sought feedback on new ways to use AI to detect fraud. In a public request for information, the agency said Medicare scrutinizes fewer claims for payment than commercial insurers do.

About 99.7% of Medicare fee-for-service claims are processed and paid within 17 days without any medical review, CMS said at the time.

A version of this article appeared on Medscape.com .

A new Senate bill would require Medicare to test two tools routinely used by credit card companies to prevent fraud: Artificial intelligence (AI)-trained algorithms to detect suspicious activity and a system to quickly alert Medicare patients on whose behalf payment is being sought.

Senator Mike Braun (R-IN) recently introduced the Medicare Transaction Fraud Prevention Act, which calls for a 2-year test of this approach.

The experiment, targeted to start in 2025, would focus on durable medical equipment and clinical diagnostic laboratory tests and cover Medicare beneficiaries who receive electronic notices about claims.

The legislation would direct the Center for Medicare and Medicaid Services (CMS) to test the use of predictive risk-scoring algorithms in finding fraud. The program would be modeled on the systems that credit card companies already use. Transactions could be scored from 1 (least risky) to 99 (most risky).

CMS would then check directly by email or phone call with selected Medicare enrollees about transactions considered to present a high risk for fraud.

Many consumers have benefited from this approach when used to check for fraud on their credit cards, Braun noted during a November hearing of the Senate Special Committee on Aging. Credit card companies often can intervene before a fraudulent transaction is cleared.

“There’s no reason we wouldn’t want to minimally at least mimic that,” Braun said at the hearing.

Asking Medicare enrollees to verify certain purchases could give CMS increased access to vital predictive data, test proof of concept, and save hundreds of millions of dollars, Braun said.

Concerns Raised

So far, Braun has only one cosponsor for the bill, Senator Bill Cassidy, MD (R-LA), and the bill has drawn some criticism.

Brett Meeks, executive director of the Health Innovation Alliance, a trade group representing technology companies, insurers, and consumer organizations, objected to requiring Medicare enrollees to verify flagged orders. CMS should internally root out fraud through technology, not burden seniors, Meeks told this news organization.

Meeks said he has been following the discussion about the use of AI in addressing Medicare fraud. Had a bill broadly targeted Medicare fraud through AI, his alliance might have backed it, he said. But the current proposed legislation has a narrower focus.

Focusing on durable medical equipment, for example, could have unintended consequences like denying power wheelchairs to people with debilitating conditions like multiple sclerosis, Meeks said.

But Braun’s bill won a quick nod of approval from a researcher who studies the use of AI to detect Medicare fraud. Taghi M. Khoshgoftaar, PhD, director of the Data Mining and Machine Learning Lab at Florida Atlantic University, Boca Raton, Florida, said he sees an advantage to Braun’s approach of involving Medicare enrollees in the protection of their benefits.

The bill does not authorize funding for the pilot project, and it’s unclear what it would cost.

Detecting Medicare Fraud

The federal government has stepped up Medicare fraud investigations in recent years, and more doctors are getting caught.

A study published in 2018 examined cases of physicians excluded from Medicare using data from the US Office of Inspector General (OIG) at the Department of Health and Human Services.

The OIG has the right to exclude clinicians from Medicare for fraud or other reasons. Chen and coauthors looked at Medicare physician exclusions from 2007 to 2017. They found that exclusions due to fraud increased an estimated 14% per year on average from a base level of 139 exclusions in 2007.

In 2019, CMS sought feedback on new ways to use AI to detect fraud. In a public request for information, the agency said Medicare scrutinizes fewer claims for payment than commercial insurers do.

About 99.7% of Medicare fee-for-service claims are processed and paid within 17 days without any medical review, CMS said at the time.

A version of this article appeared on Medscape.com .

As emergency medicine doctors, we regularly give medical advice to family and close friends when they get sick or are injured and don’t know what to do. In a matter of moments, we triage, diagnose, and assemble a logical plan, whatever the issue may be. This skill comes from our training and years of experience in treating emergencies and also routine medical matters. The value proposition is clear.

Frankly, it’s a service everyone should have. Think about the potential time and money saved if this option for medical care and triage was broadly available. Overtriage would plummet. That’s when people run to the emergency department (ED) and wait endless hours, only to be reassured or receive limited treatment. Undertriage would also decline. That’s when people should go to the ED but, unwisely, wait. For example, this may occur when symptoms of dizziness end up being a stroke.

Why doesn’t everyone have an ED doctor they can call? The primary reason is that the current system mostly doesn’t support it. The most common scenario is that insurance companies pay us to see patients in an expensive box called the ED. Most EDs are situated within an even more expensive box, called a hospital.

Here’s the good news: Better access to emergency care and people who are formally trained in emergency medicine and routine matters of urgent care is increasing.

One example is telemedicine, where a remote doctor — either your own or a doctor through an app — conducts a visit. Telemedicine is more common since the pandemic, now that insurance pays for it. In emergency situations, it’s rare that your own doctor can see you immediately by telemedicine. By contrast, direct-to-consumer telemedicine (eg, Teladoc, Doctor On Demand, and others) connects you with a random doctor.

In many apps, it’s unclear not only who the doctor is, but more importantly, what their specific medical specialty or training is. It may be an ED doctor evaluating your child’s fever, or it may be a retired general surgeon or an adult rheumatology specialist in the midst of their fellowship, making an extra buck, who may have no pediatric training.
 

Training Matters

Clinical training and whether the doctor knows you matters. A recent JAMA study from Ontario, Canada, found that patients with virtual visits who saw outside family physicians (whom they had never met) compared with their own family physicians were 66% more likely to visit an ED within 7 days after the visit. This illustrates the importance of understanding your personal history in assessing acute symptoms.

Some healthcare systems do use ED physicians for on-demand telehealth services, such as Thomas Jefferson’s JeffConnect. Amazon Clinic recently entered this space, providing condition-specific acute or chronic care to adults aged 18-64 years for a fee that is, notably, not covered by insurance.

A second innovative approach, albeit not specifically in the realm of a personal emergency medicine doctor, is artificial intelligence (AI)–powered kiosks. A concierge medicine company known as Forward recently unveiled an innovative concept known as CarePods that are now available in Sacramento, California; Chandler, Arizona; and Chicago. For a membership fee, you swipe into what looks like an oversize, space-age porta-potty. You sit in a chair and run through a series of health apps, which includes a biometric body scan along with mental health screenings. It even takes your blood (without a needle) and sequences your DNA. Results are reviewed by a doctor (not yours) who talks to you by video. They advertise that AI helps make the diagnosis. Although diagnostic AI is emerging and exciting, its benefit is not clear in emergency conditions. Yet, one clear value in a kiosk over telemedicine is the ability to obtain vital signs and lab results, which are useful for diagnosis.

Another approach is the telehealth offerings used in integrated systems of care, such as Kaiser Permanente. Kaiser is both an insurance company and a deliverer of healthcare services. Kaiser maintains a nurse call center and can handle urgent e-visits. Integrated systems not only help triage patients’ acute issues but also have access to their personal health histories. They can also provide a definitive plan for in-person treatment or a specific referral. A downside of integrated care is that it often limits your choice of provider.

Insurance companies also maintain call-in lines such as HumanaFirst, which is also staffed by nurses. We have not seen data on the calls such services receive, but we doubt people that want to call their insurance company when sick or injured, knowing that the insurer benefits when you receive less care. Additionally, studies have found that nurse-only triage is not as effective as physician triage and results in higher ED referral rates.
 

The Concierge Option

Probably the closest thing to having your own personal emergency medicine doctor is concierge medicine, which combines personalized care and accessibility. Concierge doctors come in many forms, but they usually charge a fixed fee for 24/7 availability and same-day appointments. A downside of concierge medicine is its expense ($2000–$3500 per year), and that many don’t take insurance. Concierge medicine is also criticized because, as doctors gravitate toward it, people in the community often lose their physician if they can’t afford the fees.

Ultimately, remote medical advice for emergency care is clearly evolving in new ways. The inability of traditional care models to achieve this goal will lead to innovation to improve the available options that have led us to think outside of the proverbial “box” we refer to as the ED-in-the-case.

At this time, will any option come close to having a personal emergency medicine physician willing to answer your questions, real-time, as with family and close friends? We think not.

But the future certainly holds promise for alternatives that will hopefully make payers and the Centers for Medicare & Medicaid Services take notice. Innovations in personalized care that reduce costs will be critical in our current healthcare landscape.
 

Dr. Pines is clinical professor of emergency medicine at George Washington University in Washington, DC, and chief of clinical innovation at US Acute Care Solutions in Canton, Ohio. He disclosed ties with CSL Behring and Abbott Point-of-Care. Dr. Glatter is assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical advisor for Medscape and hosts the Hot Topics in EM series. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

As emergency medicine doctors, we regularly give medical advice to family and close friends when they get sick or are injured and don’t know what to do. In a matter of moments, we triage, diagnose, and assemble a logical plan, whatever the issue may be. This skill comes from our training and years of experience in treating emergencies and also routine medical matters. The value proposition is clear.

Frankly, it’s a service everyone should have. Think about the potential time and money saved if this option for medical care and triage was broadly available. Overtriage would plummet. That’s when people run to the emergency department (ED) and wait endless hours, only to be reassured or receive limited treatment. Undertriage would also decline. That’s when people should go to the ED but, unwisely, wait. For example, this may occur when symptoms of dizziness end up being a stroke.

Why doesn’t everyone have an ED doctor they can call? The primary reason is that the current system mostly doesn’t support it. The most common scenario is that insurance companies pay us to see patients in an expensive box called the ED. Most EDs are situated within an even more expensive box, called a hospital.

Here’s the good news: Better access to emergency care and people who are formally trained in emergency medicine and routine matters of urgent care is increasing.

One example is telemedicine, where a remote doctor — either your own or a doctor through an app — conducts a visit. Telemedicine is more common since the pandemic, now that insurance pays for it. In emergency situations, it’s rare that your own doctor can see you immediately by telemedicine. By contrast, direct-to-consumer telemedicine (eg, Teladoc, Doctor On Demand, and others) connects you with a random doctor.

In many apps, it’s unclear not only who the doctor is, but more importantly, what their specific medical specialty or training is. It may be an ED doctor evaluating your child’s fever, or it may be a retired general surgeon or an adult rheumatology specialist in the midst of their fellowship, making an extra buck, who may have no pediatric training.
 

Training Matters

Clinical training and whether the doctor knows you matters. A recent JAMA study from Ontario, Canada, found that patients with virtual visits who saw outside family physicians (whom they had never met) compared with their own family physicians were 66% more likely to visit an ED within 7 days after the visit. This illustrates the importance of understanding your personal history in assessing acute symptoms.

Some healthcare systems do use ED physicians for on-demand telehealth services, such as Thomas Jefferson’s JeffConnect. Amazon Clinic recently entered this space, providing condition-specific acute or chronic care to adults aged 18-64 years for a fee that is, notably, not covered by insurance.

A second innovative approach, albeit not specifically in the realm of a personal emergency medicine doctor, is artificial intelligence (AI)–powered kiosks. A concierge medicine company known as Forward recently unveiled an innovative concept known as CarePods that are now available in Sacramento, California; Chandler, Arizona; and Chicago. For a membership fee, you swipe into what looks like an oversize, space-age porta-potty. You sit in a chair and run through a series of health apps, which includes a biometric body scan along with mental health screenings. It even takes your blood (without a needle) and sequences your DNA. Results are reviewed by a doctor (not yours) who talks to you by video. They advertise that AI helps make the diagnosis. Although diagnostic AI is emerging and exciting, its benefit is not clear in emergency conditions. Yet, one clear value in a kiosk over telemedicine is the ability to obtain vital signs and lab results, which are useful for diagnosis.

Another approach is the telehealth offerings used in integrated systems of care, such as Kaiser Permanente. Kaiser is both an insurance company and a deliverer of healthcare services. Kaiser maintains a nurse call center and can handle urgent e-visits. Integrated systems not only help triage patients’ acute issues but also have access to their personal health histories. They can also provide a definitive plan for in-person treatment or a specific referral. A downside of integrated care is that it often limits your choice of provider.

Insurance companies also maintain call-in lines such as HumanaFirst, which is also staffed by nurses. We have not seen data on the calls such services receive, but we doubt people that want to call their insurance company when sick or injured, knowing that the insurer benefits when you receive less care. Additionally, studies have found that nurse-only triage is not as effective as physician triage and results in higher ED referral rates.
 

The Concierge Option

Probably the closest thing to having your own personal emergency medicine doctor is concierge medicine, which combines personalized care and accessibility. Concierge doctors come in many forms, but they usually charge a fixed fee for 24/7 availability and same-day appointments. A downside of concierge medicine is its expense ($2000–$3500 per year), and that many don’t take insurance. Concierge medicine is also criticized because, as doctors gravitate toward it, people in the community often lose their physician if they can’t afford the fees.

Ultimately, remote medical advice for emergency care is clearly evolving in new ways. The inability of traditional care models to achieve this goal will lead to innovation to improve the available options that have led us to think outside of the proverbial “box” we refer to as the ED-in-the-case.

At this time, will any option come close to having a personal emergency medicine physician willing to answer your questions, real-time, as with family and close friends? We think not.

But the future certainly holds promise for alternatives that will hopefully make payers and the Centers for Medicare & Medicaid Services take notice. Innovations in personalized care that reduce costs will be critical in our current healthcare landscape.
 

Dr. Pines is clinical professor of emergency medicine at George Washington University in Washington, DC, and chief of clinical innovation at US Acute Care Solutions in Canton, Ohio. He disclosed ties with CSL Behring and Abbott Point-of-Care. Dr. Glatter is assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical advisor for Medscape and hosts the Hot Topics in EM series. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

As emergency medicine doctors, we regularly give medical advice to family and close friends when they get sick or are injured and don’t know what to do. In a matter of moments, we triage, diagnose, and assemble a logical plan, whatever the issue may be. This skill comes from our training and years of experience in treating emergencies and also routine medical matters. The value proposition is clear.

Frankly, it’s a service everyone should have. Think about the potential time and money saved if this option for medical care and triage was broadly available. Overtriage would plummet. That’s when people run to the emergency department (ED) and wait endless hours, only to be reassured or receive limited treatment. Undertriage would also decline. That’s when people should go to the ED but, unwisely, wait. For example, this may occur when symptoms of dizziness end up being a stroke.

Why doesn’t everyone have an ED doctor they can call? The primary reason is that the current system mostly doesn’t support it. The most common scenario is that insurance companies pay us to see patients in an expensive box called the ED. Most EDs are situated within an even more expensive box, called a hospital.

Here’s the good news: Better access to emergency care and people who are formally trained in emergency medicine and routine matters of urgent care is increasing.

One example is telemedicine, where a remote doctor — either your own or a doctor through an app — conducts a visit. Telemedicine is more common since the pandemic, now that insurance pays for it. In emergency situations, it’s rare that your own doctor can see you immediately by telemedicine. By contrast, direct-to-consumer telemedicine (eg, Teladoc, Doctor On Demand, and others) connects you with a random doctor.

In many apps, it’s unclear not only who the doctor is, but more importantly, what their specific medical specialty or training is. It may be an ED doctor evaluating your child’s fever, or it may be a retired general surgeon or an adult rheumatology specialist in the midst of their fellowship, making an extra buck, who may have no pediatric training.
 

Training Matters

Clinical training and whether the doctor knows you matters. A recent JAMA study from Ontario, Canada, found that patients with virtual visits who saw outside family physicians (whom they had never met) compared with their own family physicians were 66% more likely to visit an ED within 7 days after the visit. This illustrates the importance of understanding your personal history in assessing acute symptoms.

Some healthcare systems do use ED physicians for on-demand telehealth services, such as Thomas Jefferson’s JeffConnect. Amazon Clinic recently entered this space, providing condition-specific acute or chronic care to adults aged 18-64 years for a fee that is, notably, not covered by insurance.

A second innovative approach, albeit not specifically in the realm of a personal emergency medicine doctor, is artificial intelligence (AI)–powered kiosks. A concierge medicine company known as Forward recently unveiled an innovative concept known as CarePods that are now available in Sacramento, California; Chandler, Arizona; and Chicago. For a membership fee, you swipe into what looks like an oversize, space-age porta-potty. You sit in a chair and run through a series of health apps, which includes a biometric body scan along with mental health screenings. It even takes your blood (without a needle) and sequences your DNA. Results are reviewed by a doctor (not yours) who talks to you by video. They advertise that AI helps make the diagnosis. Although diagnostic AI is emerging and exciting, its benefit is not clear in emergency conditions. Yet, one clear value in a kiosk over telemedicine is the ability to obtain vital signs and lab results, which are useful for diagnosis.

Another approach is the telehealth offerings used in integrated systems of care, such as Kaiser Permanente. Kaiser is both an insurance company and a deliverer of healthcare services. Kaiser maintains a nurse call center and can handle urgent e-visits. Integrated systems not only help triage patients’ acute issues but also have access to their personal health histories. They can also provide a definitive plan for in-person treatment or a specific referral. A downside of integrated care is that it often limits your choice of provider.

Insurance companies also maintain call-in lines such as HumanaFirst, which is also staffed by nurses. We have not seen data on the calls such services receive, but we doubt people that want to call their insurance company when sick or injured, knowing that the insurer benefits when you receive less care. Additionally, studies have found that nurse-only triage is not as effective as physician triage and results in higher ED referral rates.
 

The Concierge Option

Probably the closest thing to having your own personal emergency medicine doctor is concierge medicine, which combines personalized care and accessibility. Concierge doctors come in many forms, but they usually charge a fixed fee for 24/7 availability and same-day appointments. A downside of concierge medicine is its expense ($2000–$3500 per year), and that many don’t take insurance. Concierge medicine is also criticized because, as doctors gravitate toward it, people in the community often lose their physician if they can’t afford the fees.

Ultimately, remote medical advice for emergency care is clearly evolving in new ways. The inability of traditional care models to achieve this goal will lead to innovation to improve the available options that have led us to think outside of the proverbial “box” we refer to as the ED-in-the-case.

At this time, will any option come close to having a personal emergency medicine physician willing to answer your questions, real-time, as with family and close friends? We think not.

But the future certainly holds promise for alternatives that will hopefully make payers and the Centers for Medicare & Medicaid Services take notice. Innovations in personalized care that reduce costs will be critical in our current healthcare landscape.
 

Dr. Pines is clinical professor of emergency medicine at George Washington University in Washington, DC, and chief of clinical innovation at US Acute Care Solutions in Canton, Ohio. He disclosed ties with CSL Behring and Abbott Point-of-Care. Dr. Glatter is assistant professor of emergency medicine at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is a medical advisor for Medscape and hosts the Hot Topics in EM series. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Clinicians at Valley-Wide Health Systems never know who will appear at their clinic in San Luis, a town of about 600 people in southern Colorado.

“If someone’s in labor, they’ll show up. If someone has a laceration, they’ll show up,” said nurse practitioner Emelin Martinez, the chief medical officer for the healthcare system serving 13 rural Colorado counties.

But she struggled to find a full-time medical provider for that clinic, the only one in Costilla County. Born and raised in the area, Martinez filled some of the gap by driving about 45 minutes from Alamosa, the nearest city, once a week for months. A physician assistant from another town chipped in, too.

As one of the nation’s more than 1000 federally designated primary care shortage areas, Costilla County has many carrots to dangle in front of medical providers willing to practice there, including federal student loan repayments, bonus Medicare payments, and expedited visas for foreign clinicians. Still, Ms. Martinez said, its latest opening remained unfilled for more than a year. Not a single physician applied.

Policymakers have long tried to lure more primary care providers to the areas of the nation that have fewer than one physician for every 3500 residents. Recent examples include the Biden administration boosting funding in 2022 to address shortages and Sen. Bernie Sanders (I-Vt.) pushing sweeping primary care legislation in 2023.

But researchers steeped in the issue have a persistent frustration: It’s hard to know if any policy is working given that the data the federal government collects on primary care shortage areas has been flawed for a long time. One of the biggest gaps is that the system counts only physicians, not the myriad other healthcare professionals who now provide much of our nation›s primary care.

Additionally, a Health Affairs study shows the federal designations, which help allocate an estimated $1 billion in annual funding through at least 20 federal programs aimed at boosting primary care capacity, haven›t helped much.

In fact, Costilla County is among more than 180 federally designated areas that have remained stuck on the primary care shortage list for at least 40 years, according to a KFF Health News analysis. That›s even as the overall number of licensed US physicians more than doubled from 1990 to 2022 to over 1 million, according to the Federation of State Medical Boards, outpacing overall population growth.

No one disputes that much of the nation is starved for primary care clinicians, with patients having to wait weeks to get appointments or travel long distances for basic preventive care. Many doctors decide against primary care career paths, let alone practicing in isolated communities, because those jobs entail heavy workloads and earn less money and respect than specialists. But how does the nation solve the problem without knowing exactly where it is? And what tools must be used? Does a physician need to be the one providing the care?

Whitney Zahnd, president of the board of the Iowa Rural Health Association, said the fact that some rural areas have had such federal shortage designations for decades doesn’t prove they are ineffective. “Had the program not been there, would it have been even worse?” she said.

Federal funding supports 18,000 primary care doctors, nurse practitioners, and physician assistants to provide care to more than 18 million patients in the highest-need urban and rural communities across the country, said David Bowman, a spokesperson for the Health Resources and Services Administration, which manages the shortage designations. He said more than 80% of clinicians who get such scholarships or loan repayments continue to practice in shortage areas beyond their obligation of several years.

But that doesn’t mean they stick around forever.

Justin Markowski, a Yale School of Public Health doctoral student, coauthored the Health Affairs study that found the federal shortage designation makes no difference in upping physician density long-term. He is skeptical of policy ideas that promise big primary care fixes. That includes the Biden administration’s investment in more scholarships and loan repayments through the National Health Service Corps.

“You’re just throwing more money at a set of programs that don’t really seem to work,” he said. “We’ll see in a few years, but I’ll be shocked if it actually moved any physicians or any other advanced practice providers.”

One possible explanation for the persistence of shortage areas is that such incentives are too small or too fleeting.

But another issue is how shortages are measured. The government considers geographic shortage areas, now numbering just over 1000, but also population groups such as migrant farmworkers and individual facilities such as prisons that lack enough providers. Yet it’s up to state offices to identify populations and locations that might qualify as shortage areas and submit them to HRSA, which then scores the extent of any shortages. The funding and staffing for those state offices vary, creating an uneven foundation from which to map actual shortages.

“Some states became very adept at the equivalent of gerrymandering, where they were piecing together census blocks or census tracts in odd shapes in order to maximize the areas that are eligible,” said Stephen Petterson, a senior scholar at the Robert Graham Center, a policy think tank in Washington, DC, that focuses on primary care.

The federal Government Accountability Office has highlighted such issues since at least 1995, when it released a report identifying widespread data problems with the shortage area system and concluding it had “little assurance that federal funds are used where most needed.” The report noted one of the persistent shortcomings is that the system counts only physicians, not other key primary care providers.

Since 1998, federal officials have made three attempts to update the 1970s-era rules that define what counts as a shortage area. The authors of the Affordable Care Act tried most recently, tasking a committee of experts to decide on an update.

Among other things, the committee concluded in its 2011 report that nurse practitioners, physician assistants, and certified nurse midwives should be counted as primary care providers. But the recommendations fell short by just a handful of votes.

“We failed and the committee as a whole failed and HRSA failed by not moving the process forward,” said Petterson, who presented to the committee on how to comprehensively measure primary care needs.

Steve Holloway, who directs the Colorado health department’s Primary Care Office, served on the committee. Without action at the federal level, he then led a team to create Colorado’s own health professional shortage area designations that factor in nurse practitioners and physician assistants, not just doctors.

He said it’s taken about 6 years to create a tool and map of Colorado to answer a deceptively simple question: “How many actual flesh-and-blood, live clinicians are seeing patients?”

Ed Salsberg, who was the lead federal government representative on that committee and who headed HRSA’s National Center for Health Workforce Analysis, said the rest of the nation needs more precise data, too.

“It’s so important for the nation to target its resources to the highest-need communities,” he said. “It’s time again to try one more time to develop an improved methodology.”

In the past few years, more readily available data from insurance claims has allowed researchers to distinguish the medical providers who are practicing primary care from those who have specialized or retired.

Candice Chen, an associate professor of health policy and management at George Washington University’s Fitzhugh Mullan Institute for Health Workforce Equity, used claims data that reflects one large slice of the American population — about 66 million Medicaid beneficiaries — to map the primary care workforce.

Meanwhile, Monica O’Reilly-Jacob, a nurse-scientist who recently moved from Boston College to Columbia University’s School of Nursing, studied Medicare claims to conclude that fewer than 70% of physicians typically considered primary care providers were actually providing primary care. The rest, she said, often find more lucrative positions, such as subspecializing or working in hospitals. By contrast, nurse practitioners are likely undercounted. Her study found that close to half are providing primary care.

But such publicly available data leaves out much of the country, given that fewer than 40% of Americans are insured through Medicaid or Medicare.

“There’s no government organization that’s tracking: Who trained in what, where, and where are they now, and what are they practicing,” said Alison Huffstetler, medical director of the Robert Graham Center. “And if we don’t know who is doing what kind of care — and where — then there is no way for us to equitably manage the patient-to-clinician ratio across every state.”

In Costilla County, Ms. Martinez finally found someone to provide primary care: An experienced physician assistant who moved from Texas in December.

The physician assistant’s presence should bump the county out of its dire shortage, according to Colorado’s measure. But since he isn’t a physician, he’ll remain invisible in the national data and Costilla County will likely remain on the books as a federal shortage area.

Data reporter Hannah Recht, data editor Holly K. Hacker, and rural editor/correspondent Tony Leys contributed to this report.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — an independent source of health policy research, polling, and journalism.

Clinicians at Valley-Wide Health Systems never know who will appear at their clinic in San Luis, a town of about 600 people in southern Colorado.

“If someone’s in labor, they’ll show up. If someone has a laceration, they’ll show up,” said nurse practitioner Emelin Martinez, the chief medical officer for the healthcare system serving 13 rural Colorado counties.

But she struggled to find a full-time medical provider for that clinic, the only one in Costilla County. Born and raised in the area, Martinez filled some of the gap by driving about 45 minutes from Alamosa, the nearest city, once a week for months. A physician assistant from another town chipped in, too.

As one of the nation’s more than 1000 federally designated primary care shortage areas, Costilla County has many carrots to dangle in front of medical providers willing to practice there, including federal student loan repayments, bonus Medicare payments, and expedited visas for foreign clinicians. Still, Ms. Martinez said, its latest opening remained unfilled for more than a year. Not a single physician applied.

Policymakers have long tried to lure more primary care providers to the areas of the nation that have fewer than one physician for every 3500 residents. Recent examples include the Biden administration boosting funding in 2022 to address shortages and Sen. Bernie Sanders (I-Vt.) pushing sweeping primary care legislation in 2023.

But researchers steeped in the issue have a persistent frustration: It’s hard to know if any policy is working given that the data the federal government collects on primary care shortage areas has been flawed for a long time. One of the biggest gaps is that the system counts only physicians, not the myriad other healthcare professionals who now provide much of our nation›s primary care.

Additionally, a Health Affairs study shows the federal designations, which help allocate an estimated $1 billion in annual funding through at least 20 federal programs aimed at boosting primary care capacity, haven›t helped much.

In fact, Costilla County is among more than 180 federally designated areas that have remained stuck on the primary care shortage list for at least 40 years, according to a KFF Health News analysis. That›s even as the overall number of licensed US physicians more than doubled from 1990 to 2022 to over 1 million, according to the Federation of State Medical Boards, outpacing overall population growth.

No one disputes that much of the nation is starved for primary care clinicians, with patients having to wait weeks to get appointments or travel long distances for basic preventive care. Many doctors decide against primary care career paths, let alone practicing in isolated communities, because those jobs entail heavy workloads and earn less money and respect than specialists. But how does the nation solve the problem without knowing exactly where it is? And what tools must be used? Does a physician need to be the one providing the care?

Whitney Zahnd, president of the board of the Iowa Rural Health Association, said the fact that some rural areas have had such federal shortage designations for decades doesn’t prove they are ineffective. “Had the program not been there, would it have been even worse?” she said.

Federal funding supports 18,000 primary care doctors, nurse practitioners, and physician assistants to provide care to more than 18 million patients in the highest-need urban and rural communities across the country, said David Bowman, a spokesperson for the Health Resources and Services Administration, which manages the shortage designations. He said more than 80% of clinicians who get such scholarships or loan repayments continue to practice in shortage areas beyond their obligation of several years.

But that doesn’t mean they stick around forever.

Justin Markowski, a Yale School of Public Health doctoral student, coauthored the Health Affairs study that found the federal shortage designation makes no difference in upping physician density long-term. He is skeptical of policy ideas that promise big primary care fixes. That includes the Biden administration’s investment in more scholarships and loan repayments through the National Health Service Corps.

“You’re just throwing more money at a set of programs that don’t really seem to work,” he said. “We’ll see in a few years, but I’ll be shocked if it actually moved any physicians or any other advanced practice providers.”

One possible explanation for the persistence of shortage areas is that such incentives are too small or too fleeting.

But another issue is how shortages are measured. The government considers geographic shortage areas, now numbering just over 1000, but also population groups such as migrant farmworkers and individual facilities such as prisons that lack enough providers. Yet it’s up to state offices to identify populations and locations that might qualify as shortage areas and submit them to HRSA, which then scores the extent of any shortages. The funding and staffing for those state offices vary, creating an uneven foundation from which to map actual shortages.

“Some states became very adept at the equivalent of gerrymandering, where they were piecing together census blocks or census tracts in odd shapes in order to maximize the areas that are eligible,” said Stephen Petterson, a senior scholar at the Robert Graham Center, a policy think tank in Washington, DC, that focuses on primary care.

The federal Government Accountability Office has highlighted such issues since at least 1995, when it released a report identifying widespread data problems with the shortage area system and concluding it had “little assurance that federal funds are used where most needed.” The report noted one of the persistent shortcomings is that the system counts only physicians, not other key primary care providers.

Since 1998, federal officials have made three attempts to update the 1970s-era rules that define what counts as a shortage area. The authors of the Affordable Care Act tried most recently, tasking a committee of experts to decide on an update.

Among other things, the committee concluded in its 2011 report that nurse practitioners, physician assistants, and certified nurse midwives should be counted as primary care providers. But the recommendations fell short by just a handful of votes.

“We failed and the committee as a whole failed and HRSA failed by not moving the process forward,” said Petterson, who presented to the committee on how to comprehensively measure primary care needs.

Steve Holloway, who directs the Colorado health department’s Primary Care Office, served on the committee. Without action at the federal level, he then led a team to create Colorado’s own health professional shortage area designations that factor in nurse practitioners and physician assistants, not just doctors.

He said it’s taken about 6 years to create a tool and map of Colorado to answer a deceptively simple question: “How many actual flesh-and-blood, live clinicians are seeing patients?”

Ed Salsberg, who was the lead federal government representative on that committee and who headed HRSA’s National Center for Health Workforce Analysis, said the rest of the nation needs more precise data, too.

“It’s so important for the nation to target its resources to the highest-need communities,” he said. “It’s time again to try one more time to develop an improved methodology.”

In the past few years, more readily available data from insurance claims has allowed researchers to distinguish the medical providers who are practicing primary care from those who have specialized or retired.

Candice Chen, an associate professor of health policy and management at George Washington University’s Fitzhugh Mullan Institute for Health Workforce Equity, used claims data that reflects one large slice of the American population — about 66 million Medicaid beneficiaries — to map the primary care workforce.

Meanwhile, Monica O’Reilly-Jacob, a nurse-scientist who recently moved from Boston College to Columbia University’s School of Nursing, studied Medicare claims to conclude that fewer than 70% of physicians typically considered primary care providers were actually providing primary care. The rest, she said, often find more lucrative positions, such as subspecializing or working in hospitals. By contrast, nurse practitioners are likely undercounted. Her study found that close to half are providing primary care.

But such publicly available data leaves out much of the country, given that fewer than 40% of Americans are insured through Medicaid or Medicare.

“There’s no government organization that’s tracking: Who trained in what, where, and where are they now, and what are they practicing,” said Alison Huffstetler, medical director of the Robert Graham Center. “And if we don’t know who is doing what kind of care — and where — then there is no way for us to equitably manage the patient-to-clinician ratio across every state.”

In Costilla County, Ms. Martinez finally found someone to provide primary care: An experienced physician assistant who moved from Texas in December.

The physician assistant’s presence should bump the county out of its dire shortage, according to Colorado’s measure. But since he isn’t a physician, he’ll remain invisible in the national data and Costilla County will likely remain on the books as a federal shortage area.

Data reporter Hannah Recht, data editor Holly K. Hacker, and rural editor/correspondent Tony Leys contributed to this report.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — an independent source of health policy research, polling, and journalism.

Clinicians at Valley-Wide Health Systems never know who will appear at their clinic in San Luis, a town of about 600 people in southern Colorado.

“If someone’s in labor, they’ll show up. If someone has a laceration, they’ll show up,” said nurse practitioner Emelin Martinez, the chief medical officer for the healthcare system serving 13 rural Colorado counties.

But she struggled to find a full-time medical provider for that clinic, the only one in Costilla County. Born and raised in the area, Martinez filled some of the gap by driving about 45 minutes from Alamosa, the nearest city, once a week for months. A physician assistant from another town chipped in, too.

As one of the nation’s more than 1000 federally designated primary care shortage areas, Costilla County has many carrots to dangle in front of medical providers willing to practice there, including federal student loan repayments, bonus Medicare payments, and expedited visas for foreign clinicians. Still, Ms. Martinez said, its latest opening remained unfilled for more than a year. Not a single physician applied.

Policymakers have long tried to lure more primary care providers to the areas of the nation that have fewer than one physician for every 3500 residents. Recent examples include the Biden administration boosting funding in 2022 to address shortages and Sen. Bernie Sanders (I-Vt.) pushing sweeping primary care legislation in 2023.

But researchers steeped in the issue have a persistent frustration: It’s hard to know if any policy is working given that the data the federal government collects on primary care shortage areas has been flawed for a long time. One of the biggest gaps is that the system counts only physicians, not the myriad other healthcare professionals who now provide much of our nation›s primary care.

Additionally, a Health Affairs study shows the federal designations, which help allocate an estimated $1 billion in annual funding through at least 20 federal programs aimed at boosting primary care capacity, haven›t helped much.

In fact, Costilla County is among more than 180 federally designated areas that have remained stuck on the primary care shortage list for at least 40 years, according to a KFF Health News analysis. That›s even as the overall number of licensed US physicians more than doubled from 1990 to 2022 to over 1 million, according to the Federation of State Medical Boards, outpacing overall population growth.

No one disputes that much of the nation is starved for primary care clinicians, with patients having to wait weeks to get appointments or travel long distances for basic preventive care. Many doctors decide against primary care career paths, let alone practicing in isolated communities, because those jobs entail heavy workloads and earn less money and respect than specialists. But how does the nation solve the problem without knowing exactly where it is? And what tools must be used? Does a physician need to be the one providing the care?

Whitney Zahnd, president of the board of the Iowa Rural Health Association, said the fact that some rural areas have had such federal shortage designations for decades doesn’t prove they are ineffective. “Had the program not been there, would it have been even worse?” she said.

Federal funding supports 18,000 primary care doctors, nurse practitioners, and physician assistants to provide care to more than 18 million patients in the highest-need urban and rural communities across the country, said David Bowman, a spokesperson for the Health Resources and Services Administration, which manages the shortage designations. He said more than 80% of clinicians who get such scholarships or loan repayments continue to practice in shortage areas beyond their obligation of several years.

But that doesn’t mean they stick around forever.

Justin Markowski, a Yale School of Public Health doctoral student, coauthored the Health Affairs study that found the federal shortage designation makes no difference in upping physician density long-term. He is skeptical of policy ideas that promise big primary care fixes. That includes the Biden administration’s investment in more scholarships and loan repayments through the National Health Service Corps.

“You’re just throwing more money at a set of programs that don’t really seem to work,” he said. “We’ll see in a few years, but I’ll be shocked if it actually moved any physicians or any other advanced practice providers.”

One possible explanation for the persistence of shortage areas is that such incentives are too small or too fleeting.

But another issue is how shortages are measured. The government considers geographic shortage areas, now numbering just over 1000, but also population groups such as migrant farmworkers and individual facilities such as prisons that lack enough providers. Yet it’s up to state offices to identify populations and locations that might qualify as shortage areas and submit them to HRSA, which then scores the extent of any shortages. The funding and staffing for those state offices vary, creating an uneven foundation from which to map actual shortages.

“Some states became very adept at the equivalent of gerrymandering, where they were piecing together census blocks or census tracts in odd shapes in order to maximize the areas that are eligible,” said Stephen Petterson, a senior scholar at the Robert Graham Center, a policy think tank in Washington, DC, that focuses on primary care.

The federal Government Accountability Office has highlighted such issues since at least 1995, when it released a report identifying widespread data problems with the shortage area system and concluding it had “little assurance that federal funds are used where most needed.” The report noted one of the persistent shortcomings is that the system counts only physicians, not other key primary care providers.

Since 1998, federal officials have made three attempts to update the 1970s-era rules that define what counts as a shortage area. The authors of the Affordable Care Act tried most recently, tasking a committee of experts to decide on an update.

Among other things, the committee concluded in its 2011 report that nurse practitioners, physician assistants, and certified nurse midwives should be counted as primary care providers. But the recommendations fell short by just a handful of votes.

“We failed and the committee as a whole failed and HRSA failed by not moving the process forward,” said Petterson, who presented to the committee on how to comprehensively measure primary care needs.

Steve Holloway, who directs the Colorado health department’s Primary Care Office, served on the committee. Without action at the federal level, he then led a team to create Colorado’s own health professional shortage area designations that factor in nurse practitioners and physician assistants, not just doctors.

He said it’s taken about 6 years to create a tool and map of Colorado to answer a deceptively simple question: “How many actual flesh-and-blood, live clinicians are seeing patients?”

Ed Salsberg, who was the lead federal government representative on that committee and who headed HRSA’s National Center for Health Workforce Analysis, said the rest of the nation needs more precise data, too.

“It’s so important for the nation to target its resources to the highest-need communities,” he said. “It’s time again to try one more time to develop an improved methodology.”

In the past few years, more readily available data from insurance claims has allowed researchers to distinguish the medical providers who are practicing primary care from those who have specialized or retired.

Candice Chen, an associate professor of health policy and management at George Washington University’s Fitzhugh Mullan Institute for Health Workforce Equity, used claims data that reflects one large slice of the American population — about 66 million Medicaid beneficiaries — to map the primary care workforce.

Meanwhile, Monica O’Reilly-Jacob, a nurse-scientist who recently moved from Boston College to Columbia University’s School of Nursing, studied Medicare claims to conclude that fewer than 70% of physicians typically considered primary care providers were actually providing primary care. The rest, she said, often find more lucrative positions, such as subspecializing or working in hospitals. By contrast, nurse practitioners are likely undercounted. Her study found that close to half are providing primary care.

But such publicly available data leaves out much of the country, given that fewer than 40% of Americans are insured through Medicaid or Medicare.

“There’s no government organization that’s tracking: Who trained in what, where, and where are they now, and what are they practicing,” said Alison Huffstetler, medical director of the Robert Graham Center. “And if we don’t know who is doing what kind of care — and where — then there is no way for us to equitably manage the patient-to-clinician ratio across every state.”

In Costilla County, Ms. Martinez finally found someone to provide primary care: An experienced physician assistant who moved from Texas in December.

The physician assistant’s presence should bump the county out of its dire shortage, according to Colorado’s measure. But since he isn’t a physician, he’ll remain invisible in the national data and Costilla County will likely remain on the books as a federal shortage area.

Data reporter Hannah Recht, data editor Holly K. Hacker, and rural editor/correspondent Tony Leys contributed to this report.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — an independent source of health policy research, polling, and journalism.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Men with metastatic castration-resistant prostate cancer (mCRPC) that had progressed despite treatment with novel hormonal therapy had a slight but statistically significant improvement in progression-free survival (PFS) with a combination of a targeted agent and immunotherapy compared with a second-line novel hormonal therapy.

The combination of the tyrosine kinase inhibitor (TKI), cabozantinib (Cabometyx), and the immune checkpoint inhibitor (ICI), atezolizumab (Tecentriq), was associated with a median PFS of 6.3 months vs 4.2 months for patients assigned to second hormonal therapy with either abiraterone (Zytiga) and prednisone, or enzalutamide (Xtandi) in the CONTACT-02 trial, Neeraj Agarwal, MD, reported at the ASCO Genitourinary Cancers Symposium. 

“CONTACT 2 is the first phase 3 trial of the TKI/ICI combination to show statistically significant improvement in PFS in patients with mCRPC,” said Dr. Agarwal, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.

­­The data support the combination of cabozantinib and atezolizumab as a potential new treatment option for patients with mCRPC that has progressed on novel hormonal therapy, he said.
 

Study Design Questioned

That opinion, however, was not shared by Kim N. Chi, MD, of the University of British Columbia in Vancouver, BC, Canada, the invited discussant.

Dr. Chi acknowledged that the study results as presented were positive, but also pointed to several limitations, including the small difference between the treatment groups in radiographic progression-free survival (rPFS).

“I would say the rPFS benefit is modest, and in the absence of other improvements the difference in the median rPFS is equivalent from one scan to the next in the scanning cycle. I would argue about the clinical significance of that,” he said.

He also noted that there was no improvement in the investigational arm in patient-reported outcomes, and that pain progression and quality-of-life deterioration occurred within 2 to 4 months, which is “quite quick.”

Additionally, he questioned the choice of an androgen receptor pathway inhibitor (ARPI) switch as the control arm of the study.

“I’d also argue that ARPI switch is not the best standard of care for this patient population with measurable disease and 40% visceral metastases; there are better options,” he said.

For example, in phase 3 trials, docetaxel and cabazitaxel (Jevtana) have consistently demonstrated radiographic PFS of 8 to 9 months. In addition, lutetium-177–PSMA-617, a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the tumor microenvironment, has also been shown to have PFS and overall survival benefits, he said.

“Irrespective of regulatory decisions, I personally could not recommend this at this time, given the data that we’ve seen and the better options that are available for this patient population,” Dr. Chi said.
 

Real-World Practice

“Kim Chi offered a pretty fair critique and summary of the control arm, but in real world practice, ARPI switch, from abi [abiraterone] to enza [enzalutamide] or enza to abi continues to be used in routine clinical practice for various reasons,” Xin Gao, MD, a genitourinary oncologist at Mass General Cancer Center in Boston, said in an interview.

“There are patients who can’t tolerate chemotherapy or don’t want chemotherapy, and we do know also that there are patients who can benefit from an ARPI switch, especially some patients with more indolent disease,” said Dr. Gao, who attended the presentation but was not involved in the study.

He noted that some patients being switched from abiraterone to enzalutamide have clinical responses, and that the ARPIs are generally more tolerable than chemotherapy.

In addition, CONTACT-02 is one of a series of trials in which ARPI switch was used as the control arm, and many of these trials were initiated before there were data confirming the superior efficacy of some newer therapeutic options, Dr. Gao noted.

He agreed, however that there is growing evidence to show that ARPI switch may not be the optimal choice for patients with more measurable disease, especially visceral metastases, and other more aggressive forms of mCRPC.
 

CONTACT-02 Details

Investigators in the phase 3 study screened 866 men with mCRPC and after stratification by liver metastases, prior docetaxel use for castration-sensitive prostate cancer, and disease stage for which the first novel hormonal therapy was given. About 500 patients (507) were randomized to receive either oral cabozantinib 40 mg daily plus intravenous atezolizumab 1200 mg every 3 weeks or second hormonal therapy with either abiraterone 1000 mg with oral prednisone 5 mg twice daily, or oral enzalutamide 160 mg daily.

After a median follow-up of 14.3 months in the PFS intention-to-treat population, the median ­PFS by blinded central review was 6.3 months with cabozantinib/atezolizumab and 4.2 months with second hormonal therapy. This translated into a hazard ratio of 0.64 (P = .0002). The results were similar for a PFS analysis according to Prostate Cancer Working Group 3 criteria.

The combination was also associated with modest improvements in PFS in prespecified subgroups, including patients who had liver or bone metastases and those who had previously received docetaxel.

There were no significant differences in overall survival at the time of data cutoff. Overall survival data were not mature and will be reported at a later date.

Disease control rates, a composite of complete and partial responses and stable disease, were 73% with the combination and 55% with second hormonal therapy (P value not shown).
 

Safety Data

The safety analysis indicated that patients found the ARPI switch easier to tolerate than the combination.

Adverse events leading to dose reductions occurred in 40% of patients on the combination, vs 3% of patients on second hormonal therapy, and treatment-related adverse events leading to discontinuation occurred in 13% and 2%, respectively.

Grade 3 or 4 adverse events occurred in 48% of patients assigned to the combination vs. 23% of patients assigned to the ARPI switch.

In all, 8% of patients on the combination and 12% on second hormonal therapy died on study, but none of the deaths were deemed to be treatment related.­­

CONTACT-02 was sponsored by Exelixis in partnerships with Ipsen and Takeda.

Dr. Agarwal disclosed institutional research funding from Exelixis, Roche, Takeda, and others, and travel expenses from Pfizer. Dr. Chi disclosed honoraria, a consulting/advisory role and institutional research funding with Roche and others. Dr. Gao has served as a consultant or advisor to several companies, not including the sponsors of the study, and has served as principal investigator at his institution, which has received research funding from Exelixis, Takeda, and others.

Once the standard treatment for adult patients with acute lymphocytic leukemia (ALL), stem cell transplants have fallen out of favor somewhat in recent years, with immunotherapy and pediatric-inspired chemotherapy regimens moving to the forefront. But hematologists differ on how to treat relapsed/refractory patients with Philadelphia-chromosome negative (Ph-negative) ALL who are minimal residual disease (MRD)-negative.

Allogeneic hematopoietic stem cell transplants (HSCT) are still part of the hematology armamentarium for relapsed/refractory (R/R) patients with Ph-negative ALL who are MRD positive. However, when asked about the best treatment strategy for patients who are MRD-negative, hematologist Mark R. Litzow, MD, of the Mayo Clinic in Rochester, Minnesota, said in an interview, “There is no firm consensus about that.”

Discussing how medicine has evolved over the past 20 to 30 years, Dr. Litzow recalled that HSCT used to be standard treatment for adult patients with ALL. “We felt that in most instances, chemotherapy alone was not going to be effective in curing them. A vast majority would relapse,” he said. Nowadays, however, specialists differ on the use of HSCT in patients with Ph-negative, MRD-negative ALL.

A pair of commentaries in the January issue of The Lancet Hematology tackle this topic from different perspectives. On one hand, hematologist Patrice Chevallier, MD, of the University of Nantes in France, argues that for such patients, HSCT “remains a valid option,”and MRD status shouldn’t be the sole factor used for a decision.

However, hematologist Nicolas Boissel, MD, PhD, of Paris Cité University, contends that detectable early MRD is the “only robust predictor” of HSCT benefit in patients under 60 with Ph-negative ALL, and it has “unproven” benefit in older patients.

As Dr. Chevallier notes, “allogeneic HSCT is indicated in patients defined as having a high risk of relapse. Currently, a high level of residual leukemic cells after treatment is recognized as the strongest, and sometimes sole, criterion defining high-risk patients.”

As first- and second-line therapy in pediatric patients and as first-line therapy in adults, the “rule” is to offer HSCT to MRD-positive patients but not MRD-negative ones, he writes. “In older patients and those who are relapsed or refractory, the recent demonstration of efficient immunotherapies and cell therapies has launched the debate on the role of MRD status and the question of whether or not to transplant patients who are MRD-negative in both settings.”

Dr. Chevallier notes that “there is no standard definition of an MRD-negative status,” and the best timing for evaluation is unknown. Further, he adds, a “variable proportion of MRD-negative patients still relapse after treatment — up to 25% of patients who respond early and more than 50% of patients who respond late.”

He also points out that there’s an 80% chance that patients will convert from MRD negative to MRD positive after blinatumomab therapy, and he highlights the low long-term survival rate (20%) after brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy.

As for older patients, Dr. Chevallier observes that improved chemo-immunotherapy and conditioning regimens could spark a rethinking of the feasibility of HSCT. However, for now, in those patients, “MRD is not decisional, and allogeneic HSCT is not a routine practice,” he writes.

In his commentary, Dr. Boissel points out that there have been no controlled studies of HSCT in the first-remission setting, although he writes that some data suggests that HSCT may be helpful for patients in high-risk genetic subgroups, regardless of MRD status. On the other hand, “converging observations suggest no benefit of HSCT in MRD-positive patients treated with blinatumomab in the front-line setting.”

If MRD monitoring is unavailable, Dr. Boissel adds, “it seems reasonable to use early blast clearance or other baseline high-risk features to indicate HSCT.”

How can hematologists make the best decision about HSCT?

In an interview, City of Hope Medical Center (Duarte, California) hematologist-oncologist Ibrahim T. Aldoss, MD, said that chemotherapy — with or without immunotherapy — can often be enough to treat younger patients without high-risk genetic factors. “Potentially, these patients can be spared from transplants,” he said, although patients with resistant MRD “clearly need transplants.”

The risks of transplants are significant, he noted. While they can reduce the risk of relapse, the risk of dying during remission is higher vs chemotherapy. “So you have to balance the risks that you’re willing to take,” he said, keeping in mind that some patients can be cured with chemotherapy.

In addition, Dr. Aldoss said, acute graft-versus-host disease in the first few months after transplant can become chronic. “Many years later, patients can be struggling to where it actually impacts their daily activity. And unfortunately, patients can die from it.”

In the big picture, “you cannot have a generalized statement about whether you shouldn’t do transplants in every MRD-negative patient,” he said. However, “if you do achieve MRD negativity, most patients likely don’t need transplants.”

The Mayo Clinic’s Dr. Litzow urged colleagues to consider several factors when making decisions. Do patients have a high level of comorbidities that would raise the risk of death from HSCT? He noted that there’s nearly a 20% risk of death from HSCT, and comorbidities can boost the risk to 40%-50%.

Also, does the patient have a suitable donor? While advances have boosted the number of eligible donors, he said, “not everybody has an ideal donor.”

If a patient is MRD-negative but not a good candidate for a transplant, Dr. Litzow said consolidation therapy followed by maintenance therapy may be indicated. “Continue to check their bone marrow and their blood periodically as they’re going through treatment and reassess their MRD status to make sure they’re staying negative. If they turn MRD-positive during the course of their therapy, then we have to step back and rethink the role of transplant.”

As for cost, Dr. Litzow points out that HSCT is very expensive, although ALL is an accepted indication for HSCT. However, “if someone doesn’t have medical insurance, then it can be difficult to consider them having a transplant.”

What’s next? In his commentary, Dr. Boissel writes that his team aims to study whether HSCT is helpful in patients with high-risk B-cell ALL “who reach MRD negativity after a consolidation phase including blinatumomab.”

Dr. Aldoss discloses relationships with Amgen, Kite, Pfizer, Jazz, AbbVie, Sobi, Agios, Autolus, and MacroGenics. Dr. Litzow reports ties with Amgen. Dr. Boissel declares relationships with Amgen, Pfizer, Novartis, and Servier. Dr. Chevallier has no disclosures.

Once the standard treatment for adult patients with acute lymphocytic leukemia (ALL), stem cell transplants have fallen out of favor somewhat in recent years, with immunotherapy and pediatric-inspired chemotherapy regimens moving to the forefront. But hematologists differ on how to treat relapsed/refractory patients with Philadelphia-chromosome negative (Ph-negative) ALL who are minimal residual disease (MRD)-negative.

Allogeneic hematopoietic stem cell transplants (HSCT) are still part of the hematology armamentarium for relapsed/refractory (R/R) patients with Ph-negative ALL who are MRD positive. However, when asked about the best treatment strategy for patients who are MRD-negative, hematologist Mark R. Litzow, MD, of the Mayo Clinic in Rochester, Minnesota, said in an interview, “There is no firm consensus about that.”

Discussing how medicine has evolved over the past 20 to 30 years, Dr. Litzow recalled that HSCT used to be standard treatment for adult patients with ALL. “We felt that in most instances, chemotherapy alone was not going to be effective in curing them. A vast majority would relapse,” he said. Nowadays, however, specialists differ on the use of HSCT in patients with Ph-negative, MRD-negative ALL.

A pair of commentaries in the January issue of The Lancet Hematology tackle this topic from different perspectives. On one hand, hematologist Patrice Chevallier, MD, of the University of Nantes in France, argues that for such patients, HSCT “remains a valid option,”and MRD status shouldn’t be the sole factor used for a decision.

However, hematologist Nicolas Boissel, MD, PhD, of Paris Cité University, contends that detectable early MRD is the “only robust predictor” of HSCT benefit in patients under 60 with Ph-negative ALL, and it has “unproven” benefit in older patients.

As Dr. Chevallier notes, “allogeneic HSCT is indicated in patients defined as having a high risk of relapse. Currently, a high level of residual leukemic cells after treatment is recognized as the strongest, and sometimes sole, criterion defining high-risk patients.”

As first- and second-line therapy in pediatric patients and as first-line therapy in adults, the “rule” is to offer HSCT to MRD-positive patients but not MRD-negative ones, he writes. “In older patients and those who are relapsed or refractory, the recent demonstration of efficient immunotherapies and cell therapies has launched the debate on the role of MRD status and the question of whether or not to transplant patients who are MRD-negative in both settings.”

Dr. Chevallier notes that “there is no standard definition of an MRD-negative status,” and the best timing for evaluation is unknown. Further, he adds, a “variable proportion of MRD-negative patients still relapse after treatment — up to 25% of patients who respond early and more than 50% of patients who respond late.”

He also points out that there’s an 80% chance that patients will convert from MRD negative to MRD positive after blinatumomab therapy, and he highlights the low long-term survival rate (20%) after brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy.

As for older patients, Dr. Chevallier observes that improved chemo-immunotherapy and conditioning regimens could spark a rethinking of the feasibility of HSCT. However, for now, in those patients, “MRD is not decisional, and allogeneic HSCT is not a routine practice,” he writes.

In his commentary, Dr. Boissel points out that there have been no controlled studies of HSCT in the first-remission setting, although he writes that some data suggests that HSCT may be helpful for patients in high-risk genetic subgroups, regardless of MRD status. On the other hand, “converging observations suggest no benefit of HSCT in MRD-positive patients treated with blinatumomab in the front-line setting.”

If MRD monitoring is unavailable, Dr. Boissel adds, “it seems reasonable to use early blast clearance or other baseline high-risk features to indicate HSCT.”

How can hematologists make the best decision about HSCT?

In an interview, City of Hope Medical Center (Duarte, California) hematologist-oncologist Ibrahim T. Aldoss, MD, said that chemotherapy — with or without immunotherapy — can often be enough to treat younger patients without high-risk genetic factors. “Potentially, these patients can be spared from transplants,” he said, although patients with resistant MRD “clearly need transplants.”

The risks of transplants are significant, he noted. While they can reduce the risk of relapse, the risk of dying during remission is higher vs chemotherapy. “So you have to balance the risks that you’re willing to take,” he said, keeping in mind that some patients can be cured with chemotherapy.

In addition, Dr. Aldoss said, acute graft-versus-host disease in the first few months after transplant can become chronic. “Many years later, patients can be struggling to where it actually impacts their daily activity. And unfortunately, patients can die from it.”

In the big picture, “you cannot have a generalized statement about whether you shouldn’t do transplants in every MRD-negative patient,” he said. However, “if you do achieve MRD negativity, most patients likely don’t need transplants.”

The Mayo Clinic’s Dr. Litzow urged colleagues to consider several factors when making decisions. Do patients have a high level of comorbidities that would raise the risk of death from HSCT? He noted that there’s nearly a 20% risk of death from HSCT, and comorbidities can boost the risk to 40%-50%.

Also, does the patient have a suitable donor? While advances have boosted the number of eligible donors, he said, “not everybody has an ideal donor.”

If a patient is MRD-negative but not a good candidate for a transplant, Dr. Litzow said consolidation therapy followed by maintenance therapy may be indicated. “Continue to check their bone marrow and their blood periodically as they’re going through treatment and reassess their MRD status to make sure they’re staying negative. If they turn MRD-positive during the course of their therapy, then we have to step back and rethink the role of transplant.”

As for cost, Dr. Litzow points out that HSCT is very expensive, although ALL is an accepted indication for HSCT. However, “if someone doesn’t have medical insurance, then it can be difficult to consider them having a transplant.”

What’s next? In his commentary, Dr. Boissel writes that his team aims to study whether HSCT is helpful in patients with high-risk B-cell ALL “who reach MRD negativity after a consolidation phase including blinatumomab.”

Dr. Aldoss discloses relationships with Amgen, Kite, Pfizer, Jazz, AbbVie, Sobi, Agios, Autolus, and MacroGenics. Dr. Litzow reports ties with Amgen. Dr. Boissel declares relationships with Amgen, Pfizer, Novartis, and Servier. Dr. Chevallier has no disclosures.

Once the standard treatment for adult patients with acute lymphocytic leukemia (ALL), stem cell transplants have fallen out of favor somewhat in recent years, with immunotherapy and pediatric-inspired chemotherapy regimens moving to the forefront. But hematologists differ on how to treat relapsed/refractory patients with Philadelphia-chromosome negative (Ph-negative) ALL who are minimal residual disease (MRD)-negative.

Allogeneic hematopoietic stem cell transplants (HSCT) are still part of the hematology armamentarium for relapsed/refractory (R/R) patients with Ph-negative ALL who are MRD positive. However, when asked about the best treatment strategy for patients who are MRD-negative, hematologist Mark R. Litzow, MD, of the Mayo Clinic in Rochester, Minnesota, said in an interview, “There is no firm consensus about that.”

Discussing how medicine has evolved over the past 20 to 30 years, Dr. Litzow recalled that HSCT used to be standard treatment for adult patients with ALL. “We felt that in most instances, chemotherapy alone was not going to be effective in curing them. A vast majority would relapse,” he said. Nowadays, however, specialists differ on the use of HSCT in patients with Ph-negative, MRD-negative ALL.

A pair of commentaries in the January issue of The Lancet Hematology tackle this topic from different perspectives. On one hand, hematologist Patrice Chevallier, MD, of the University of Nantes in France, argues that for such patients, HSCT “remains a valid option,”and MRD status shouldn’t be the sole factor used for a decision.

However, hematologist Nicolas Boissel, MD, PhD, of Paris Cité University, contends that detectable early MRD is the “only robust predictor” of HSCT benefit in patients under 60 with Ph-negative ALL, and it has “unproven” benefit in older patients.

As Dr. Chevallier notes, “allogeneic HSCT is indicated in patients defined as having a high risk of relapse. Currently, a high level of residual leukemic cells after treatment is recognized as the strongest, and sometimes sole, criterion defining high-risk patients.”

As first- and second-line therapy in pediatric patients and as first-line therapy in adults, the “rule” is to offer HSCT to MRD-positive patients but not MRD-negative ones, he writes. “In older patients and those who are relapsed or refractory, the recent demonstration of efficient immunotherapies and cell therapies has launched the debate on the role of MRD status and the question of whether or not to transplant patients who are MRD-negative in both settings.”

Dr. Chevallier notes that “there is no standard definition of an MRD-negative status,” and the best timing for evaluation is unknown. Further, he adds, a “variable proportion of MRD-negative patients still relapse after treatment — up to 25% of patients who respond early and more than 50% of patients who respond late.”

He also points out that there’s an 80% chance that patients will convert from MRD negative to MRD positive after blinatumomab therapy, and he highlights the low long-term survival rate (20%) after brexucabtagene autoleucel (Tecartus), a CAR T-cell therapy.

As for older patients, Dr. Chevallier observes that improved chemo-immunotherapy and conditioning regimens could spark a rethinking of the feasibility of HSCT. However, for now, in those patients, “MRD is not decisional, and allogeneic HSCT is not a routine practice,” he writes.

In his commentary, Dr. Boissel points out that there have been no controlled studies of HSCT in the first-remission setting, although he writes that some data suggests that HSCT may be helpful for patients in high-risk genetic subgroups, regardless of MRD status. On the other hand, “converging observations suggest no benefit of HSCT in MRD-positive patients treated with blinatumomab in the front-line setting.”

If MRD monitoring is unavailable, Dr. Boissel adds, “it seems reasonable to use early blast clearance or other baseline high-risk features to indicate HSCT.”

How can hematologists make the best decision about HSCT?

In an interview, City of Hope Medical Center (Duarte, California) hematologist-oncologist Ibrahim T. Aldoss, MD, said that chemotherapy — with or without immunotherapy — can often be enough to treat younger patients without high-risk genetic factors. “Potentially, these patients can be spared from transplants,” he said, although patients with resistant MRD “clearly need transplants.”

The risks of transplants are significant, he noted. While they can reduce the risk of relapse, the risk of dying during remission is higher vs chemotherapy. “So you have to balance the risks that you’re willing to take,” he said, keeping in mind that some patients can be cured with chemotherapy.

In addition, Dr. Aldoss said, acute graft-versus-host disease in the first few months after transplant can become chronic. “Many years later, patients can be struggling to where it actually impacts their daily activity. And unfortunately, patients can die from it.”

In the big picture, “you cannot have a generalized statement about whether you shouldn’t do transplants in every MRD-negative patient,” he said. However, “if you do achieve MRD negativity, most patients likely don’t need transplants.”

The Mayo Clinic’s Dr. Litzow urged colleagues to consider several factors when making decisions. Do patients have a high level of comorbidities that would raise the risk of death from HSCT? He noted that there’s nearly a 20% risk of death from HSCT, and comorbidities can boost the risk to 40%-50%.

Also, does the patient have a suitable donor? While advances have boosted the number of eligible donors, he said, “not everybody has an ideal donor.”

If a patient is MRD-negative but not a good candidate for a transplant, Dr. Litzow said consolidation therapy followed by maintenance therapy may be indicated. “Continue to check their bone marrow and their blood periodically as they’re going through treatment and reassess their MRD status to make sure they’re staying negative. If they turn MRD-positive during the course of their therapy, then we have to step back and rethink the role of transplant.”

As for cost, Dr. Litzow points out that HSCT is very expensive, although ALL is an accepted indication for HSCT. However, “if someone doesn’t have medical insurance, then it can be difficult to consider them having a transplant.”

What’s next? In his commentary, Dr. Boissel writes that his team aims to study whether HSCT is helpful in patients with high-risk B-cell ALL “who reach MRD negativity after a consolidation phase including blinatumomab.”

Dr. Aldoss discloses relationships with Amgen, Kite, Pfizer, Jazz, AbbVie, Sobi, Agios, Autolus, and MacroGenics. Dr. Litzow reports ties with Amgen. Dr. Boissel declares relationships with Amgen, Pfizer, Novartis, and Servier. Dr. Chevallier has no disclosures.