A proactive approach to therapeutic drug monitoring during maintenance therapy with infliximab in the treatment of inflammatory bowel diseases (IBDs) and other chronic immune-mediated inflammatory diseases significantly improves sustained disease control, compared with standard care, which was defined as no therapeutic drug monitoring, new research shows.

“This trial showed that therapeutic drug monitoring improved infliximab [maintenance] treatment by preventing disease flares without increasing drug consumption,” reported the authors of the study published in JAMA.

Infliximab and other tumor necrosis factor (TNF)–inhibitor drugs offer significant benefits in the treatment of IBDs and other chronic inflammatory diseases; however, up to 50% of patients become nonresponsive to the therapy within the first years of treatment, posing risks of disease worsening and possible organ damage.

To address the problem, therapeutic drug monitoring has been recommended, more so with IBD guidelines than rheumatoid arthritis; these have included measures such as dose adjustment or drug switching when there is evidence that disease control is not being maintained.

However, with low serum drug concentrations and the development of antidrug antibodies believed to be key indicators of a waning response, there is growing interest in a more proactive monitoring approach, involving scheduled assessments of serum and antibody levels, performed regardless of any signs of disease activity changes, and the provision of dosing adjustments, if needed.

In the earlier Norwegian Drug Monitoring (NORDRUM) A trial, first author Silje Watterdal Syversen, MD, PhD, of the division of rheumatology and research, Diakonhjemmet Hospital, Oslo, Norway, and colleagues evaluated the effects of the proactive drug monitoring approach during the initiation phase of infliximab treatment, but found no significant improvement in the study of 411 patients in terms of the primary outcome of remission rates.

For the current NORDRUM B trial, they sought to instead determine if benefits of the proactive therapeutic drug monitoring may be more apparent during the maintenance phase of infliximab treatment.

The trial involved 458 adults at 20 hospitals in Norway who had immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37), and who were undergoing maintenance therapy with infliximab.

The patients, who had a median of about 40 weeks’ prior infliximab therapy, were randomized 1:1 to receive either proactive therapeutic drug monitoring, consisting of scheduled monitoring of serum drug levels and antidrug antibodies and adjustments in dose and intervals as needed according to a trial algorithm (n = 228), or standard infliximab therapy, without the regular drug and antibody level monitoring (n = 230).

Over a 52-week follow-up, the primary outcome of sustained disease control without disease worsening was significantly higher in the proactive therapeutic drug monitoring group (73.6%; n = 167) versus standard care (55.9%; n = 127; P < .001). The risk of disease worsening was meanwhile significantly greater with standard care versus proactive drug monitoring (hazard ratio, 2.1).

Serum infliximab levels remained within the therapeutic range throughout the study period in 30% of patients receiving proactive therapeutic drug monitoring, compared with 17% in the standard care group, and low serum infliximab levels (≤2 mg/L) occurred at least once during the study period among 19% and 27% of the two groups, respectively.

Clinically significant levels of antidrug antibodies (≥50 mcg/L) occurred in 9.2% of the therapeutic drug monitoring patients and 15.0% of the standard care group.

About 55% of patients were also using concomitant immunosuppressive therapy, and the findings were consistent among those who did and did not use the drugs. There no significant differences in adverse events between the therapeutic drug-monitoring (60%) and standard care groups (63%).

Importantly, while the mean dose of infliximab during the trial was 4.8 mg/kg in both groups, an increase in dosage after disease worsening was more common in the standard therapy group (51%) than in the therapeutic drug monitoring group (31.6%), underscoring the improved dose control provided with the proactive therapeutic drug monitoring, the authors note.

The findings suggest “proactive therapeutic drug monitoring might be more important during maintenance therapy, a period during which low drug levels could be an important risk factor for therapeutic failure,” the authors conclude.

In commenting to this news organizatin, Dr. Syversen noted that, despite the variety of IMIDs, there were no significant differences with IBDs or other disorders.

“Our data show consistent findings across all diseases included,” she said.

Furthermore, “in the present study, and [prior research] using the same definition of disease worsening, IBD patients in general had a comparable flare rate as compared to inflammatory arthritis.”
 

Caveats include severe illness, potential cost challenges

Commenting on the research, Stephen B. Hanauer, MD, noted that a potential exception to the lack of benefit previously observed during treatment induction could be patients with severe illness.

“In patients with more severe disease and in particular with low albumin, [which is] more common in IBD than other immune-mediated inflammatory diseases, there is rapid metabolism and clearance of monoclonal antibodies early that limit efficacy of standard induction dosing,” said Dr. Hanauer, a professor of medicine and medical director of the Digestive Health Center at Northwestern University, Chicago. 

Northwestern University

Noting that the average duration of treatment in the study prior to randomization was nearly a year (about 40 weeks), he added that a key question is “How to initiate therapeutic drug monitoring earlier in course to further optimize induction and prevent loss of response in maintenance.”

Dr. Hanauer shared that, “in our practice, we use a combination of proactive and reactive therapeutic drug monitoring based on individual patients and their history with prior biologics.”
 

Findings may usher in ‘new era’ in immune-mediated inflammatory disease treatment

In an editorial published in JAMA with the study, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, both of Harvard Medical School in Boston, further commented that “maintaining disease control in nearly 3 of 4 patients represents a meaningful improvement over standard care.”

However, key challenges with the approach include the potential need for additional nurses and others to help monitor patients, and associated costs, which insurance providers may not always cover, they noted.

Another consideration is a lack of effective tools for monitoring measures including antidrug antibodies, they added, and “additional clinical trials within specific disease subgroups are needed.”

However, addressing such barriers “may help introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases,” the editorialists write.

Niels Vande Casteele, PharmD, PhD, an associate professor at the department of medicine, University of California, San Diego, and affiliate faculty, Skaggs School of Pharmacy & Pharmaceutical Sciences, commented that the study is “an important milestone in the field of therapeutic drug monitoring of biologics for immunoinflammatory diseases.”

“The ability of proactive therapeutic drug monitoring to achieve sustained disease control without increased drug consumption is [a] notable finding,” he said in an interview.

Noting a limitation, Dr. Casteele suggested the inclusion of more specific measures of disease activity could have provided clearer insights.

“In particular for gastrointestinal diseases, we know that symptoms do not correlate well with inflammatory disease activity,” he said. “As such, I would have preferred to see clinical symptoms being complemented with endoscopic and histologic finds to confirm disease activity.”

Ultimately, he said that the results suggest “proactive therapeutic drug monitoring is not required for all patients, but it is beneficial in some to achieve sustained disease control over a prolonged period of time.”

This study received funding by grants from the Norwegian Regional Health Authorities (interregional KLINBEFORSK grants) and the South-Eastern Norway Regional Health Authorities; study authors reported relationships with various pharmaceutical companies, including Pfizer, which makes infliximab. Dr. Wallace reported research support from Bristol Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio, Zenas Biopharma, and MedPace. Dr. Sparks reported consultancy fees from AbbVie, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr. Hanauer is a consultant and lecturer for Abbvie, Janssen, and Takeda and consultant for Pfizer, Celltrion, Amgen, Samsung Bioepis. Dr. Casteele has received research grants and personal fees from R-Biopharm, Takeda and UCB; and personal fees from AcelaBio, Alimentiv, Celltrion, Prometheus, Procise DX, and Vividion for activities that were all outside of the reviewed study.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

A proactive approach to therapeutic drug monitoring during maintenance therapy with infliximab in the treatment of inflammatory bowel diseases (IBDs) and other chronic immune-mediated inflammatory diseases significantly improves sustained disease control, compared with standard care, which was defined as no therapeutic drug monitoring, new research shows.

“This trial showed that therapeutic drug monitoring improved infliximab [maintenance] treatment by preventing disease flares without increasing drug consumption,” reported the authors of the study published in JAMA.

Infliximab and other tumor necrosis factor (TNF)–inhibitor drugs offer significant benefits in the treatment of IBDs and other chronic inflammatory diseases; however, up to 50% of patients become nonresponsive to the therapy within the first years of treatment, posing risks of disease worsening and possible organ damage.

To address the problem, therapeutic drug monitoring has been recommended, more so with IBD guidelines than rheumatoid arthritis; these have included measures such as dose adjustment or drug switching when there is evidence that disease control is not being maintained.

However, with low serum drug concentrations and the development of antidrug antibodies believed to be key indicators of a waning response, there is growing interest in a more proactive monitoring approach, involving scheduled assessments of serum and antibody levels, performed regardless of any signs of disease activity changes, and the provision of dosing adjustments, if needed.

In the earlier Norwegian Drug Monitoring (NORDRUM) A trial, first author Silje Watterdal Syversen, MD, PhD, of the division of rheumatology and research, Diakonhjemmet Hospital, Oslo, Norway, and colleagues evaluated the effects of the proactive drug monitoring approach during the initiation phase of infliximab treatment, but found no significant improvement in the study of 411 patients in terms of the primary outcome of remission rates.

For the current NORDRUM B trial, they sought to instead determine if benefits of the proactive therapeutic drug monitoring may be more apparent during the maintenance phase of infliximab treatment.

The trial involved 458 adults at 20 hospitals in Norway who had immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37), and who were undergoing maintenance therapy with infliximab.

The patients, who had a median of about 40 weeks’ prior infliximab therapy, were randomized 1:1 to receive either proactive therapeutic drug monitoring, consisting of scheduled monitoring of serum drug levels and antidrug antibodies and adjustments in dose and intervals as needed according to a trial algorithm (n = 228), or standard infliximab therapy, without the regular drug and antibody level monitoring (n = 230).

Over a 52-week follow-up, the primary outcome of sustained disease control without disease worsening was significantly higher in the proactive therapeutic drug monitoring group (73.6%; n = 167) versus standard care (55.9%; n = 127; P < .001). The risk of disease worsening was meanwhile significantly greater with standard care versus proactive drug monitoring (hazard ratio, 2.1).

Serum infliximab levels remained within the therapeutic range throughout the study period in 30% of patients receiving proactive therapeutic drug monitoring, compared with 17% in the standard care group, and low serum infliximab levels (≤2 mg/L) occurred at least once during the study period among 19% and 27% of the two groups, respectively.

Clinically significant levels of antidrug antibodies (≥50 mcg/L) occurred in 9.2% of the therapeutic drug monitoring patients and 15.0% of the standard care group.

About 55% of patients were also using concomitant immunosuppressive therapy, and the findings were consistent among those who did and did not use the drugs. There no significant differences in adverse events between the therapeutic drug-monitoring (60%) and standard care groups (63%).

Importantly, while the mean dose of infliximab during the trial was 4.8 mg/kg in both groups, an increase in dosage after disease worsening was more common in the standard therapy group (51%) than in the therapeutic drug monitoring group (31.6%), underscoring the improved dose control provided with the proactive therapeutic drug monitoring, the authors note.

The findings suggest “proactive therapeutic drug monitoring might be more important during maintenance therapy, a period during which low drug levels could be an important risk factor for therapeutic failure,” the authors conclude.

In commenting to this news organizatin, Dr. Syversen noted that, despite the variety of IMIDs, there were no significant differences with IBDs or other disorders.

“Our data show consistent findings across all diseases included,” she said.

Furthermore, “in the present study, and [prior research] using the same definition of disease worsening, IBD patients in general had a comparable flare rate as compared to inflammatory arthritis.”
 

Caveats include severe illness, potential cost challenges

Commenting on the research, Stephen B. Hanauer, MD, noted that a potential exception to the lack of benefit previously observed during treatment induction could be patients with severe illness.

“In patients with more severe disease and in particular with low albumin, [which is] more common in IBD than other immune-mediated inflammatory diseases, there is rapid metabolism and clearance of monoclonal antibodies early that limit efficacy of standard induction dosing,” said Dr. Hanauer, a professor of medicine and medical director of the Digestive Health Center at Northwestern University, Chicago. 

Northwestern University

Noting that the average duration of treatment in the study prior to randomization was nearly a year (about 40 weeks), he added that a key question is “How to initiate therapeutic drug monitoring earlier in course to further optimize induction and prevent loss of response in maintenance.”

Dr. Hanauer shared that, “in our practice, we use a combination of proactive and reactive therapeutic drug monitoring based on individual patients and their history with prior biologics.”
 

Findings may usher in ‘new era’ in immune-mediated inflammatory disease treatment

In an editorial published in JAMA with the study, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, both of Harvard Medical School in Boston, further commented that “maintaining disease control in nearly 3 of 4 patients represents a meaningful improvement over standard care.”

However, key challenges with the approach include the potential need for additional nurses and others to help monitor patients, and associated costs, which insurance providers may not always cover, they noted.

Another consideration is a lack of effective tools for monitoring measures including antidrug antibodies, they added, and “additional clinical trials within specific disease subgroups are needed.”

However, addressing such barriers “may help introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases,” the editorialists write.

Niels Vande Casteele, PharmD, PhD, an associate professor at the department of medicine, University of California, San Diego, and affiliate faculty, Skaggs School of Pharmacy & Pharmaceutical Sciences, commented that the study is “an important milestone in the field of therapeutic drug monitoring of biologics for immunoinflammatory diseases.”

“The ability of proactive therapeutic drug monitoring to achieve sustained disease control without increased drug consumption is [a] notable finding,” he said in an interview.

Noting a limitation, Dr. Casteele suggested the inclusion of more specific measures of disease activity could have provided clearer insights.

“In particular for gastrointestinal diseases, we know that symptoms do not correlate well with inflammatory disease activity,” he said. “As such, I would have preferred to see clinical symptoms being complemented with endoscopic and histologic finds to confirm disease activity.”

Ultimately, he said that the results suggest “proactive therapeutic drug monitoring is not required for all patients, but it is beneficial in some to achieve sustained disease control over a prolonged period of time.”

This study received funding by grants from the Norwegian Regional Health Authorities (interregional KLINBEFORSK grants) and the South-Eastern Norway Regional Health Authorities; study authors reported relationships with various pharmaceutical companies, including Pfizer, which makes infliximab. Dr. Wallace reported research support from Bristol Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio, Zenas Biopharma, and MedPace. Dr. Sparks reported consultancy fees from AbbVie, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr. Hanauer is a consultant and lecturer for Abbvie, Janssen, and Takeda and consultant for Pfizer, Celltrion, Amgen, Samsung Bioepis. Dr. Casteele has received research grants and personal fees from R-Biopharm, Takeda and UCB; and personal fees from AcelaBio, Alimentiv, Celltrion, Prometheus, Procise DX, and Vividion for activities that were all outside of the reviewed study.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

A proactive approach to therapeutic drug monitoring during maintenance therapy with infliximab in the treatment of inflammatory bowel diseases (IBDs) and other chronic immune-mediated inflammatory diseases significantly improves sustained disease control, compared with standard care, which was defined as no therapeutic drug monitoring, new research shows.

“This trial showed that therapeutic drug monitoring improved infliximab [maintenance] treatment by preventing disease flares without increasing drug consumption,” reported the authors of the study published in JAMA.

Infliximab and other tumor necrosis factor (TNF)–inhibitor drugs offer significant benefits in the treatment of IBDs and other chronic inflammatory diseases; however, up to 50% of patients become nonresponsive to the therapy within the first years of treatment, posing risks of disease worsening and possible organ damage.

To address the problem, therapeutic drug monitoring has been recommended, more so with IBD guidelines than rheumatoid arthritis; these have included measures such as dose adjustment or drug switching when there is evidence that disease control is not being maintained.

However, with low serum drug concentrations and the development of antidrug antibodies believed to be key indicators of a waning response, there is growing interest in a more proactive monitoring approach, involving scheduled assessments of serum and antibody levels, performed regardless of any signs of disease activity changes, and the provision of dosing adjustments, if needed.

In the earlier Norwegian Drug Monitoring (NORDRUM) A trial, first author Silje Watterdal Syversen, MD, PhD, of the division of rheumatology and research, Diakonhjemmet Hospital, Oslo, Norway, and colleagues evaluated the effects of the proactive drug monitoring approach during the initiation phase of infliximab treatment, but found no significant improvement in the study of 411 patients in terms of the primary outcome of remission rates.

For the current NORDRUM B trial, they sought to instead determine if benefits of the proactive therapeutic drug monitoring may be more apparent during the maintenance phase of infliximab treatment.

The trial involved 458 adults at 20 hospitals in Norway who had immune-mediated inflammatory diseases (IMIDs), including rheumatoid arthritis (n = 80), spondyloarthritis (n = 138), psoriatic arthritis (n = 54), ulcerative colitis (n = 81), Crohn’s disease (n = 68), or psoriasis (n = 37), and who were undergoing maintenance therapy with infliximab.

The patients, who had a median of about 40 weeks’ prior infliximab therapy, were randomized 1:1 to receive either proactive therapeutic drug monitoring, consisting of scheduled monitoring of serum drug levels and antidrug antibodies and adjustments in dose and intervals as needed according to a trial algorithm (n = 228), or standard infliximab therapy, without the regular drug and antibody level monitoring (n = 230).

Over a 52-week follow-up, the primary outcome of sustained disease control without disease worsening was significantly higher in the proactive therapeutic drug monitoring group (73.6%; n = 167) versus standard care (55.9%; n = 127; P < .001). The risk of disease worsening was meanwhile significantly greater with standard care versus proactive drug monitoring (hazard ratio, 2.1).

Serum infliximab levels remained within the therapeutic range throughout the study period in 30% of patients receiving proactive therapeutic drug monitoring, compared with 17% in the standard care group, and low serum infliximab levels (≤2 mg/L) occurred at least once during the study period among 19% and 27% of the two groups, respectively.

Clinically significant levels of antidrug antibodies (≥50 mcg/L) occurred in 9.2% of the therapeutic drug monitoring patients and 15.0% of the standard care group.

About 55% of patients were also using concomitant immunosuppressive therapy, and the findings were consistent among those who did and did not use the drugs. There no significant differences in adverse events between the therapeutic drug-monitoring (60%) and standard care groups (63%).

Importantly, while the mean dose of infliximab during the trial was 4.8 mg/kg in both groups, an increase in dosage after disease worsening was more common in the standard therapy group (51%) than in the therapeutic drug monitoring group (31.6%), underscoring the improved dose control provided with the proactive therapeutic drug monitoring, the authors note.

The findings suggest “proactive therapeutic drug monitoring might be more important during maintenance therapy, a period during which low drug levels could be an important risk factor for therapeutic failure,” the authors conclude.

In commenting to this news organizatin, Dr. Syversen noted that, despite the variety of IMIDs, there were no significant differences with IBDs or other disorders.

“Our data show consistent findings across all diseases included,” she said.

Furthermore, “in the present study, and [prior research] using the same definition of disease worsening, IBD patients in general had a comparable flare rate as compared to inflammatory arthritis.”
 

Caveats include severe illness, potential cost challenges

Commenting on the research, Stephen B. Hanauer, MD, noted that a potential exception to the lack of benefit previously observed during treatment induction could be patients with severe illness.

“In patients with more severe disease and in particular with low albumin, [which is] more common in IBD than other immune-mediated inflammatory diseases, there is rapid metabolism and clearance of monoclonal antibodies early that limit efficacy of standard induction dosing,” said Dr. Hanauer, a professor of medicine and medical director of the Digestive Health Center at Northwestern University, Chicago. 

Northwestern University

Noting that the average duration of treatment in the study prior to randomization was nearly a year (about 40 weeks), he added that a key question is “How to initiate therapeutic drug monitoring earlier in course to further optimize induction and prevent loss of response in maintenance.”

Dr. Hanauer shared that, “in our practice, we use a combination of proactive and reactive therapeutic drug monitoring based on individual patients and their history with prior biologics.”
 

Findings may usher in ‘new era’ in immune-mediated inflammatory disease treatment

In an editorial published in JAMA with the study, Zachary S. Wallace, MD, and Jeffrey A. Sparks, MD, both of Harvard Medical School in Boston, further commented that “maintaining disease control in nearly 3 of 4 patients represents a meaningful improvement over standard care.”

However, key challenges with the approach include the potential need for additional nurses and others to help monitor patients, and associated costs, which insurance providers may not always cover, they noted.

Another consideration is a lack of effective tools for monitoring measures including antidrug antibodies, they added, and “additional clinical trials within specific disease subgroups are needed.”

However, addressing such barriers “may help introduce a new era in treatment approach to maintenance therapy for patients with immune-mediated inflammatory diseases,” the editorialists write.

Niels Vande Casteele, PharmD, PhD, an associate professor at the department of medicine, University of California, San Diego, and affiliate faculty, Skaggs School of Pharmacy & Pharmaceutical Sciences, commented that the study is “an important milestone in the field of therapeutic drug monitoring of biologics for immunoinflammatory diseases.”

“The ability of proactive therapeutic drug monitoring to achieve sustained disease control without increased drug consumption is [a] notable finding,” he said in an interview.

Noting a limitation, Dr. Casteele suggested the inclusion of more specific measures of disease activity could have provided clearer insights.

“In particular for gastrointestinal diseases, we know that symptoms do not correlate well with inflammatory disease activity,” he said. “As such, I would have preferred to see clinical symptoms being complemented with endoscopic and histologic finds to confirm disease activity.”

Ultimately, he said that the results suggest “proactive therapeutic drug monitoring is not required for all patients, but it is beneficial in some to achieve sustained disease control over a prolonged period of time.”

This study received funding by grants from the Norwegian Regional Health Authorities (interregional KLINBEFORSK grants) and the South-Eastern Norway Regional Health Authorities; study authors reported relationships with various pharmaceutical companies, including Pfizer, which makes infliximab. Dr. Wallace reported research support from Bristol Myers Squibb and Principia/Sanofi and consulting fees from Viela Bio, Zenas Biopharma, and MedPace. Dr. Sparks reported consultancy fees from AbbVie, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. Dr. Hanauer is a consultant and lecturer for Abbvie, Janssen, and Takeda and consultant for Pfizer, Celltrion, Amgen, Samsung Bioepis. Dr. Casteele has received research grants and personal fees from R-Biopharm, Takeda and UCB; and personal fees from AcelaBio, Alimentiv, Celltrion, Prometheus, Procise DX, and Vividion for activities that were all outside of the reviewed study.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD. 

An Alaska physician has been sentenced to 34 months in prison followed by 3 years of supervised release and fined $25,000 for illegally dispensing and distributing controlled substances to his patients.

According to court documents, between January 2014 and October 2019, family physician David Chisholm, MD, 64, of Wasilla, Alaska, wrote more than 20,000 prescriptions to approximately 350 patients for oxycodone, methadone, and hydrocodone, often prescribing the pills using variations of patients’ names in an attempt to avoid being red-flagged by payers.

When Walmart refused to continue filling the prescriptions, Dr. Chisholm told his staff to advise the patients to use other pharmacies. In addition, he often prescribed combinations of medications, such as concurrent opioids, benzodiazepines, sedatives, and carisoprodol, thus increasing the chances that his patients would become addicted to or overdose on the drugs. Chisholm, who pleaded guilty in June, acknowledged to federal officials that his prescriptions were a significant contributing factor to the overdose deaths of five of his patients during this time, according to a statement by the U.S. Attorney’s Office for the District of Alaska.

According to the Anchorage Daily News, Dr. Chisholm, who was not board certified in pain medicine, said his reason for prescribing the drugs was not to make money but to help patients suffering from chronic pain and because he enjoyed the challenge.

Dr. Chisholm’s attorney, Nick Oberheiden, told CNN his client “sacrificed his reputation as a patient advocate and his years of service to the Alaskan community” in overprescribing opioids. “He expressed his sincere remorse in open court and he accepts the consequences of his misconduct. He hopes that his case serves as a warning to other physicians facing the same dilemma when treating chronic pain.”

He surrendered his medical license in November 2020 before being formally charged in April 2021.
 

Texas hospital CEO, seven doctors settle kickback

A hospital executive and seven physicians have agreed to pay a total of $1.1 million to settle allegations that they violated the Anti-Kickback Statute and Stark Law. The eight have also agreed to cooperate in investigations and litigation involving other parties.

The Texas physicians involved in the settlement are internist Jaspaul Bhangoo, MD, of Denton; family physician Robert Megna, DO, of Ferris; cardiologist Baxter Montgomery, MD, of Houston; internist Murtaza Mussaji, DO, of Houston; family physician David Sneed, DO, of Austin; family physician Kevin Lewis, DO, of Houston; and family physician Angela Mosley-Nunnery, MD, of Kingwood.

Also settling was Richard DeFoore, former CEO of Jones County Regional Healthcare (dba Stamford Memorial Hospital).

The physicians were accused of accepting payments from organizations in exchange for ordering lab tests from True Health Diagnostics, Little River Healthcare, and Boston Heart. The payments to the physicians were disguised as investment returns but, according to the allegations, were in fact offered in exchange for the doctors’ referrals. Mr. DeFoore, the hospital executive involved in the settlement, allegedly oversaw a similar scheme that benefited the now-defunct Stamford Memorial.

“Paying kickbacks to physicians distorts the medical decision-making process, corrupts our health care system, and increases the cost of healthcare funded by the taxpayer,” Brit Featherston, U.S. attorney for the Eastern District of Texas, said in a statement announcing the agreement. “Laboratories, marketers, and physicians cannot immunize their conduct by attempting to disguise the kickbacks as some sort of investment arrangement.”
 

Practice administrative assistant sentenced for fraudulent prescriptions

An administrative assistant at an Illinois orthopedics office was sentenced to a year and a day in federal prison for writing fraudulent prescriptions for opioids.

Amanda Biesiada, 39, of Alsip, Ill., who worked as an administrative assistant at Hinsdale Orthopaedics in Westmont, Ill., was not a licensed physician and could not legally write the prescriptions unless instructed to do so and supervised by licensed doctors.

According to a statement by the U.S. Attorney’s Office for the Northern District of Illinois, the prescriptions for hydrocodone, oxycodone, and other controlled substances – 85 prescriptions in all from 2017 to 2019 – were made out to an acquaintance of Biesiada’s and written without the knowledge or approval of the providers in whose names she wrote them.

Federal officials said Ms. Biesiada attempted to conceal the fraudulent prescriptions by marking them “filed in error” in the practice’s prescription system.
 

Lab owner pleads guilty to $6.9 million testing fraud scheme

A Florida lab owner has pleaded guilty to conspiracy to defraud Medicare through false and fraudulent claims totaling more than $6.9 million.

According to court documents, Christopher Licata, 45, of Delray Beach, Fla., admitted to bribing patient brokers to refer orders for medically unnecessary genetic testing to his lab. The tests were then billed to Medicare.

Mr. Licata and the patient brokers entered sham agreements meant to disguise the true purpose of the payments, according to a statement from the Department of Justice. The 45-year-old owner of Boca Toxicology (dba Lab Dynamics) pleaded guilty to one count of conspiring to commit health care fraud.

The scheme began in 2018; however, once the pandemic began, Mr. Licata shifted strategies, playing on patients’ fears of COVID-19 to bundle inexpensive COVID tests with more expensive medically unnecessary tests. These tests included respiratory pathogen panels and genetic testing for cardiovascular disease, cancer, diabetes, Alzheimer’s disease, and other illnesses. In all, Mr. Licata’s laboratory submitted over $6.9 million in false and fraudulent claims to Medicare for these unnecessary tests, according to the DOJ statement.

The case is a part of the U.S. Attorney General’s COVID-19 Fraud Enforcement Task Force that was established to enhance the efforts of agencies and governments across the country to combat and prevent pandemic-related fraud.

Mr. Licata faces a maximum penalty of 10 years in prison. His sentencing is scheduled for March 24.

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

An Alaska physician has been sentenced to 34 months in prison followed by 3 years of supervised release and fined $25,000 for illegally dispensing and distributing controlled substances to his patients.

According to court documents, between January 2014 and October 2019, family physician David Chisholm, MD, 64, of Wasilla, Alaska, wrote more than 20,000 prescriptions to approximately 350 patients for oxycodone, methadone, and hydrocodone, often prescribing the pills using variations of patients’ names in an attempt to avoid being red-flagged by payers.

When Walmart refused to continue filling the prescriptions, Dr. Chisholm told his staff to advise the patients to use other pharmacies. In addition, he often prescribed combinations of medications, such as concurrent opioids, benzodiazepines, sedatives, and carisoprodol, thus increasing the chances that his patients would become addicted to or overdose on the drugs. Chisholm, who pleaded guilty in June, acknowledged to federal officials that his prescriptions were a significant contributing factor to the overdose deaths of five of his patients during this time, according to a statement by the U.S. Attorney’s Office for the District of Alaska.

According to the Anchorage Daily News, Dr. Chisholm, who was not board certified in pain medicine, said his reason for prescribing the drugs was not to make money but to help patients suffering from chronic pain and because he enjoyed the challenge.

Dr. Chisholm’s attorney, Nick Oberheiden, told CNN his client “sacrificed his reputation as a patient advocate and his years of service to the Alaskan community” in overprescribing opioids. “He expressed his sincere remorse in open court and he accepts the consequences of his misconduct. He hopes that his case serves as a warning to other physicians facing the same dilemma when treating chronic pain.”

He surrendered his medical license in November 2020 before being formally charged in April 2021.
 

Texas hospital CEO, seven doctors settle kickback

A hospital executive and seven physicians have agreed to pay a total of $1.1 million to settle allegations that they violated the Anti-Kickback Statute and Stark Law. The eight have also agreed to cooperate in investigations and litigation involving other parties.

The Texas physicians involved in the settlement are internist Jaspaul Bhangoo, MD, of Denton; family physician Robert Megna, DO, of Ferris; cardiologist Baxter Montgomery, MD, of Houston; internist Murtaza Mussaji, DO, of Houston; family physician David Sneed, DO, of Austin; family physician Kevin Lewis, DO, of Houston; and family physician Angela Mosley-Nunnery, MD, of Kingwood.

Also settling was Richard DeFoore, former CEO of Jones County Regional Healthcare (dba Stamford Memorial Hospital).

The physicians were accused of accepting payments from organizations in exchange for ordering lab tests from True Health Diagnostics, Little River Healthcare, and Boston Heart. The payments to the physicians were disguised as investment returns but, according to the allegations, were in fact offered in exchange for the doctors’ referrals. Mr. DeFoore, the hospital executive involved in the settlement, allegedly oversaw a similar scheme that benefited the now-defunct Stamford Memorial.

“Paying kickbacks to physicians distorts the medical decision-making process, corrupts our health care system, and increases the cost of healthcare funded by the taxpayer,” Brit Featherston, U.S. attorney for the Eastern District of Texas, said in a statement announcing the agreement. “Laboratories, marketers, and physicians cannot immunize their conduct by attempting to disguise the kickbacks as some sort of investment arrangement.”
 

Practice administrative assistant sentenced for fraudulent prescriptions

An administrative assistant at an Illinois orthopedics office was sentenced to a year and a day in federal prison for writing fraudulent prescriptions for opioids.

Amanda Biesiada, 39, of Alsip, Ill., who worked as an administrative assistant at Hinsdale Orthopaedics in Westmont, Ill., was not a licensed physician and could not legally write the prescriptions unless instructed to do so and supervised by licensed doctors.

According to a statement by the U.S. Attorney’s Office for the Northern District of Illinois, the prescriptions for hydrocodone, oxycodone, and other controlled substances – 85 prescriptions in all from 2017 to 2019 – were made out to an acquaintance of Biesiada’s and written without the knowledge or approval of the providers in whose names she wrote them.

Federal officials said Ms. Biesiada attempted to conceal the fraudulent prescriptions by marking them “filed in error” in the practice’s prescription system.
 

Lab owner pleads guilty to $6.9 million testing fraud scheme

A Florida lab owner has pleaded guilty to conspiracy to defraud Medicare through false and fraudulent claims totaling more than $6.9 million.

According to court documents, Christopher Licata, 45, of Delray Beach, Fla., admitted to bribing patient brokers to refer orders for medically unnecessary genetic testing to his lab. The tests were then billed to Medicare.

Mr. Licata and the patient brokers entered sham agreements meant to disguise the true purpose of the payments, according to a statement from the Department of Justice. The 45-year-old owner of Boca Toxicology (dba Lab Dynamics) pleaded guilty to one count of conspiring to commit health care fraud.

The scheme began in 2018; however, once the pandemic began, Mr. Licata shifted strategies, playing on patients’ fears of COVID-19 to bundle inexpensive COVID tests with more expensive medically unnecessary tests. These tests included respiratory pathogen panels and genetic testing for cardiovascular disease, cancer, diabetes, Alzheimer’s disease, and other illnesses. In all, Mr. Licata’s laboratory submitted over $6.9 million in false and fraudulent claims to Medicare for these unnecessary tests, according to the DOJ statement.

The case is a part of the U.S. Attorney General’s COVID-19 Fraud Enforcement Task Force that was established to enhance the efforts of agencies and governments across the country to combat and prevent pandemic-related fraud.

Mr. Licata faces a maximum penalty of 10 years in prison. His sentencing is scheduled for March 24.

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

An Alaska physician has been sentenced to 34 months in prison followed by 3 years of supervised release and fined $25,000 for illegally dispensing and distributing controlled substances to his patients.

According to court documents, between January 2014 and October 2019, family physician David Chisholm, MD, 64, of Wasilla, Alaska, wrote more than 20,000 prescriptions to approximately 350 patients for oxycodone, methadone, and hydrocodone, often prescribing the pills using variations of patients’ names in an attempt to avoid being red-flagged by payers.

When Walmart refused to continue filling the prescriptions, Dr. Chisholm told his staff to advise the patients to use other pharmacies. In addition, he often prescribed combinations of medications, such as concurrent opioids, benzodiazepines, sedatives, and carisoprodol, thus increasing the chances that his patients would become addicted to or overdose on the drugs. Chisholm, who pleaded guilty in June, acknowledged to federal officials that his prescriptions were a significant contributing factor to the overdose deaths of five of his patients during this time, according to a statement by the U.S. Attorney’s Office for the District of Alaska.

According to the Anchorage Daily News, Dr. Chisholm, who was not board certified in pain medicine, said his reason for prescribing the drugs was not to make money but to help patients suffering from chronic pain and because he enjoyed the challenge.

Dr. Chisholm’s attorney, Nick Oberheiden, told CNN his client “sacrificed his reputation as a patient advocate and his years of service to the Alaskan community” in overprescribing opioids. “He expressed his sincere remorse in open court and he accepts the consequences of his misconduct. He hopes that his case serves as a warning to other physicians facing the same dilemma when treating chronic pain.”

He surrendered his medical license in November 2020 before being formally charged in April 2021.
 

Texas hospital CEO, seven doctors settle kickback

A hospital executive and seven physicians have agreed to pay a total of $1.1 million to settle allegations that they violated the Anti-Kickback Statute and Stark Law. The eight have also agreed to cooperate in investigations and litigation involving other parties.

The Texas physicians involved in the settlement are internist Jaspaul Bhangoo, MD, of Denton; family physician Robert Megna, DO, of Ferris; cardiologist Baxter Montgomery, MD, of Houston; internist Murtaza Mussaji, DO, of Houston; family physician David Sneed, DO, of Austin; family physician Kevin Lewis, DO, of Houston; and family physician Angela Mosley-Nunnery, MD, of Kingwood.

Also settling was Richard DeFoore, former CEO of Jones County Regional Healthcare (dba Stamford Memorial Hospital).

The physicians were accused of accepting payments from organizations in exchange for ordering lab tests from True Health Diagnostics, Little River Healthcare, and Boston Heart. The payments to the physicians were disguised as investment returns but, according to the allegations, were in fact offered in exchange for the doctors’ referrals. Mr. DeFoore, the hospital executive involved in the settlement, allegedly oversaw a similar scheme that benefited the now-defunct Stamford Memorial.

“Paying kickbacks to physicians distorts the medical decision-making process, corrupts our health care system, and increases the cost of healthcare funded by the taxpayer,” Brit Featherston, U.S. attorney for the Eastern District of Texas, said in a statement announcing the agreement. “Laboratories, marketers, and physicians cannot immunize their conduct by attempting to disguise the kickbacks as some sort of investment arrangement.”
 

Practice administrative assistant sentenced for fraudulent prescriptions

An administrative assistant at an Illinois orthopedics office was sentenced to a year and a day in federal prison for writing fraudulent prescriptions for opioids.

Amanda Biesiada, 39, of Alsip, Ill., who worked as an administrative assistant at Hinsdale Orthopaedics in Westmont, Ill., was not a licensed physician and could not legally write the prescriptions unless instructed to do so and supervised by licensed doctors.

According to a statement by the U.S. Attorney’s Office for the Northern District of Illinois, the prescriptions for hydrocodone, oxycodone, and other controlled substances – 85 prescriptions in all from 2017 to 2019 – were made out to an acquaintance of Biesiada’s and written without the knowledge or approval of the providers in whose names she wrote them.

Federal officials said Ms. Biesiada attempted to conceal the fraudulent prescriptions by marking them “filed in error” in the practice’s prescription system.
 

Lab owner pleads guilty to $6.9 million testing fraud scheme

A Florida lab owner has pleaded guilty to conspiracy to defraud Medicare through false and fraudulent claims totaling more than $6.9 million.

According to court documents, Christopher Licata, 45, of Delray Beach, Fla., admitted to bribing patient brokers to refer orders for medically unnecessary genetic testing to his lab. The tests were then billed to Medicare.

Mr. Licata and the patient brokers entered sham agreements meant to disguise the true purpose of the payments, according to a statement from the Department of Justice. The 45-year-old owner of Boca Toxicology (dba Lab Dynamics) pleaded guilty to one count of conspiring to commit health care fraud.

The scheme began in 2018; however, once the pandemic began, Mr. Licata shifted strategies, playing on patients’ fears of COVID-19 to bundle inexpensive COVID tests with more expensive medically unnecessary tests. These tests included respiratory pathogen panels and genetic testing for cardiovascular disease, cancer, diabetes, Alzheimer’s disease, and other illnesses. In all, Mr. Licata’s laboratory submitted over $6.9 million in false and fraudulent claims to Medicare for these unnecessary tests, according to the DOJ statement.

The case is a part of the U.S. Attorney General’s COVID-19 Fraud Enforcement Task Force that was established to enhance the efforts of agencies and governments across the country to combat and prevent pandemic-related fraud.

Mr. Licata faces a maximum penalty of 10 years in prison. His sentencing is scheduled for March 24.

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

Dhaval Bhatt had been warned about hospital emergency departments.

“People always told me to avoid the ER in America unless you are really dying,” said Dr. Bhatt, an immigrant from India who got a PhD in pharmacology in the United States and is now a research scientist at Washington University, St. Louis.

But when Dr. Bhatt’s 2-year-old son burned his hand on the kitchen stove on a Wednesday morning in April, the family’s pediatrician directed them the next day to the local children’s hospital.

Dr. Bhatt was traveling. So, his wife, Mansi Bhatt, took their son to the hospital and was sent to the ED. A nurse practitioner took the toddler’s vitals and looked at the wound. She said a surgeon would inspect it more closely.

When the surgeon didn’t appear after more than an hour, Dr. Bhatt’s wife took her son home. The hospital told her to make a follow-up appointment with a doctor, which turned out to be unnecessary because the burn healed quickly.

Then the bill came.

The patient: Martand Bhatt, a toddler covered by a UnitedHealthcare insurance plan provided by the employer of his father, Dhaval Bhatt.

Medical service: An ED visit for a burn sustained when Martand touched an electric stove.

Total bill: $1,012. UnitedHealthcare’s negotiated rate was $858.92, all of which the Bhatts were responsible for because their plan had a $3,000 deductible.

Service provider: SSM Health Cardinal Glennon Children’s Hospital, one of 23 hospitals owned by SSM Health, a Catholic, nonprofit health system with more than $8 billion in annual revenue.

What gives: Many patients don’t understand that they can rack up huge bills almost as soon as they walk through the doors of an ED.

Unlike a restaurant or a mechanic who won’t charge if someone gets tired of waiting for a table or an inspection of a rattling engine, hospital emergency rooms almost invariably charge patients as soon as they check in.

And once they register, patients will be billed – often a lot – whether treatment was rendered or not.

Martand Bhatt received almost no medical service. A nurse practitioner looked over the toddler, listened to his heart and stomach, and looked in his nose, mouth and ears, according to provider notes prepared by the hospital and shared with KHN by Dr. Bhatt.

The nurse didn’t change the dressing on the wound or order any testing.

“My objection to this is that there was no care provided,” Dr. Bhatt wrote to Bill of the Month.

“My wife did not drive for 45 minutes to get to an ER and wait for an additional 1½ hours for someone to tell me that our child’s vitals – weight, height, temperature and blood pressure – were okay,” Dr. Bhatt continued. “We already knew that. ... It is absolutely ridiculous and unethical.”

When the Bhatts left the ED, Martand was “alert, active and well appearing,” according to the notes.

The nurse’s assessment of Martand cost $192, which was discounted by UnitedHealthcare to a negotiated rate of $38.92. The bulk of the Bhatts’ bill – $820 – was something called a facility fee.

Hospital officials defend these fees as necessary to keep the ED open 24 hours a day as a community asset.

SSM Health spokesperson Stephanie Zoller Mueller declined to discuss the details of Martand’s medical condition even though the Bhatts gave their permission for the hospital to do so.

In an email, Ms. Zoller Mueller said the charges were “appropriate” based on the “acuity of condition, discharge instructions, vital sign monitoring, traumatic wound care, [and] numerous assessments.”

She added: “A patient does not have to receive additional treatment – procedure, labs, x-rays, etc. – to validate an ED-level charge.”

But some patient advocates say these facility fees are applied much too widely and should be limited to patients who actually receive medical care.

“It’s just not appropriate for someone to be charged if they’re not provided treatment,” said Adam Fox, deputy director of the Colorado Consumer Health Initiative. “Patients aren’t availing themselves of a facility if they don’t get care.”

At the very least, hospitals could communicate more clearly to patients about the fees they may be charged for coming to an ED, said Maureen Hensley-Quinn, senior program director at the National Academy for State Health Policy.

“People should know that when they walk in to receive care, there is this fee that they will be assessed,” Ms. Hensley-Quinn said.

Hospitals could also post at the entrance to the ED standard fees for different levels of emergency care.

Dr. Bhatt’s fee still could have been lower if the hospital had classified his son’s injury as minor. But, again, the hospital billing process worked against the family and in favor of the hospital’s bottom line.

Emergency visits are usually classified for billing on a scale from 1 to 5. Level 1 is minor and routine; level 5 requires complex care for life-threatening conditions. And hospitals are increasingly using the highest-severity codes to classify emergency visits, research shows.

“There are financial incentives for billing at a higher severity,” said Aditi Sen, who directs policy and research at the nonprofit Health Care Cost Institute, which has studied ED coding.

Despite the lack of severity of Martand’s wound and the absence of medical care, his visit was classified as level 3, a moderate-severity problem.

Resolution: Incensed that he’d been charged so much, Dr. Bhatt made numerous attempts to get the hospital to reduce the charges. He also appealed to UnitedHealthcare to review the charges.

His efforts failed. In August, Dr. Bhatt received a letter from an SSM Health “patient advocate” informing him that the hospital would not adjust the bill and instructing him to contact patient billing to arrange for payment.

While Dr. Bhatt was trying to reach the patient advocate by phone, his bill was sent to Medicredit, a collection agency, which began sending him notices and calling him.

After KHN contacted SSM Health, Dr. Bhatt received a call from someone who worked on “patient financial experience” issues at the hospital.

The hospital agreed to forgive the $820 facility fee. Dr. Bhatt agreed to pay the remaining $38.92, the professional fee for the ED nurse’s work. Dr. Bhatt also received a notice from Medicredit that it would take no further action against him.

The takeaway: The Bhatts did what most parents would do when a pediatrician advises them to take their child to the hospital.

But EDs are among the most expensive places to get care in the U.S. health system.

If you have a relatively low-level issue, think twice before even registering at the front desk, the act that initiates the billing process. If your doctor doesn’t have same-day appointments or after-hours service, think about urgent care, which is often much cheaper if the center isn’t attached to a hospital.

And remember that if you go to a hospital ED with a relatively minor issue, chances are that you’ll have to wait, as the Bhatts did. Patients with more serious problems will be seen first.

Once you’re taken past the front desk, you will almost certainly be hit with a substantial facility fee even if you don’t receive care.

Appealing that fee to the hospital can occasionally be successful, but there are no guarantees. And, as Dr. Bhatt learned, don’t expect the health insurer to offer much help. Most insurers won’t challenge how a medical visit is coded except on extremely expensive medical claims that will cost them money.

In this case, Dr. Bhatt was on the hook for the whole fee because he had a high-deductible plan, so the insurer had little incentive to take up his cause.

For now, patients’ best hope, many advocates believe, is to publicize the high prices that hospitals charge for their services, inside and outside the ED.

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

Dhaval Bhatt had been warned about hospital emergency departments.

“People always told me to avoid the ER in America unless you are really dying,” said Dr. Bhatt, an immigrant from India who got a PhD in pharmacology in the United States and is now a research scientist at Washington University, St. Louis.

But when Dr. Bhatt’s 2-year-old son burned his hand on the kitchen stove on a Wednesday morning in April, the family’s pediatrician directed them the next day to the local children’s hospital.

Dr. Bhatt was traveling. So, his wife, Mansi Bhatt, took their son to the hospital and was sent to the ED. A nurse practitioner took the toddler’s vitals and looked at the wound. She said a surgeon would inspect it more closely.

When the surgeon didn’t appear after more than an hour, Dr. Bhatt’s wife took her son home. The hospital told her to make a follow-up appointment with a doctor, which turned out to be unnecessary because the burn healed quickly.

Then the bill came.

The patient: Martand Bhatt, a toddler covered by a UnitedHealthcare insurance plan provided by the employer of his father, Dhaval Bhatt.

Medical service: An ED visit for a burn sustained when Martand touched an electric stove.

Total bill: $1,012. UnitedHealthcare’s negotiated rate was $858.92, all of which the Bhatts were responsible for because their plan had a $3,000 deductible.

Service provider: SSM Health Cardinal Glennon Children’s Hospital, one of 23 hospitals owned by SSM Health, a Catholic, nonprofit health system with more than $8 billion in annual revenue.

What gives: Many patients don’t understand that they can rack up huge bills almost as soon as they walk through the doors of an ED.

Unlike a restaurant or a mechanic who won’t charge if someone gets tired of waiting for a table or an inspection of a rattling engine, hospital emergency rooms almost invariably charge patients as soon as they check in.

And once they register, patients will be billed – often a lot – whether treatment was rendered or not.

Martand Bhatt received almost no medical service. A nurse practitioner looked over the toddler, listened to his heart and stomach, and looked in his nose, mouth and ears, according to provider notes prepared by the hospital and shared with KHN by Dr. Bhatt.

The nurse didn’t change the dressing on the wound or order any testing.

“My objection to this is that there was no care provided,” Dr. Bhatt wrote to Bill of the Month.

“My wife did not drive for 45 minutes to get to an ER and wait for an additional 1½ hours for someone to tell me that our child’s vitals – weight, height, temperature and blood pressure – were okay,” Dr. Bhatt continued. “We already knew that. ... It is absolutely ridiculous and unethical.”

When the Bhatts left the ED, Martand was “alert, active and well appearing,” according to the notes.

The nurse’s assessment of Martand cost $192, which was discounted by UnitedHealthcare to a negotiated rate of $38.92. The bulk of the Bhatts’ bill – $820 – was something called a facility fee.

Hospital officials defend these fees as necessary to keep the ED open 24 hours a day as a community asset.

SSM Health spokesperson Stephanie Zoller Mueller declined to discuss the details of Martand’s medical condition even though the Bhatts gave their permission for the hospital to do so.

In an email, Ms. Zoller Mueller said the charges were “appropriate” based on the “acuity of condition, discharge instructions, vital sign monitoring, traumatic wound care, [and] numerous assessments.”

She added: “A patient does not have to receive additional treatment – procedure, labs, x-rays, etc. – to validate an ED-level charge.”

But some patient advocates say these facility fees are applied much too widely and should be limited to patients who actually receive medical care.

“It’s just not appropriate for someone to be charged if they’re not provided treatment,” said Adam Fox, deputy director of the Colorado Consumer Health Initiative. “Patients aren’t availing themselves of a facility if they don’t get care.”

At the very least, hospitals could communicate more clearly to patients about the fees they may be charged for coming to an ED, said Maureen Hensley-Quinn, senior program director at the National Academy for State Health Policy.

“People should know that when they walk in to receive care, there is this fee that they will be assessed,” Ms. Hensley-Quinn said.

Hospitals could also post at the entrance to the ED standard fees for different levels of emergency care.

Dr. Bhatt’s fee still could have been lower if the hospital had classified his son’s injury as minor. But, again, the hospital billing process worked against the family and in favor of the hospital’s bottom line.

Emergency visits are usually classified for billing on a scale from 1 to 5. Level 1 is minor and routine; level 5 requires complex care for life-threatening conditions. And hospitals are increasingly using the highest-severity codes to classify emergency visits, research shows.

“There are financial incentives for billing at a higher severity,” said Aditi Sen, who directs policy and research at the nonprofit Health Care Cost Institute, which has studied ED coding.

Despite the lack of severity of Martand’s wound and the absence of medical care, his visit was classified as level 3, a moderate-severity problem.

Resolution: Incensed that he’d been charged so much, Dr. Bhatt made numerous attempts to get the hospital to reduce the charges. He also appealed to UnitedHealthcare to review the charges.

His efforts failed. In August, Dr. Bhatt received a letter from an SSM Health “patient advocate” informing him that the hospital would not adjust the bill and instructing him to contact patient billing to arrange for payment.

While Dr. Bhatt was trying to reach the patient advocate by phone, his bill was sent to Medicredit, a collection agency, which began sending him notices and calling him.

After KHN contacted SSM Health, Dr. Bhatt received a call from someone who worked on “patient financial experience” issues at the hospital.

The hospital agreed to forgive the $820 facility fee. Dr. Bhatt agreed to pay the remaining $38.92, the professional fee for the ED nurse’s work. Dr. Bhatt also received a notice from Medicredit that it would take no further action against him.

The takeaway: The Bhatts did what most parents would do when a pediatrician advises them to take their child to the hospital.

But EDs are among the most expensive places to get care in the U.S. health system.

If you have a relatively low-level issue, think twice before even registering at the front desk, the act that initiates the billing process. If your doctor doesn’t have same-day appointments or after-hours service, think about urgent care, which is often much cheaper if the center isn’t attached to a hospital.

And remember that if you go to a hospital ED with a relatively minor issue, chances are that you’ll have to wait, as the Bhatts did. Patients with more serious problems will be seen first.

Once you’re taken past the front desk, you will almost certainly be hit with a substantial facility fee even if you don’t receive care.

Appealing that fee to the hospital can occasionally be successful, but there are no guarantees. And, as Dr. Bhatt learned, don’t expect the health insurer to offer much help. Most insurers won’t challenge how a medical visit is coded except on extremely expensive medical claims that will cost them money.

In this case, Dr. Bhatt was on the hook for the whole fee because he had a high-deductible plan, so the insurer had little incentive to take up his cause.

For now, patients’ best hope, many advocates believe, is to publicize the high prices that hospitals charge for their services, inside and outside the ED.

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

Dhaval Bhatt had been warned about hospital emergency departments.

“People always told me to avoid the ER in America unless you are really dying,” said Dr. Bhatt, an immigrant from India who got a PhD in pharmacology in the United States and is now a research scientist at Washington University, St. Louis.

But when Dr. Bhatt’s 2-year-old son burned his hand on the kitchen stove on a Wednesday morning in April, the family’s pediatrician directed them the next day to the local children’s hospital.

Dr. Bhatt was traveling. So, his wife, Mansi Bhatt, took their son to the hospital and was sent to the ED. A nurse practitioner took the toddler’s vitals and looked at the wound. She said a surgeon would inspect it more closely.

When the surgeon didn’t appear after more than an hour, Dr. Bhatt’s wife took her son home. The hospital told her to make a follow-up appointment with a doctor, which turned out to be unnecessary because the burn healed quickly.

Then the bill came.

The patient: Martand Bhatt, a toddler covered by a UnitedHealthcare insurance plan provided by the employer of his father, Dhaval Bhatt.

Medical service: An ED visit for a burn sustained when Martand touched an electric stove.

Total bill: $1,012. UnitedHealthcare’s negotiated rate was $858.92, all of which the Bhatts were responsible for because their plan had a $3,000 deductible.

Service provider: SSM Health Cardinal Glennon Children’s Hospital, one of 23 hospitals owned by SSM Health, a Catholic, nonprofit health system with more than $8 billion in annual revenue.

What gives: Many patients don’t understand that they can rack up huge bills almost as soon as they walk through the doors of an ED.

Unlike a restaurant or a mechanic who won’t charge if someone gets tired of waiting for a table or an inspection of a rattling engine, hospital emergency rooms almost invariably charge patients as soon as they check in.

And once they register, patients will be billed – often a lot – whether treatment was rendered or not.

Martand Bhatt received almost no medical service. A nurse practitioner looked over the toddler, listened to his heart and stomach, and looked in his nose, mouth and ears, according to provider notes prepared by the hospital and shared with KHN by Dr. Bhatt.

The nurse didn’t change the dressing on the wound or order any testing.

“My objection to this is that there was no care provided,” Dr. Bhatt wrote to Bill of the Month.

“My wife did not drive for 45 minutes to get to an ER and wait for an additional 1½ hours for someone to tell me that our child’s vitals – weight, height, temperature and blood pressure – were okay,” Dr. Bhatt continued. “We already knew that. ... It is absolutely ridiculous and unethical.”

When the Bhatts left the ED, Martand was “alert, active and well appearing,” according to the notes.

The nurse’s assessment of Martand cost $192, which was discounted by UnitedHealthcare to a negotiated rate of $38.92. The bulk of the Bhatts’ bill – $820 – was something called a facility fee.

Hospital officials defend these fees as necessary to keep the ED open 24 hours a day as a community asset.

SSM Health spokesperson Stephanie Zoller Mueller declined to discuss the details of Martand’s medical condition even though the Bhatts gave their permission for the hospital to do so.

In an email, Ms. Zoller Mueller said the charges were “appropriate” based on the “acuity of condition, discharge instructions, vital sign monitoring, traumatic wound care, [and] numerous assessments.”

She added: “A patient does not have to receive additional treatment – procedure, labs, x-rays, etc. – to validate an ED-level charge.”

But some patient advocates say these facility fees are applied much too widely and should be limited to patients who actually receive medical care.

“It’s just not appropriate for someone to be charged if they’re not provided treatment,” said Adam Fox, deputy director of the Colorado Consumer Health Initiative. “Patients aren’t availing themselves of a facility if they don’t get care.”

At the very least, hospitals could communicate more clearly to patients about the fees they may be charged for coming to an ED, said Maureen Hensley-Quinn, senior program director at the National Academy for State Health Policy.

“People should know that when they walk in to receive care, there is this fee that they will be assessed,” Ms. Hensley-Quinn said.

Hospitals could also post at the entrance to the ED standard fees for different levels of emergency care.

Dr. Bhatt’s fee still could have been lower if the hospital had classified his son’s injury as minor. But, again, the hospital billing process worked against the family and in favor of the hospital’s bottom line.

Emergency visits are usually classified for billing on a scale from 1 to 5. Level 1 is minor and routine; level 5 requires complex care for life-threatening conditions. And hospitals are increasingly using the highest-severity codes to classify emergency visits, research shows.

“There are financial incentives for billing at a higher severity,” said Aditi Sen, who directs policy and research at the nonprofit Health Care Cost Institute, which has studied ED coding.

Despite the lack of severity of Martand’s wound and the absence of medical care, his visit was classified as level 3, a moderate-severity problem.

Resolution: Incensed that he’d been charged so much, Dr. Bhatt made numerous attempts to get the hospital to reduce the charges. He also appealed to UnitedHealthcare to review the charges.

His efforts failed. In August, Dr. Bhatt received a letter from an SSM Health “patient advocate” informing him that the hospital would not adjust the bill and instructing him to contact patient billing to arrange for payment.

While Dr. Bhatt was trying to reach the patient advocate by phone, his bill was sent to Medicredit, a collection agency, which began sending him notices and calling him.

After KHN contacted SSM Health, Dr. Bhatt received a call from someone who worked on “patient financial experience” issues at the hospital.

The hospital agreed to forgive the $820 facility fee. Dr. Bhatt agreed to pay the remaining $38.92, the professional fee for the ED nurse’s work. Dr. Bhatt also received a notice from Medicredit that it would take no further action against him.

The takeaway: The Bhatts did what most parents would do when a pediatrician advises them to take their child to the hospital.

But EDs are among the most expensive places to get care in the U.S. health system.

If you have a relatively low-level issue, think twice before even registering at the front desk, the act that initiates the billing process. If your doctor doesn’t have same-day appointments or after-hours service, think about urgent care, which is often much cheaper if the center isn’t attached to a hospital.

And remember that if you go to a hospital ED with a relatively minor issue, chances are that you’ll have to wait, as the Bhatts did. Patients with more serious problems will be seen first.

Once you’re taken past the front desk, you will almost certainly be hit with a substantial facility fee even if you don’t receive care.

Appealing that fee to the hospital can occasionally be successful, but there are no guarantees. And, as Dr. Bhatt learned, don’t expect the health insurer to offer much help. Most insurers won’t challenge how a medical visit is coded except on extremely expensive medical claims that will cost them money.

In this case, Dr. Bhatt was on the hook for the whole fee because he had a high-deductible plan, so the insurer had little incentive to take up his cause.

For now, patients’ best hope, many advocates believe, is to publicize the high prices that hospitals charge for their services, inside and outside the ED.

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

Three weekly infusions of the dissociative anesthetic ketamine coupled with mindfulness-based relapse prevention therapy may help adults with alcohol use disorder (AUD) maintain abstinence, new research suggests.

Preliminary results from a phase 2, double-blind, placebo-controlled trial show ketamine was well tolerated and, compared with placebo, associated with more days of abstinence from alcohol at 6 months.

The results suggest ketamine plus psychological therapy may be a “new, relatively brief treatment that has long lasting effects in AUD,” Celia Morgan, PhD, professor of psychopharmacology, University of Exeter, United Kingdom, told this news organization.

The study was published online Jan. 11 in the American Journal of Psychiatry.
 

Target depression

Depressive symptoms are common in patients under treatment for AUD and increase relapse risk.

“Ketamine may support alcohol abstinence by temporarily alleviating depressive symptoms during the high-risk relapse period in the weeks after detoxification,” the investigators note.

Ketamine may also provide a “temporary boost to synaptogenesis and neurogenesis, which may allow psychological therapies and new strategies for managing addiction to embed more readily,” they add.

To test these theories, the researchers recruited 96 adults (mean age, 44 years, 35 women) with severe AUD to participate in the trial.

All participants had to abstain from alcohol for at least 24 hours before the trial started and have a reading of 0.0 on a breath alcohol test at the baseline visit.

Participants were randomly allocated to one of four groups:

1. three weekly ketamine infusions of 0.8 mg/kg IV over 40 minutes plus psychological therapy

2. three saline infusions plus psychological therapy

3. three ketamine infusions plus alcohol education

4. three saline infusions plus alcohol education

The primary outcome was self-reported percentage of days abstinent, as well as confirmed alcohol relapse at 6-month follow-up.

At 6-month follow-up, ketamine was associated with a significantly greater number of days abstinent from alcohol (mean difference, 10.1%; 95% confidence interval, 1.1-19.0), “although confidence intervals were wide, consistent with a proof-of-concept study,” the authors note.

The greatest reduction in total days off alcohol occurred in the ketamine plus relapse-prevention therapy group compared with the saline plus alcohol education group (mean difference, 15.9%; 95% CI, 3.8-28.1).

There was no significant difference in relapse rate between the ketamine and placebo groups. No serious adverse effects were reported in any participant.
 

Growing evidence

These findings support some other studies that have also suggested a benefit of ketamine in AUD.

As reported by this news organization, one recent study found a single infusion of ketamine combined with counseling may help alcohol-dependent patients curb their drinking.

A separate study showed that a single dose of ketamine plus therapy that focused on reactivating drinking-related “maladaptive reward memories” reduced drinking urges and alcohol intake more than just ketamine or a placebo infusion alone.

“That ketamine can reduce both alcohol use and depression in AUD is encouraging therapeutically,” the researchers write.

“While a clear link between depression and AUD is acknowledged, alcohol and mental health services still struggle to meet the needs of dual-diagnosis patients, so ketamine may represent a solution to this long-standing comorbidity,” they add.

Dr. Morgan said in an interview that adjunctive ketamine with relapse-prevention therapy is “currently being delivered in Awakn Clinics in the U.K. and Norway, but we need to conduct the phase 3 trial in order to make the treatment more widely accessible.”
 

An ‘Intriguing new therapy’

Reached for comment, Timothy Brennan, MD, MPH, chief of clinical services, Addiction Institute of Mount Sinai, New York, said ketamine “continues to be an intriguing new therapy for a variety of mental health conditions.”

“Unfortunately, the study did not show any difference in rates of relapse to alcohol, though an improvement in days of abstinence is certainly noteworthy,” Dr. Brennan said in an interview.

“Because this was just a proof-of-concept study and did not compare ketamine to any FDA-approved pharmacotherapy for alcohol, it remains too early to recommend ketamine infusions to those suffering from alcohol use disorder,” he cautioned.

The study was supported by the Medical Research Council. Dr. Morgan has received royalties for KARE (Ketamine for Reduction of Alcoholic Relapse) therapy license distribution. KARE therapy is licensed from University of Exeter to Awakn Life Sciences. Dr. Morgan has received research funding from Awakn Life Sciences and has served as a consultant for Janssen Pharmaceuticals. Other coauthors have disclosed relationships with industry; the full list can be found with the original article. Dr. Brennan has disclosed no relevant financial relationships.

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

Three weekly infusions of the dissociative anesthetic ketamine coupled with mindfulness-based relapse prevention therapy may help adults with alcohol use disorder (AUD) maintain abstinence, new research suggests.

Preliminary results from a phase 2, double-blind, placebo-controlled trial show ketamine was well tolerated and, compared with placebo, associated with more days of abstinence from alcohol at 6 months.

The results suggest ketamine plus psychological therapy may be a “new, relatively brief treatment that has long lasting effects in AUD,” Celia Morgan, PhD, professor of psychopharmacology, University of Exeter, United Kingdom, told this news organization.

The study was published online Jan. 11 in the American Journal of Psychiatry.
 

Target depression

Depressive symptoms are common in patients under treatment for AUD and increase relapse risk.

“Ketamine may support alcohol abstinence by temporarily alleviating depressive symptoms during the high-risk relapse period in the weeks after detoxification,” the investigators note.

Ketamine may also provide a “temporary boost to synaptogenesis and neurogenesis, which may allow psychological therapies and new strategies for managing addiction to embed more readily,” they add.

To test these theories, the researchers recruited 96 adults (mean age, 44 years, 35 women) with severe AUD to participate in the trial.

All participants had to abstain from alcohol for at least 24 hours before the trial started and have a reading of 0.0 on a breath alcohol test at the baseline visit.

Participants were randomly allocated to one of four groups:

1. three weekly ketamine infusions of 0.8 mg/kg IV over 40 minutes plus psychological therapy

2. three saline infusions plus psychological therapy

3. three ketamine infusions plus alcohol education

4. three saline infusions plus alcohol education

The primary outcome was self-reported percentage of days abstinent, as well as confirmed alcohol relapse at 6-month follow-up.

At 6-month follow-up, ketamine was associated with a significantly greater number of days abstinent from alcohol (mean difference, 10.1%; 95% confidence interval, 1.1-19.0), “although confidence intervals were wide, consistent with a proof-of-concept study,” the authors note.

The greatest reduction in total days off alcohol occurred in the ketamine plus relapse-prevention therapy group compared with the saline plus alcohol education group (mean difference, 15.9%; 95% CI, 3.8-28.1).

There was no significant difference in relapse rate between the ketamine and placebo groups. No serious adverse effects were reported in any participant.
 

Growing evidence

These findings support some other studies that have also suggested a benefit of ketamine in AUD.

As reported by this news organization, one recent study found a single infusion of ketamine combined with counseling may help alcohol-dependent patients curb their drinking.

A separate study showed that a single dose of ketamine plus therapy that focused on reactivating drinking-related “maladaptive reward memories” reduced drinking urges and alcohol intake more than just ketamine or a placebo infusion alone.

“That ketamine can reduce both alcohol use and depression in AUD is encouraging therapeutically,” the researchers write.

“While a clear link between depression and AUD is acknowledged, alcohol and mental health services still struggle to meet the needs of dual-diagnosis patients, so ketamine may represent a solution to this long-standing comorbidity,” they add.

Dr. Morgan said in an interview that adjunctive ketamine with relapse-prevention therapy is “currently being delivered in Awakn Clinics in the U.K. and Norway, but we need to conduct the phase 3 trial in order to make the treatment more widely accessible.”
 

An ‘Intriguing new therapy’

Reached for comment, Timothy Brennan, MD, MPH, chief of clinical services, Addiction Institute of Mount Sinai, New York, said ketamine “continues to be an intriguing new therapy for a variety of mental health conditions.”

“Unfortunately, the study did not show any difference in rates of relapse to alcohol, though an improvement in days of abstinence is certainly noteworthy,” Dr. Brennan said in an interview.

“Because this was just a proof-of-concept study and did not compare ketamine to any FDA-approved pharmacotherapy for alcohol, it remains too early to recommend ketamine infusions to those suffering from alcohol use disorder,” he cautioned.

The study was supported by the Medical Research Council. Dr. Morgan has received royalties for KARE (Ketamine for Reduction of Alcoholic Relapse) therapy license distribution. KARE therapy is licensed from University of Exeter to Awakn Life Sciences. Dr. Morgan has received research funding from Awakn Life Sciences and has served as a consultant for Janssen Pharmaceuticals. Other coauthors have disclosed relationships with industry; the full list can be found with the original article. Dr. Brennan has disclosed no relevant financial relationships.

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

Three weekly infusions of the dissociative anesthetic ketamine coupled with mindfulness-based relapse prevention therapy may help adults with alcohol use disorder (AUD) maintain abstinence, new research suggests.

Preliminary results from a phase 2, double-blind, placebo-controlled trial show ketamine was well tolerated and, compared with placebo, associated with more days of abstinence from alcohol at 6 months.

The results suggest ketamine plus psychological therapy may be a “new, relatively brief treatment that has long lasting effects in AUD,” Celia Morgan, PhD, professor of psychopharmacology, University of Exeter, United Kingdom, told this news organization.

The study was published online Jan. 11 in the American Journal of Psychiatry.
 

Target depression

Depressive symptoms are common in patients under treatment for AUD and increase relapse risk.

“Ketamine may support alcohol abstinence by temporarily alleviating depressive symptoms during the high-risk relapse period in the weeks after detoxification,” the investigators note.

Ketamine may also provide a “temporary boost to synaptogenesis and neurogenesis, which may allow psychological therapies and new strategies for managing addiction to embed more readily,” they add.

To test these theories, the researchers recruited 96 adults (mean age, 44 years, 35 women) with severe AUD to participate in the trial.

All participants had to abstain from alcohol for at least 24 hours before the trial started and have a reading of 0.0 on a breath alcohol test at the baseline visit.

Participants were randomly allocated to one of four groups:

1. three weekly ketamine infusions of 0.8 mg/kg IV over 40 minutes plus psychological therapy

2. three saline infusions plus psychological therapy

3. three ketamine infusions plus alcohol education

4. three saline infusions plus alcohol education

The primary outcome was self-reported percentage of days abstinent, as well as confirmed alcohol relapse at 6-month follow-up.

At 6-month follow-up, ketamine was associated with a significantly greater number of days abstinent from alcohol (mean difference, 10.1%; 95% confidence interval, 1.1-19.0), “although confidence intervals were wide, consistent with a proof-of-concept study,” the authors note.

The greatest reduction in total days off alcohol occurred in the ketamine plus relapse-prevention therapy group compared with the saline plus alcohol education group (mean difference, 15.9%; 95% CI, 3.8-28.1).

There was no significant difference in relapse rate between the ketamine and placebo groups. No serious adverse effects were reported in any participant.
 

Growing evidence

These findings support some other studies that have also suggested a benefit of ketamine in AUD.

As reported by this news organization, one recent study found a single infusion of ketamine combined with counseling may help alcohol-dependent patients curb their drinking.

A separate study showed that a single dose of ketamine plus therapy that focused on reactivating drinking-related “maladaptive reward memories” reduced drinking urges and alcohol intake more than just ketamine or a placebo infusion alone.

“That ketamine can reduce both alcohol use and depression in AUD is encouraging therapeutically,” the researchers write.

“While a clear link between depression and AUD is acknowledged, alcohol and mental health services still struggle to meet the needs of dual-diagnosis patients, so ketamine may represent a solution to this long-standing comorbidity,” they add.

Dr. Morgan said in an interview that adjunctive ketamine with relapse-prevention therapy is “currently being delivered in Awakn Clinics in the U.K. and Norway, but we need to conduct the phase 3 trial in order to make the treatment more widely accessible.”
 

An ‘Intriguing new therapy’

Reached for comment, Timothy Brennan, MD, MPH, chief of clinical services, Addiction Institute of Mount Sinai, New York, said ketamine “continues to be an intriguing new therapy for a variety of mental health conditions.”

“Unfortunately, the study did not show any difference in rates of relapse to alcohol, though an improvement in days of abstinence is certainly noteworthy,” Dr. Brennan said in an interview.

“Because this was just a proof-of-concept study and did not compare ketamine to any FDA-approved pharmacotherapy for alcohol, it remains too early to recommend ketamine infusions to those suffering from alcohol use disorder,” he cautioned.

The study was supported by the Medical Research Council. Dr. Morgan has received royalties for KARE (Ketamine for Reduction of Alcoholic Relapse) therapy license distribution. KARE therapy is licensed from University of Exeter to Awakn Life Sciences. Dr. Morgan has received research funding from Awakn Life Sciences and has served as a consultant for Janssen Pharmaceuticals. Other coauthors have disclosed relationships with industry; the full list can be found with the original article. Dr. Brennan has disclosed no relevant financial relationships.

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

Some details have been changed to protect the patient’s identity.

The first thing I noticed about Mr. Barry as I entered the intensive care unit was his left foot: Half of it was black, shriveled, and gangrenous, jutting out from under the white blanket. The soft rays of the morning sun illuminated his gaunt, unshaven, hollow cheeks. Sedated on propofol, with a green endotracheal tube sticking out of his chapped lips, he looked frail. His nurse, Becky, had just cleaned him after he passed tarry, maroon-colored stool. As she turned him over, I saw that the skin over his tailbone was broken. He had a large decubitus ulcer, the edges of which were now dried and black. The Foley bag, hanging next to his bed, was empty; there had been no urine for several hours now.

No one knew much about Mr. Barry. I don’t mean his current medical status – I mean what he did in life, who he loved, whether he had kids, what he valued. All we knew was that he was 83 years old and lived alone. No prior records in our system. No advanced directives. No information on any family. One of his neighbors called 911 after he was not seen for at least 10 days. Emergency medical services found Mr. Barry in bed, nearly lifeless. In the emergency room, he was noted to be in shock, with a dangerously low blood pressure. He was dry as a bone with markedly elevated sodium levels. His laboratory makers for kidney and liver function were deranged. He was admitted to the medical ICU with a diagnosis of hypovolemic shock and/or septic shock with multiorgan dysfunction. With 48 hours of supportive management with intravenous fluids and antibiotics, he did not improve. Blood cultures were positive for gram-positive cocci. The doses for medications used to maintain the blood pressure increased steadily. He also developed gastrointestinal bleeding.
 

Futile vs. potentially inappropriate

I was called for a cardiology consult because he had transient ST elevation in inferolateral leads on the monitor. Given his clinical scenario, the likelihood of type 1 myocardial infarction from plaque rupture was low; the ST elevations were probably related to vasospasm from increasing pressor requirement. Diagnostic cardiac catheterization showed clean coronary arteries. Continuous renal replacement therapy was soon started. Given Mr Barry’s multiorgan dysfunction and extremely poor prognosis, I recommended making all efforts to find his family or surrogate decision-maker to discuss goals of care or having a two-physician sign-off to place a DNR order.

Despite all efforts, we could not trace the family. We physicians vary individually on how we define value as related to life. We also vary on the degree of uncertainty about prognostication that we are comfortable with. This is one of the reasons the term “futility” is controversial and there is a push to use “potentially inappropriate” instead. The primary team had a different threshold for placing a DNR order and did not do it. That night, after I left the hospital, Mr Barry had a PEA (pulseless electrical activity) arrest and was resuscitated after 10 minutes of CPR. The next day, I noticed his bruised chest. He was on multiple medications to support his blood pressure.
 

My patient and a Hemingway protagonist

Whether by coincidence or irony, I started reading Ernest Hemingway’s short story “The Snows of Kilimanjaro” the same day that I met Mr. Barry. He reminded me of the story’s protagonist, Harry, lying on the cot with a gangrenous leg, waiting to die. Harry could sense death approaching. He reminisced about his past. All he wanted was to drink his “whiskey-soda.” “Darling, don’t drink that. We have to do everything we can,” his wife said. “You do it. I am tired,” Harry said, and continued to drink his whiskey-soda.

Mr. Barry looked tired. Tired of life? I can’t say with certainty. However, if I had to guess, the medical team’s heroics meant nothing to him. Unfortunately, he was not awake like Harry and could not do what he wished. I wondered what snippets of his life flashed before him as he lay on his bed at home for days. Did he want to have a whiskey-soda before dying? But we are not letting him die. Not easily anyway. We have to do everything we can: medications, coronary angiogram, dialysis, multiple rounds of CPR. Why?

In this country, we need permission to forgo CPR. If there are no advanced directives or next of kin available to discuss end-of-life care, performing CPR is the default status for all hospitalized patients, irrespective of the underlying severity of the illness. A unilateral DNR order written by a physician in good conscience (in a medically futile situation), but to which the patient has not consented, is generally invalid in most U.S. states. If health directives are not available, CPR will be administered on the presumption that the patient would want us to “do everything we can.” The medicolegal consequences and fear of not administering CPR is more profound than being found wrong and defying a patient’s wishes against CPR.

In patients with outside-hospital cardiac arrest, especially if related to ventricular fibrillation, early bystander CPR improves the survival rate. Hence, it makes sense for first responders and paramedics to administer CPR as the default option, focusing on the technique, rather than thinking about its utility based on the patient’s underlying comorbidities.

In the inpatient setting, however, physicians have enough information to comprehensively evaluate the patient. In a cohort of 5,690 critically ill ICU patients, obtained from a U.S. registry, the rate of survival to discharge after inpatient cardiac arrest is very low at 12.5%. Chronic health conditions, malignancy, end-stage renal disease, multiorgan dysfunction, need for vasopressor support, prior CPR, initial rhythm of asystole, or PEA advanced age were all associated with a less than 10% survival rate after CPR.

Dying is a process. Administering CPR to a dying patient is of little to no value. For Mr. Barry, it resulted in a bruised chest and broken ribs. James R. Jude, MD, one of the pioneers of closed chest compression, or modern-day CPR, wrote in 1965 that “resuscitation of the dying patient with irreparable damage to lungs, heart, kidneys, brain or any other vital system of the body has no medical, ethical, or moral justification. The techniques described in this monograph were designed to resuscitate the victim of acute insult, whether be it from drowning, electrical shock, untoward effect of drugs, anesthetic accident, heart block, acute myocardial infarction, or surgery.”

Yet, doctors continue to provide futile treatments at end of life for a variety of reasons: concerns about medico-legal risks, discomfort or inexperience with death and dying, uncertainty in prognostication, family requests, and organizational barriers such as lack of palliative services that can help lead end-of-life care discussions. Despite knowing that CPR has little benefit in critically ill patients with terminal illness and multiorgan dysfunction, we often ask the patient and their surrogate decision-makers: “If your heart stops, do you want us to restore your heart by pressing on the chest and giving electric shocks?” The very act of asking the question implies that CPR may be beneficial. We often do not go over the risks or offer an opinion on whether CPR should be performed. We take a neutral stance.

Anoxic brain injury, pain from broken ribs, and low likelihood of survival to discharge with acceptable neurologic recovery are rarely discussed in detail. Laypeople may overestimate the chances of survival after CPR and they may not comprehend that it does not reverse the dying process in patients with a terminal illness. When you ask about CPR, most families hear: “Do you want your loved one to live?” and the answer is nearly always “Yes.” We then administer CPR, thinking that we are respecting the patient’s autonomy in the medical decision-making process. However, in end-of-life care, elderly patients or surrogates may not fully understand the complexities involved or the outcomes of CPR. So, are we truly respecting their autonomy?
 

When to offer CPR?

In 2011, Billings and Krakauer, palliative care specialists from Massachusetts General Hospital, Boston, suggested that we focus on understanding our patient’s values and goals of care, and then decide whether to offer CPR, rather than taking a neutral stance. With this approach, we continue to respect the patient’s autonomy and also affirm our responsibility in providing care consistent with medical reality. We need to have the humility to accept that death is inevitable. Taking care of the dying to ensure a peaceful and dignified death is as much our moral and ethical responsibility as respecting a patient’s autonomy.

It has been 10 years since a group of physicians from Columbia University Medical Center, Harvard Medical School, MGH, and Boston Children’s Hospital proposed changes to how we determine resuscitation status. Instead of assuming that CPR is always wanted, they suggested three distinct approaches: consider CPR when the benefits versus risks are uncertain, and the patient is not end stage; recommend against CPR when there is a low likelihood of benefit and high likelihood of harm (e.g., patients with anoxic brain injury, advanced incurable cancer, or end-stage multiorgan dysfunction); and do not offer CPR to patients who will die imminently and have no chance of surviving CPR (e.g., patients with multiorgan dysfunction, increasing pressor requirements, and those who are actively dying without a single immediately reversible cause). I agree with their proposal.

Mr. Barry was actively dying. Unfortunately, we had neither his advanced directives nor access to family members or surrogates to discuss values and goals of care. Given the futility of administering CPR again, and based on our humanitarian principles, a moral and ethical responsibility to ensure a peaceful dying process, I and another ICU attending placed the DNR order. He passed away, peacefully, within a few hours.

That evening, as I was sitting on my porch reading the last page of “The Snows of Kilimanjaro,” my phone pinged. It was an email asking me to complete the final attestation for the death certificate. I imagined that Mr. Barry knew where he was going. He probably had his own special place – something beautiful and majestic, great and tall, dazzlingly white in the hot sun, like the snow-capped mountain of Kilimanjaro that Harry saw at the time of his death.

Dr. Mallidi is a general cardiologist at Zuckerberg San Francisco General Hospital, UCSF. He disclosed no relevant financial relationships.

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

Some details have been changed to protect the patient’s identity.

The first thing I noticed about Mr. Barry as I entered the intensive care unit was his left foot: Half of it was black, shriveled, and gangrenous, jutting out from under the white blanket. The soft rays of the morning sun illuminated his gaunt, unshaven, hollow cheeks. Sedated on propofol, with a green endotracheal tube sticking out of his chapped lips, he looked frail. His nurse, Becky, had just cleaned him after he passed tarry, maroon-colored stool. As she turned him over, I saw that the skin over his tailbone was broken. He had a large decubitus ulcer, the edges of which were now dried and black. The Foley bag, hanging next to his bed, was empty; there had been no urine for several hours now.

No one knew much about Mr. Barry. I don’t mean his current medical status – I mean what he did in life, who he loved, whether he had kids, what he valued. All we knew was that he was 83 years old and lived alone. No prior records in our system. No advanced directives. No information on any family. One of his neighbors called 911 after he was not seen for at least 10 days. Emergency medical services found Mr. Barry in bed, nearly lifeless. In the emergency room, he was noted to be in shock, with a dangerously low blood pressure. He was dry as a bone with markedly elevated sodium levels. His laboratory makers for kidney and liver function were deranged. He was admitted to the medical ICU with a diagnosis of hypovolemic shock and/or septic shock with multiorgan dysfunction. With 48 hours of supportive management with intravenous fluids and antibiotics, he did not improve. Blood cultures were positive for gram-positive cocci. The doses for medications used to maintain the blood pressure increased steadily. He also developed gastrointestinal bleeding.
 

Futile vs. potentially inappropriate

I was called for a cardiology consult because he had transient ST elevation in inferolateral leads on the monitor. Given his clinical scenario, the likelihood of type 1 myocardial infarction from plaque rupture was low; the ST elevations were probably related to vasospasm from increasing pressor requirement. Diagnostic cardiac catheterization showed clean coronary arteries. Continuous renal replacement therapy was soon started. Given Mr Barry’s multiorgan dysfunction and extremely poor prognosis, I recommended making all efforts to find his family or surrogate decision-maker to discuss goals of care or having a two-physician sign-off to place a DNR order.

Despite all efforts, we could not trace the family. We physicians vary individually on how we define value as related to life. We also vary on the degree of uncertainty about prognostication that we are comfortable with. This is one of the reasons the term “futility” is controversial and there is a push to use “potentially inappropriate” instead. The primary team had a different threshold for placing a DNR order and did not do it. That night, after I left the hospital, Mr Barry had a PEA (pulseless electrical activity) arrest and was resuscitated after 10 minutes of CPR. The next day, I noticed his bruised chest. He was on multiple medications to support his blood pressure.
 

My patient and a Hemingway protagonist

Whether by coincidence or irony, I started reading Ernest Hemingway’s short story “The Snows of Kilimanjaro” the same day that I met Mr. Barry. He reminded me of the story’s protagonist, Harry, lying on the cot with a gangrenous leg, waiting to die. Harry could sense death approaching. He reminisced about his past. All he wanted was to drink his “whiskey-soda.” “Darling, don’t drink that. We have to do everything we can,” his wife said. “You do it. I am tired,” Harry said, and continued to drink his whiskey-soda.

Mr. Barry looked tired. Tired of life? I can’t say with certainty. However, if I had to guess, the medical team’s heroics meant nothing to him. Unfortunately, he was not awake like Harry and could not do what he wished. I wondered what snippets of his life flashed before him as he lay on his bed at home for days. Did he want to have a whiskey-soda before dying? But we are not letting him die. Not easily anyway. We have to do everything we can: medications, coronary angiogram, dialysis, multiple rounds of CPR. Why?

In this country, we need permission to forgo CPR. If there are no advanced directives or next of kin available to discuss end-of-life care, performing CPR is the default status for all hospitalized patients, irrespective of the underlying severity of the illness. A unilateral DNR order written by a physician in good conscience (in a medically futile situation), but to which the patient has not consented, is generally invalid in most U.S. states. If health directives are not available, CPR will be administered on the presumption that the patient would want us to “do everything we can.” The medicolegal consequences and fear of not administering CPR is more profound than being found wrong and defying a patient’s wishes against CPR.

In patients with outside-hospital cardiac arrest, especially if related to ventricular fibrillation, early bystander CPR improves the survival rate. Hence, it makes sense for first responders and paramedics to administer CPR as the default option, focusing on the technique, rather than thinking about its utility based on the patient’s underlying comorbidities.

In the inpatient setting, however, physicians have enough information to comprehensively evaluate the patient. In a cohort of 5,690 critically ill ICU patients, obtained from a U.S. registry, the rate of survival to discharge after inpatient cardiac arrest is very low at 12.5%. Chronic health conditions, malignancy, end-stage renal disease, multiorgan dysfunction, need for vasopressor support, prior CPR, initial rhythm of asystole, or PEA advanced age were all associated with a less than 10% survival rate after CPR.

Dying is a process. Administering CPR to a dying patient is of little to no value. For Mr. Barry, it resulted in a bruised chest and broken ribs. James R. Jude, MD, one of the pioneers of closed chest compression, or modern-day CPR, wrote in 1965 that “resuscitation of the dying patient with irreparable damage to lungs, heart, kidneys, brain or any other vital system of the body has no medical, ethical, or moral justification. The techniques described in this monograph were designed to resuscitate the victim of acute insult, whether be it from drowning, electrical shock, untoward effect of drugs, anesthetic accident, heart block, acute myocardial infarction, or surgery.”

Yet, doctors continue to provide futile treatments at end of life for a variety of reasons: concerns about medico-legal risks, discomfort or inexperience with death and dying, uncertainty in prognostication, family requests, and organizational barriers such as lack of palliative services that can help lead end-of-life care discussions. Despite knowing that CPR has little benefit in critically ill patients with terminal illness and multiorgan dysfunction, we often ask the patient and their surrogate decision-makers: “If your heart stops, do you want us to restore your heart by pressing on the chest and giving electric shocks?” The very act of asking the question implies that CPR may be beneficial. We often do not go over the risks or offer an opinion on whether CPR should be performed. We take a neutral stance.

Anoxic brain injury, pain from broken ribs, and low likelihood of survival to discharge with acceptable neurologic recovery are rarely discussed in detail. Laypeople may overestimate the chances of survival after CPR and they may not comprehend that it does not reverse the dying process in patients with a terminal illness. When you ask about CPR, most families hear: “Do you want your loved one to live?” and the answer is nearly always “Yes.” We then administer CPR, thinking that we are respecting the patient’s autonomy in the medical decision-making process. However, in end-of-life care, elderly patients or surrogates may not fully understand the complexities involved or the outcomes of CPR. So, are we truly respecting their autonomy?
 

When to offer CPR?

In 2011, Billings and Krakauer, palliative care specialists from Massachusetts General Hospital, Boston, suggested that we focus on understanding our patient’s values and goals of care, and then decide whether to offer CPR, rather than taking a neutral stance. With this approach, we continue to respect the patient’s autonomy and also affirm our responsibility in providing care consistent with medical reality. We need to have the humility to accept that death is inevitable. Taking care of the dying to ensure a peaceful and dignified death is as much our moral and ethical responsibility as respecting a patient’s autonomy.

It has been 10 years since a group of physicians from Columbia University Medical Center, Harvard Medical School, MGH, and Boston Children’s Hospital proposed changes to how we determine resuscitation status. Instead of assuming that CPR is always wanted, they suggested three distinct approaches: consider CPR when the benefits versus risks are uncertain, and the patient is not end stage; recommend against CPR when there is a low likelihood of benefit and high likelihood of harm (e.g., patients with anoxic brain injury, advanced incurable cancer, or end-stage multiorgan dysfunction); and do not offer CPR to patients who will die imminently and have no chance of surviving CPR (e.g., patients with multiorgan dysfunction, increasing pressor requirements, and those who are actively dying without a single immediately reversible cause). I agree with their proposal.

Mr. Barry was actively dying. Unfortunately, we had neither his advanced directives nor access to family members or surrogates to discuss values and goals of care. Given the futility of administering CPR again, and based on our humanitarian principles, a moral and ethical responsibility to ensure a peaceful dying process, I and another ICU attending placed the DNR order. He passed away, peacefully, within a few hours.

That evening, as I was sitting on my porch reading the last page of “The Snows of Kilimanjaro,” my phone pinged. It was an email asking me to complete the final attestation for the death certificate. I imagined that Mr. Barry knew where he was going. He probably had his own special place – something beautiful and majestic, great and tall, dazzlingly white in the hot sun, like the snow-capped mountain of Kilimanjaro that Harry saw at the time of his death.

Dr. Mallidi is a general cardiologist at Zuckerberg San Francisco General Hospital, UCSF. He disclosed no relevant financial relationships.

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

Some details have been changed to protect the patient’s identity.

The first thing I noticed about Mr. Barry as I entered the intensive care unit was his left foot: Half of it was black, shriveled, and gangrenous, jutting out from under the white blanket. The soft rays of the morning sun illuminated his gaunt, unshaven, hollow cheeks. Sedated on propofol, with a green endotracheal tube sticking out of his chapped lips, he looked frail. His nurse, Becky, had just cleaned him after he passed tarry, maroon-colored stool. As she turned him over, I saw that the skin over his tailbone was broken. He had a large decubitus ulcer, the edges of which were now dried and black. The Foley bag, hanging next to his bed, was empty; there had been no urine for several hours now.

No one knew much about Mr. Barry. I don’t mean his current medical status – I mean what he did in life, who he loved, whether he had kids, what he valued. All we knew was that he was 83 years old and lived alone. No prior records in our system. No advanced directives. No information on any family. One of his neighbors called 911 after he was not seen for at least 10 days. Emergency medical services found Mr. Barry in bed, nearly lifeless. In the emergency room, he was noted to be in shock, with a dangerously low blood pressure. He was dry as a bone with markedly elevated sodium levels. His laboratory makers for kidney and liver function were deranged. He was admitted to the medical ICU with a diagnosis of hypovolemic shock and/or septic shock with multiorgan dysfunction. With 48 hours of supportive management with intravenous fluids and antibiotics, he did not improve. Blood cultures were positive for gram-positive cocci. The doses for medications used to maintain the blood pressure increased steadily. He also developed gastrointestinal bleeding.
 

Futile vs. potentially inappropriate

I was called for a cardiology consult because he had transient ST elevation in inferolateral leads on the monitor. Given his clinical scenario, the likelihood of type 1 myocardial infarction from plaque rupture was low; the ST elevations were probably related to vasospasm from increasing pressor requirement. Diagnostic cardiac catheterization showed clean coronary arteries. Continuous renal replacement therapy was soon started. Given Mr Barry’s multiorgan dysfunction and extremely poor prognosis, I recommended making all efforts to find his family or surrogate decision-maker to discuss goals of care or having a two-physician sign-off to place a DNR order.

Despite all efforts, we could not trace the family. We physicians vary individually on how we define value as related to life. We also vary on the degree of uncertainty about prognostication that we are comfortable with. This is one of the reasons the term “futility” is controversial and there is a push to use “potentially inappropriate” instead. The primary team had a different threshold for placing a DNR order and did not do it. That night, after I left the hospital, Mr Barry had a PEA (pulseless electrical activity) arrest and was resuscitated after 10 minutes of CPR. The next day, I noticed his bruised chest. He was on multiple medications to support his blood pressure.
 

My patient and a Hemingway protagonist

Whether by coincidence or irony, I started reading Ernest Hemingway’s short story “The Snows of Kilimanjaro” the same day that I met Mr. Barry. He reminded me of the story’s protagonist, Harry, lying on the cot with a gangrenous leg, waiting to die. Harry could sense death approaching. He reminisced about his past. All he wanted was to drink his “whiskey-soda.” “Darling, don’t drink that. We have to do everything we can,” his wife said. “You do it. I am tired,” Harry said, and continued to drink his whiskey-soda.

Mr. Barry looked tired. Tired of life? I can’t say with certainty. However, if I had to guess, the medical team’s heroics meant nothing to him. Unfortunately, he was not awake like Harry and could not do what he wished. I wondered what snippets of his life flashed before him as he lay on his bed at home for days. Did he want to have a whiskey-soda before dying? But we are not letting him die. Not easily anyway. We have to do everything we can: medications, coronary angiogram, dialysis, multiple rounds of CPR. Why?

In this country, we need permission to forgo CPR. If there are no advanced directives or next of kin available to discuss end-of-life care, performing CPR is the default status for all hospitalized patients, irrespective of the underlying severity of the illness. A unilateral DNR order written by a physician in good conscience (in a medically futile situation), but to which the patient has not consented, is generally invalid in most U.S. states. If health directives are not available, CPR will be administered on the presumption that the patient would want us to “do everything we can.” The medicolegal consequences and fear of not administering CPR is more profound than being found wrong and defying a patient’s wishes against CPR.

In patients with outside-hospital cardiac arrest, especially if related to ventricular fibrillation, early bystander CPR improves the survival rate. Hence, it makes sense for first responders and paramedics to administer CPR as the default option, focusing on the technique, rather than thinking about its utility based on the patient’s underlying comorbidities.

In the inpatient setting, however, physicians have enough information to comprehensively evaluate the patient. In a cohort of 5,690 critically ill ICU patients, obtained from a U.S. registry, the rate of survival to discharge after inpatient cardiac arrest is very low at 12.5%. Chronic health conditions, malignancy, end-stage renal disease, multiorgan dysfunction, need for vasopressor support, prior CPR, initial rhythm of asystole, or PEA advanced age were all associated with a less than 10% survival rate after CPR.

Dying is a process. Administering CPR to a dying patient is of little to no value. For Mr. Barry, it resulted in a bruised chest and broken ribs. James R. Jude, MD, one of the pioneers of closed chest compression, or modern-day CPR, wrote in 1965 that “resuscitation of the dying patient with irreparable damage to lungs, heart, kidneys, brain or any other vital system of the body has no medical, ethical, or moral justification. The techniques described in this monograph were designed to resuscitate the victim of acute insult, whether be it from drowning, electrical shock, untoward effect of drugs, anesthetic accident, heart block, acute myocardial infarction, or surgery.”

Yet, doctors continue to provide futile treatments at end of life for a variety of reasons: concerns about medico-legal risks, discomfort or inexperience with death and dying, uncertainty in prognostication, family requests, and organizational barriers such as lack of palliative services that can help lead end-of-life care discussions. Despite knowing that CPR has little benefit in critically ill patients with terminal illness and multiorgan dysfunction, we often ask the patient and their surrogate decision-makers: “If your heart stops, do you want us to restore your heart by pressing on the chest and giving electric shocks?” The very act of asking the question implies that CPR may be beneficial. We often do not go over the risks or offer an opinion on whether CPR should be performed. We take a neutral stance.

Anoxic brain injury, pain from broken ribs, and low likelihood of survival to discharge with acceptable neurologic recovery are rarely discussed in detail. Laypeople may overestimate the chances of survival after CPR and they may not comprehend that it does not reverse the dying process in patients with a terminal illness. When you ask about CPR, most families hear: “Do you want your loved one to live?” and the answer is nearly always “Yes.” We then administer CPR, thinking that we are respecting the patient’s autonomy in the medical decision-making process. However, in end-of-life care, elderly patients or surrogates may not fully understand the complexities involved or the outcomes of CPR. So, are we truly respecting their autonomy?
 

When to offer CPR?

In 2011, Billings and Krakauer, palliative care specialists from Massachusetts General Hospital, Boston, suggested that we focus on understanding our patient’s values and goals of care, and then decide whether to offer CPR, rather than taking a neutral stance. With this approach, we continue to respect the patient’s autonomy and also affirm our responsibility in providing care consistent with medical reality. We need to have the humility to accept that death is inevitable. Taking care of the dying to ensure a peaceful and dignified death is as much our moral and ethical responsibility as respecting a patient’s autonomy.

It has been 10 years since a group of physicians from Columbia University Medical Center, Harvard Medical School, MGH, and Boston Children’s Hospital proposed changes to how we determine resuscitation status. Instead of assuming that CPR is always wanted, they suggested three distinct approaches: consider CPR when the benefits versus risks are uncertain, and the patient is not end stage; recommend against CPR when there is a low likelihood of benefit and high likelihood of harm (e.g., patients with anoxic brain injury, advanced incurable cancer, or end-stage multiorgan dysfunction); and do not offer CPR to patients who will die imminently and have no chance of surviving CPR (e.g., patients with multiorgan dysfunction, increasing pressor requirements, and those who are actively dying without a single immediately reversible cause). I agree with their proposal.

Mr. Barry was actively dying. Unfortunately, we had neither his advanced directives nor access to family members or surrogates to discuss values and goals of care. Given the futility of administering CPR again, and based on our humanitarian principles, a moral and ethical responsibility to ensure a peaceful dying process, I and another ICU attending placed the DNR order. He passed away, peacefully, within a few hours.

That evening, as I was sitting on my porch reading the last page of “The Snows of Kilimanjaro,” my phone pinged. It was an email asking me to complete the final attestation for the death certificate. I imagined that Mr. Barry knew where he was going. He probably had his own special place – something beautiful and majestic, great and tall, dazzlingly white in the hot sun, like the snow-capped mountain of Kilimanjaro that Harry saw at the time of his death.

Dr. Mallidi is a general cardiologist at Zuckerberg San Francisco General Hospital, UCSF. He disclosed no relevant financial relationships.

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

The goal of advanced ovarian cancer surgery is to remove all gross disease, or all visible and palpable disease implants. This became the established standard when improved survival was consistently observed among patients who had undergone complete surgical resection. Traditionally, definitions of no gross residual disease have been left in the hands, and eyes, of the surgeon. However, new technology has emerged which affords surgeons the ability to visualize ovarian cancer deposits that are imperceptible to the naked eye. But will this improve upon the poor cure rates for advanced ovarian cancer?

Many are familiar with the traditional definitions of “optimal” (less than 1 cm–sized deposits at any one location) and “suboptimal” (greater than 1 cm–sized deposits remaining) when referring to surgical cytoreduction of ovarian cancer. This nomenclature was introduced to define, categorize, and prognosticate patient groups after surgery. In recent years we have moved away from these descriptive definitions of ovarian cancer resection, borrowing from surgical oncology measures of surgical outcomes where “R0” defines surgical resection with negative margins, “R1” includes resection with positive microscopic margins (negative for tumor intraoperatively, but positive on microscopic pathology), and “R2” refers to macroscopic residual disease remaining.¹

In ovarian cancer, surgeons have adopted the expression R0 to include patients in whom there is no gross visible or palpable residual disease, a special, favorable subgrouping of the previous “optimal” group. R1 is applied to patients with macroscopic, residual disease that fits within the traditional “optimal” cytoreduction classification (<1 cm in any one location). Obviously, these are significant variations to the traditional surgical oncology definitions, but not without supporting data. For example, patients with no gross residual disease (now defined as “R0”) have been observed to have improved survival, compared with patients who are “optimally” debulked but with R1 (<1 cm) residual disease.² Therefore, this new goal of complete surgical resection has replaced the previous standard of “optimal” cytoreduction in which small macroscopic residual disease was acceptable.

Whether or not a surgery is completed with no gross residual disease is a subjective assessment made by the surgeon, and in practice, highly inaccurate. When a posttrial ad hoc analysis of 1,873 patients with advanced ovarian cancer who had been enrolled in a Gynecologic Oncology Group cooperative trial correlated surgeons’ assessments of “optimal” cytoreduction with objective postoperative radiographic findings (performed, on average, less than 1 month postoperatively) they found that postoperative CT scans identified lesions >1 cm in 40% of cases that had been characterized by surgeons as an “optimal” cytoreduction.³ Most commonly, discrepant lesions were identified in the upper abdominal quadrants and retroperitoneal aortic nodal regions. Therefore, surgeons’ subjective assessment of cytoreduction is prone to error, and given how important the completeness of cytoreduction is for clinical outcomes, there is interest in discovering methods to improve upon surgeons’ ability to discriminate volume of disease.

Pafolacianine (Cytalux, On Target Laboratories) is a novel drug that binds a fluorescent molecule to folic acid targeting the folate alpha receptors which are overexpressed on nonmucinous epithelial ovarian cancer cells compared with adjacent nonmalignant tissues.⁴ The drug is intravenously infused preoperatively and then visualized with companion near-infrared imaging devices during surgery to visualize its fluorescent signal where it is bound to ovarian cancer implants. In a phase 2 study of 178 patients with confirmed or suspected ovarian cancer, pafolacianine was able to detect implants of ovarian cancer in 26.9% of cases where the surgeon’s visual inspection was negative.⁵ Of note, the false-positive rate of this drug was not trivial, at 20%. Based on this efficacy data, the drug has been granted FDA approved for use in ovarian cancer surgery to augment the surgeon’s visualization of cancer. However, important questions remain unanswered by these preliminary data.

Will removal of additional microscopic ovarian cancer implants, only seen by pafolacianine, improve the survival of patients with ovarian cancer, and what effect will the addition of this extra surgery have on their surgical morbidity and risk? The use of pafolacianine to augment ovarian cancer debulking surgeries pivots on the premise that ovarian cancer outcomes are determined by surgical “effort” more than the biology of the disease. Otherwise said: The more we surgically remove, the more we cure. But this seems an old-fashioned notion, increasingly challenged by data. It has been shown that, when ovarian cancer debulking surgeries are necessarily more radical because of extensive disease distribution, prognosis is worse, compared with those patients with less extensive disease distribution.⁶ The effect of surgical effort contributes less than that of predetermined patterns of disease presentation. Additionally, genomic traits are different in tumors that are objectively determined to be not amenable to optimal cytoreduction, compared with resectable tumors.⁷ These data suggest that it is the disease, more than the surgeon, that most influences outcomes.

Additionally, the question of whether surgical removal of microscopic disease improves ovarian cancer survival has already been addressed with negative findings. The LION trial randomized 647 women with advanced ovarian cancer to primary cytoreductive surgery either with or without routine lymphadenectomy of clinically negative nodes.⁸ This study found no survival benefit to resecting clinically negative, microscopically positive nodes. In light of these data, it is difficult to imagine that there would be different results with the resection of microscopic peritoneal disease implants identified by pafolacianine.

While pafolacianine promises to move us closer to a true “R0” (negative margins) resection of ovarian cancer, is this even a feasible goal in a disease that is widely metastatic, particularly in the peritoneal cavity? What do “negative margins” mean in the peritoneal cavity? The sensitivity of pafolacianine in detecting microscopic disease is obviously not so high that it can guarantee patients a complete resection of a disseminated disease, and we still do not know what absolute benefit is derived from moving a little bit further on the continuum of surgical resection.

Perhaps augmentation of debulking is not the only, or best, use of pafolacianine for ovarian cancer surgery. Perhaps it might serve a role in diagnostics or staging of the disease rather than for a therapeutic purpose. In the meantime, we await ongoing clinical trials in this space to better inform clinicians what benefits, or harms, they might expect from the addition of this new drug as we continue to define the “optimal” surgical procedure for advanced ovarian cancer.

Dr. Emma Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.

References

1. Hermanek P, Wittekind C. Semin Surg Oncol 1994;10:12-20.

2. Elattar A et al. Cochrane Database Syst Rev 2011 Aug 10;2011(8):CD007565.

3. Eskander RN et al. Gynecol Oncol 2018;149:525-30.

4. Randall LM et al. Gynecol Oncol 2019;155:63-8.

5. Food and Drug Administration. FDA approves pafolacianine for identifying malignant ovarian cancer lesions. 2021 Dec 1.

6. Horowitz NS et al. J Clin Oncol 2015;33:937-43.

7. Lee S et al. Cell Rep. 2020;31:107502.

8. Harter P et al. N Engl J Med 2019;380:822-32.

The goal of advanced ovarian cancer surgery is to remove all gross disease, or all visible and palpable disease implants. This became the established standard when improved survival was consistently observed among patients who had undergone complete surgical resection. Traditionally, definitions of no gross residual disease have been left in the hands, and eyes, of the surgeon. However, new technology has emerged which affords surgeons the ability to visualize ovarian cancer deposits that are imperceptible to the naked eye. But will this improve upon the poor cure rates for advanced ovarian cancer?

Many are familiar with the traditional definitions of “optimal” (less than 1 cm–sized deposits at any one location) and “suboptimal” (greater than 1 cm–sized deposits remaining) when referring to surgical cytoreduction of ovarian cancer. This nomenclature was introduced to define, categorize, and prognosticate patient groups after surgery. In recent years we have moved away from these descriptive definitions of ovarian cancer resection, borrowing from surgical oncology measures of surgical outcomes where “R0” defines surgical resection with negative margins, “R1” includes resection with positive microscopic margins (negative for tumor intraoperatively, but positive on microscopic pathology), and “R2” refers to macroscopic residual disease remaining.¹

In ovarian cancer, surgeons have adopted the expression R0 to include patients in whom there is no gross visible or palpable residual disease, a special, favorable subgrouping of the previous “optimal” group. R1 is applied to patients with macroscopic, residual disease that fits within the traditional “optimal” cytoreduction classification (<1 cm in any one location). Obviously, these are significant variations to the traditional surgical oncology definitions, but not without supporting data. For example, patients with no gross residual disease (now defined as “R0”) have been observed to have improved survival, compared with patients who are “optimally” debulked but with R1 (<1 cm) residual disease.² Therefore, this new goal of complete surgical resection has replaced the previous standard of “optimal” cytoreduction in which small macroscopic residual disease was acceptable.

Whether or not a surgery is completed with no gross residual disease is a subjective assessment made by the surgeon, and in practice, highly inaccurate. When a posttrial ad hoc analysis of 1,873 patients with advanced ovarian cancer who had been enrolled in a Gynecologic Oncology Group cooperative trial correlated surgeons’ assessments of “optimal” cytoreduction with objective postoperative radiographic findings (performed, on average, less than 1 month postoperatively) they found that postoperative CT scans identified lesions >1 cm in 40% of cases that had been characterized by surgeons as an “optimal” cytoreduction.³ Most commonly, discrepant lesions were identified in the upper abdominal quadrants and retroperitoneal aortic nodal regions. Therefore, surgeons’ subjective assessment of cytoreduction is prone to error, and given how important the completeness of cytoreduction is for clinical outcomes, there is interest in discovering methods to improve upon surgeons’ ability to discriminate volume of disease.

Pafolacianine (Cytalux, On Target Laboratories) is a novel drug that binds a fluorescent molecule to folic acid targeting the folate alpha receptors which are overexpressed on nonmucinous epithelial ovarian cancer cells compared with adjacent nonmalignant tissues.⁴ The drug is intravenously infused preoperatively and then visualized with companion near-infrared imaging devices during surgery to visualize its fluorescent signal where it is bound to ovarian cancer implants. In a phase 2 study of 178 patients with confirmed or suspected ovarian cancer, pafolacianine was able to detect implants of ovarian cancer in 26.9% of cases where the surgeon’s visual inspection was negative.⁵ Of note, the false-positive rate of this drug was not trivial, at 20%. Based on this efficacy data, the drug has been granted FDA approved for use in ovarian cancer surgery to augment the surgeon’s visualization of cancer. However, important questions remain unanswered by these preliminary data.

Will removal of additional microscopic ovarian cancer implants, only seen by pafolacianine, improve the survival of patients with ovarian cancer, and what effect will the addition of this extra surgery have on their surgical morbidity and risk? The use of pafolacianine to augment ovarian cancer debulking surgeries pivots on the premise that ovarian cancer outcomes are determined by surgical “effort” more than the biology of the disease. Otherwise said: The more we surgically remove, the more we cure. But this seems an old-fashioned notion, increasingly challenged by data. It has been shown that, when ovarian cancer debulking surgeries are necessarily more radical because of extensive disease distribution, prognosis is worse, compared with those patients with less extensive disease distribution.⁶ The effect of surgical effort contributes less than that of predetermined patterns of disease presentation. Additionally, genomic traits are different in tumors that are objectively determined to be not amenable to optimal cytoreduction, compared with resectable tumors.⁷ These data suggest that it is the disease, more than the surgeon, that most influences outcomes.

Additionally, the question of whether surgical removal of microscopic disease improves ovarian cancer survival has already been addressed with negative findings. The LION trial randomized 647 women with advanced ovarian cancer to primary cytoreductive surgery either with or without routine lymphadenectomy of clinically negative nodes.⁸ This study found no survival benefit to resecting clinically negative, microscopically positive nodes. In light of these data, it is difficult to imagine that there would be different results with the resection of microscopic peritoneal disease implants identified by pafolacianine.

While pafolacianine promises to move us closer to a true “R0” (negative margins) resection of ovarian cancer, is this even a feasible goal in a disease that is widely metastatic, particularly in the peritoneal cavity? What do “negative margins” mean in the peritoneal cavity? The sensitivity of pafolacianine in detecting microscopic disease is obviously not so high that it can guarantee patients a complete resection of a disseminated disease, and we still do not know what absolute benefit is derived from moving a little bit further on the continuum of surgical resection.

Perhaps augmentation of debulking is not the only, or best, use of pafolacianine for ovarian cancer surgery. Perhaps it might serve a role in diagnostics or staging of the disease rather than for a therapeutic purpose. In the meantime, we await ongoing clinical trials in this space to better inform clinicians what benefits, or harms, they might expect from the addition of this new drug as we continue to define the “optimal” surgical procedure for advanced ovarian cancer.

Dr. Emma Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.

References

1. Hermanek P, Wittekind C. Semin Surg Oncol 1994;10:12-20.

2. Elattar A et al. Cochrane Database Syst Rev 2011 Aug 10;2011(8):CD007565.

3. Eskander RN et al. Gynecol Oncol 2018;149:525-30.

4. Randall LM et al. Gynecol Oncol 2019;155:63-8.

5. Food and Drug Administration. FDA approves pafolacianine for identifying malignant ovarian cancer lesions. 2021 Dec 1.

6. Horowitz NS et al. J Clin Oncol 2015;33:937-43.

7. Lee S et al. Cell Rep. 2020;31:107502.

8. Harter P et al. N Engl J Med 2019;380:822-32.

The goal of advanced ovarian cancer surgery is to remove all gross disease, or all visible and palpable disease implants. This became the established standard when improved survival was consistently observed among patients who had undergone complete surgical resection. Traditionally, definitions of no gross residual disease have been left in the hands, and eyes, of the surgeon. However, new technology has emerged which affords surgeons the ability to visualize ovarian cancer deposits that are imperceptible to the naked eye. But will this improve upon the poor cure rates for advanced ovarian cancer?

Many are familiar with the traditional definitions of “optimal” (less than 1 cm–sized deposits at any one location) and “suboptimal” (greater than 1 cm–sized deposits remaining) when referring to surgical cytoreduction of ovarian cancer. This nomenclature was introduced to define, categorize, and prognosticate patient groups after surgery. In recent years we have moved away from these descriptive definitions of ovarian cancer resection, borrowing from surgical oncology measures of surgical outcomes where “R0” defines surgical resection with negative margins, “R1” includes resection with positive microscopic margins (negative for tumor intraoperatively, but positive on microscopic pathology), and “R2” refers to macroscopic residual disease remaining.¹

In ovarian cancer, surgeons have adopted the expression R0 to include patients in whom there is no gross visible or palpable residual disease, a special, favorable subgrouping of the previous “optimal” group. R1 is applied to patients with macroscopic, residual disease that fits within the traditional “optimal” cytoreduction classification (<1 cm in any one location). Obviously, these are significant variations to the traditional surgical oncology definitions, but not without supporting data. For example, patients with no gross residual disease (now defined as “R0”) have been observed to have improved survival, compared with patients who are “optimally” debulked but with R1 (<1 cm) residual disease.² Therefore, this new goal of complete surgical resection has replaced the previous standard of “optimal” cytoreduction in which small macroscopic residual disease was acceptable.

Whether or not a surgery is completed with no gross residual disease is a subjective assessment made by the surgeon, and in practice, highly inaccurate. When a posttrial ad hoc analysis of 1,873 patients with advanced ovarian cancer who had been enrolled in a Gynecologic Oncology Group cooperative trial correlated surgeons’ assessments of “optimal” cytoreduction with objective postoperative radiographic findings (performed, on average, less than 1 month postoperatively) they found that postoperative CT scans identified lesions >1 cm in 40% of cases that had been characterized by surgeons as an “optimal” cytoreduction.³ Most commonly, discrepant lesions were identified in the upper abdominal quadrants and retroperitoneal aortic nodal regions. Therefore, surgeons’ subjective assessment of cytoreduction is prone to error, and given how important the completeness of cytoreduction is for clinical outcomes, there is interest in discovering methods to improve upon surgeons’ ability to discriminate volume of disease.

Pafolacianine (Cytalux, On Target Laboratories) is a novel drug that binds a fluorescent molecule to folic acid targeting the folate alpha receptors which are overexpressed on nonmucinous epithelial ovarian cancer cells compared with adjacent nonmalignant tissues.⁴ The drug is intravenously infused preoperatively and then visualized with companion near-infrared imaging devices during surgery to visualize its fluorescent signal where it is bound to ovarian cancer implants. In a phase 2 study of 178 patients with confirmed or suspected ovarian cancer, pafolacianine was able to detect implants of ovarian cancer in 26.9% of cases where the surgeon’s visual inspection was negative.⁵ Of note, the false-positive rate of this drug was not trivial, at 20%. Based on this efficacy data, the drug has been granted FDA approved for use in ovarian cancer surgery to augment the surgeon’s visualization of cancer. However, important questions remain unanswered by these preliminary data.

Will removal of additional microscopic ovarian cancer implants, only seen by pafolacianine, improve the survival of patients with ovarian cancer, and what effect will the addition of this extra surgery have on their surgical morbidity and risk? The use of pafolacianine to augment ovarian cancer debulking surgeries pivots on the premise that ovarian cancer outcomes are determined by surgical “effort” more than the biology of the disease. Otherwise said: The more we surgically remove, the more we cure. But this seems an old-fashioned notion, increasingly challenged by data. It has been shown that, when ovarian cancer debulking surgeries are necessarily more radical because of extensive disease distribution, prognosis is worse, compared with those patients with less extensive disease distribution.⁶ The effect of surgical effort contributes less than that of predetermined patterns of disease presentation. Additionally, genomic traits are different in tumors that are objectively determined to be not amenable to optimal cytoreduction, compared with resectable tumors.⁷ These data suggest that it is the disease, more than the surgeon, that most influences outcomes.

Additionally, the question of whether surgical removal of microscopic disease improves ovarian cancer survival has already been addressed with negative findings. The LION trial randomized 647 women with advanced ovarian cancer to primary cytoreductive surgery either with or without routine lymphadenectomy of clinically negative nodes.⁸ This study found no survival benefit to resecting clinically negative, microscopically positive nodes. In light of these data, it is difficult to imagine that there would be different results with the resection of microscopic peritoneal disease implants identified by pafolacianine.

While pafolacianine promises to move us closer to a true “R0” (negative margins) resection of ovarian cancer, is this even a feasible goal in a disease that is widely metastatic, particularly in the peritoneal cavity? What do “negative margins” mean in the peritoneal cavity? The sensitivity of pafolacianine in detecting microscopic disease is obviously not so high that it can guarantee patients a complete resection of a disseminated disease, and we still do not know what absolute benefit is derived from moving a little bit further on the continuum of surgical resection.

Perhaps augmentation of debulking is not the only, or best, use of pafolacianine for ovarian cancer surgery. Perhaps it might serve a role in diagnostics or staging of the disease rather than for a therapeutic purpose. In the meantime, we await ongoing clinical trials in this space to better inform clinicians what benefits, or harms, they might expect from the addition of this new drug as we continue to define the “optimal” surgical procedure for advanced ovarian cancer.

Dr. Emma Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest.

References

1. Hermanek P, Wittekind C. Semin Surg Oncol 1994;10:12-20.

2. Elattar A et al. Cochrane Database Syst Rev 2011 Aug 10;2011(8):CD007565.

3. Eskander RN et al. Gynecol Oncol 2018;149:525-30.

4. Randall LM et al. Gynecol Oncol 2019;155:63-8.

5. Food and Drug Administration. FDA approves pafolacianine for identifying malignant ovarian cancer lesions. 2021 Dec 1.

6. Horowitz NS et al. J Clin Oncol 2015;33:937-43.

7. Lee S et al. Cell Rep. 2020;31:107502.

8. Harter P et al. N Engl J Med 2019;380:822-32.

Breast cancer diagnosis and treatment in young women can present unique challenges based on their life stage, including potential impact on fertility and future pregnancy. The role of GnRH analogues for ovarian protection during chemotherapy has been shown in both the POEMS-SWOG S0230 and PROMISE-GIM6 studies. Zong and colleagues conducted a phase 3 trial in China among premenopausal women with stage I-III breast cancer receiving cyclophosphamide-containing chemotherapy, with randomization to GnRHa + chemotherapy vs chemotherapy alone. Among 301 patients eligible for primary endpoint analysis, the premature ovarian insufficiency rate at 12 months was 10.3% for the GnRHa group vs 44.5% for the control group (odds ratio 0.23; P < 0.001). The rate of ovarian function recovery was also 46.4% higher in the GnRHa group. Furthermore, although survival outcomes were similar between groups, in patients <35 years of age, the tumor-free survival was higher in the GnRHa group vs control (93% vs 62%, P = 0.004) (Zong et al). These data reinforce the role of GnRHa as a means to reduce POI risk and support ovarian function recovery in young women undergoing chemotherapy for breast cancer. Measures of fertility and timing of pregnancy after breast cancer diagnosis continue to be areas of active research.

The treatment landscape for early-stage HER2-positive breast cancer continues to rapidly evolve with efforts to enhance efficacy and minimize toxicity for patients. The phase 3 KAITLIN study included 1846 patients with early-stage HER2-positive breast cancer (node-positive or node-negative, hormone receptor-negative and ≥T2 primary tumor) with randomization after surgery to adjuvant AC followed by taxane + trastuzumab + pertuzumab (AC-THP) or AC followed by T-DM1 + pertuzumab (AC-KP). In both the overall and node-positive populations, there was no significant difference in IDFS between the arms (stratified HR 0.98 and 0.97, respectively). In the overall population, the 3-year IDFS was 93.1% for AC-KP and 94.2% for AC-THP. Treatment completion rates were lower for AC-KP vs AC-THP (65.0% vs 88.4%), with T-DM1 discontinuation driven mostly by lab abnormalities (elevated liver function tests and thrombocytopenia) (Krop et al). Many patients diagnosed with early HER2-positive breast cancer (specifically those with tumors >2cm or node-positive) are treated with neoadjuvant chemotherapy + HER2-targeted therapy with subsequent tailoring of adjuvant treatment pending response, including use of T-DM1 if residual disease present. Future escalation and de-escalation strategies are being explored to further optimize outcomes and decrease side effects.

The addition of CDK 4/6 inhibitors to endocrine therapy has led to improved survival outcomes for patients diagnosed with advanced HR-positive-HER2-negative breast cancer. Lu and colleagues presented exploratory updated OS results among 672 patients with extended follow-up (median 53.5 months) from MONALEESA-7, which was a phase 3 randomized trial of ribociclib + endocrine therapy vs endocrine therapy alone among peri/pre-menopausal patients with HR-positive/HER2-negative advanced breast cancer. Median OS was 58.7 months vs 48.0 months for the ribociclib and placebo arms, respectively (HR 0.76), and a more pronounced benefit was seen in patients <40 years of age (median OS 51.3 months vs 40.5 months for ribociclib vs placebo arm; HR 0.65) (Lu et al). Furthermore, there was a significant delay in time to chemotherapy with ribociclib vs placebo (50.9 months vs 36.8 months; HR 0.69) which can certainly impact quality of life. A prior pooled analysis of the various MONALEESA trials demonstrated consistent PFS benefit with ribociclib across all intrinsic breast cancer subtypes, with the exception of basal-like and a more pronounced favorable impact in HER2-enriched. Future research to elucidate differences among CDK 4/6 inhibitors, influence of breast cancer subtype on their effect and how this can be translated to routine clinical practice are warranted.

Breast cancer diagnosis and treatment in young women can present unique challenges based on their life stage, including potential impact on fertility and future pregnancy. The role of GnRH analogues for ovarian protection during chemotherapy has been shown in both the POEMS-SWOG S0230 and PROMISE-GIM6 studies. Zong and colleagues conducted a phase 3 trial in China among premenopausal women with stage I-III breast cancer receiving cyclophosphamide-containing chemotherapy, with randomization to GnRHa + chemotherapy vs chemotherapy alone. Among 301 patients eligible for primary endpoint analysis, the premature ovarian insufficiency rate at 12 months was 10.3% for the GnRHa group vs 44.5% for the control group (odds ratio 0.23; P < 0.001). The rate of ovarian function recovery was also 46.4% higher in the GnRHa group. Furthermore, although survival outcomes were similar between groups, in patients <35 years of age, the tumor-free survival was higher in the GnRHa group vs control (93% vs 62%, P = 0.004) (Zong et al). These data reinforce the role of GnRHa as a means to reduce POI risk and support ovarian function recovery in young women undergoing chemotherapy for breast cancer. Measures of fertility and timing of pregnancy after breast cancer diagnosis continue to be areas of active research.

The treatment landscape for early-stage HER2-positive breast cancer continues to rapidly evolve with efforts to enhance efficacy and minimize toxicity for patients. The phase 3 KAITLIN study included 1846 patients with early-stage HER2-positive breast cancer (node-positive or node-negative, hormone receptor-negative and ≥T2 primary tumor) with randomization after surgery to adjuvant AC followed by taxane + trastuzumab + pertuzumab (AC-THP) or AC followed by T-DM1 + pertuzumab (AC-KP). In both the overall and node-positive populations, there was no significant difference in IDFS between the arms (stratified HR 0.98 and 0.97, respectively). In the overall population, the 3-year IDFS was 93.1% for AC-KP and 94.2% for AC-THP. Treatment completion rates were lower for AC-KP vs AC-THP (65.0% vs 88.4%), with T-DM1 discontinuation driven mostly by lab abnormalities (elevated liver function tests and thrombocytopenia) (Krop et al). Many patients diagnosed with early HER2-positive breast cancer (specifically those with tumors >2cm or node-positive) are treated with neoadjuvant chemotherapy + HER2-targeted therapy with subsequent tailoring of adjuvant treatment pending response, including use of T-DM1 if residual disease present. Future escalation and de-escalation strategies are being explored to further optimize outcomes and decrease side effects.

The addition of CDK 4/6 inhibitors to endocrine therapy has led to improved survival outcomes for patients diagnosed with advanced HR-positive-HER2-negative breast cancer. Lu and colleagues presented exploratory updated OS results among 672 patients with extended follow-up (median 53.5 months) from MONALEESA-7, which was a phase 3 randomized trial of ribociclib + endocrine therapy vs endocrine therapy alone among peri/pre-menopausal patients with HR-positive/HER2-negative advanced breast cancer. Median OS was 58.7 months vs 48.0 months for the ribociclib and placebo arms, respectively (HR 0.76), and a more pronounced benefit was seen in patients <40 years of age (median OS 51.3 months vs 40.5 months for ribociclib vs placebo arm; HR 0.65) (Lu et al). Furthermore, there was a significant delay in time to chemotherapy with ribociclib vs placebo (50.9 months vs 36.8 months; HR 0.69) which can certainly impact quality of life. A prior pooled analysis of the various MONALEESA trials demonstrated consistent PFS benefit with ribociclib across all intrinsic breast cancer subtypes, with the exception of basal-like and a more pronounced favorable impact in HER2-enriched. Future research to elucidate differences among CDK 4/6 inhibitors, influence of breast cancer subtype on their effect and how this can be translated to routine clinical practice are warranted.

Breast cancer diagnosis and treatment in young women can present unique challenges based on their life stage, including potential impact on fertility and future pregnancy. The role of GnRH analogues for ovarian protection during chemotherapy has been shown in both the POEMS-SWOG S0230 and PROMISE-GIM6 studies. Zong and colleagues conducted a phase 3 trial in China among premenopausal women with stage I-III breast cancer receiving cyclophosphamide-containing chemotherapy, with randomization to GnRHa + chemotherapy vs chemotherapy alone. Among 301 patients eligible for primary endpoint analysis, the premature ovarian insufficiency rate at 12 months was 10.3% for the GnRHa group vs 44.5% for the control group (odds ratio 0.23; P < 0.001). The rate of ovarian function recovery was also 46.4% higher in the GnRHa group. Furthermore, although survival outcomes were similar between groups, in patients <35 years of age, the tumor-free survival was higher in the GnRHa group vs control (93% vs 62%, P = 0.004) (Zong et al). These data reinforce the role of GnRHa as a means to reduce POI risk and support ovarian function recovery in young women undergoing chemotherapy for breast cancer. Measures of fertility and timing of pregnancy after breast cancer diagnosis continue to be areas of active research.

The treatment landscape for early-stage HER2-positive breast cancer continues to rapidly evolve with efforts to enhance efficacy and minimize toxicity for patients. The phase 3 KAITLIN study included 1846 patients with early-stage HER2-positive breast cancer (node-positive or node-negative, hormone receptor-negative and ≥T2 primary tumor) with randomization after surgery to adjuvant AC followed by taxane + trastuzumab + pertuzumab (AC-THP) or AC followed by T-DM1 + pertuzumab (AC-KP). In both the overall and node-positive populations, there was no significant difference in IDFS between the arms (stratified HR 0.98 and 0.97, respectively). In the overall population, the 3-year IDFS was 93.1% for AC-KP and 94.2% for AC-THP. Treatment completion rates were lower for AC-KP vs AC-THP (65.0% vs 88.4%), with T-DM1 discontinuation driven mostly by lab abnormalities (elevated liver function tests and thrombocytopenia) (Krop et al). Many patients diagnosed with early HER2-positive breast cancer (specifically those with tumors >2cm or node-positive) are treated with neoadjuvant chemotherapy + HER2-targeted therapy with subsequent tailoring of adjuvant treatment pending response, including use of T-DM1 if residual disease present. Future escalation and de-escalation strategies are being explored to further optimize outcomes and decrease side effects.

The addition of CDK 4/6 inhibitors to endocrine therapy has led to improved survival outcomes for patients diagnosed with advanced HR-positive-HER2-negative breast cancer. Lu and colleagues presented exploratory updated OS results among 672 patients with extended follow-up (median 53.5 months) from MONALEESA-7, which was a phase 3 randomized trial of ribociclib + endocrine therapy vs endocrine therapy alone among peri/pre-menopausal patients with HR-positive/HER2-negative advanced breast cancer. Median OS was 58.7 months vs 48.0 months for the ribociclib and placebo arms, respectively (HR 0.76), and a more pronounced benefit was seen in patients <40 years of age (median OS 51.3 months vs 40.5 months for ribociclib vs placebo arm; HR 0.65) (Lu et al). Furthermore, there was a significant delay in time to chemotherapy with ribociclib vs placebo (50.9 months vs 36.8 months; HR 0.69) which can certainly impact quality of life. A prior pooled analysis of the various MONALEESA trials demonstrated consistent PFS benefit with ribociclib across all intrinsic breast cancer subtypes, with the exception of basal-like and a more pronounced favorable impact in HER2-enriched. Future research to elucidate differences among CDK 4/6 inhibitors, influence of breast cancer subtype on their effect and how this can be translated to routine clinical practice are warranted.

Over the period of 1 year, secukinumab 300 mg every 2 weeks demonstrated superior efficacy compared with secukinumab 300 mg every 4 weeks in overweight patients with moderate to severe plaque psoriasis, results from a multicenter, double-blind, parallel-group trial showed.

The more frequent dosing was also associated with comparable safety, consistent with the established secukinumab safety profile.

“Weight may have an impact on pharmacokinetics and, therefore, on the clinical outcome of biologic treatment for psoriasis,” Matthias Augustin, MD, and colleagues wrote in the study, published recently in the British Journal of Dermatology. “Dose optimization may be highly beneficial for patients with higher body weight,” they noted, adding that their study supports previous study findings and pharmacokinetic/pharmacodynamic modelling data, showing that secukinumab dosed every 2 weeks “leads to a clinically and statistically significant advantage in PASI 90 response,” compared with standard dosing every 4 weeks in patients who weight 90 kg (about 198 pounds) or more, after 16 weeks of treatment, which was maintained until week 52.

For the study, Dr. Augustin, of the Institute for Health Services Research in Dermatology and Nursing at University Medical Center Hamburg-Eppendorf (Germany), and colleagues randomized 331 patients with moderate to severe chronic plaque psoriasis who weighed 90 kg or more to receive secukinumab 300 mg every 2 weeks, or secukinumab 300 mg every 4 weeks. The mean age of the patients was 47 years, 75% were male, 92% were White, and their mean body weight was 111.1 kg, with a mean body mass index of 36.1 kg/m².

Patients who did not achieve a Psoriasis Area and Severity Index (PASI) 90 at week 16 on the monthly regimen (Q4W) either remained on that regimen or were up-titrated to dosing every 2 weeks (Q2W). Of the 331 patients, 165 received Q2W dosing and 166 received Q4W dosing. The researchers found that, at 16 weeks, patients in the Q2W dosing group had significantly higher PASI 90 responses, compared with those in the Q4W group (73.2% vs. 55.5%, respectively; P = .0003; odds ratio estimate, 2.3).

At 52 weeks, a greater proportion of patients in the Q2W group maintained responses to several outcome measures, compared with those in the Q4W group, including PASI 75 (88.9% vs. 74.8%), PASI 90 (76.4% vs. 52.4%), and PASI 100 (46.7% vs. 27.3%) scores; Investigator’s Global Assessment score of 0 or 1 (75.9% vs. 55.6%); and Dermatology Life Quality Index scores of 0 or 1 (66.1% vs. 48.8%).

In addition, those who had not had a PASI 90 response at week 16 who were up-titrated to Q2W dosing demonstrated higher efficacy responses at week 32, compared with those who remained on the Q4W regimen, with PASI 90 scores of 37.7% versus 16.5%, respectively.

Both regimens were well-tolerated, consistent with the known secukinumab safety profile; safety was comparable in the treatment arms, and there was “no clear dose-response relationship seen” for the incidence of overall adverse events, serious AEs, and AEs leading to discontinuation of the study treatment, “or AEs related to the identified risks” of infections, hypersensitivity, neutropenia and potential risk of major adverse cardiovascular events, the authors wrote.

“Despite more frequent dosing, the incidence of Candida infections was numerically lower in the Q2W group versus the Q4W group,” although there were not many cases, three patients versus six patients, respectively.

 

Need for individualized treatment

“Despite a decades-long revolution in development of highly efficacious biologic treatments for psoriasis, we are only in the early stages of developing personalized clinical approaches,” said Raj Chovatiya, MD, PhD, a dermatologist at Northwestern University, Chicago, who was asked to comment on the study. “The need for individualized treatment in psoriasis is very real; not every patient may respond to therapy in the same way. Obesity is one important comorbidity of psoriasis, and increased body mass index may be associated with variable treatment outcomes with systemic therapy.”

The data from this study, he added, “suggest that dose optimization may be an important strategy to enhance psoriasis clearance in patients with suboptimal treatment outcomes on standard dosing, including those with increased weight. Future studies should examine optimal regimen of biologic therapy across a variety of patient factors.”

The study was funded by Novartis, the manufacturer of secukinumab (Cosentyx); several authors were company employees. Dr. Augustin disclosed that he has served as a consultant for or has been a paid speaker for clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Medac, Merck, MSD, Novartis, Pfizer, UCB, and Xenoport. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, and/or a member of the advisory board for AbbVie, Arcutis, Arena, Incyte, Pfizer, Regeneron, and Sanofi Genzyme.

Over the period of 1 year, secukinumab 300 mg every 2 weeks demonstrated superior efficacy compared with secukinumab 300 mg every 4 weeks in overweight patients with moderate to severe plaque psoriasis, results from a multicenter, double-blind, parallel-group trial showed.

The more frequent dosing was also associated with comparable safety, consistent with the established secukinumab safety profile.

“Weight may have an impact on pharmacokinetics and, therefore, on the clinical outcome of biologic treatment for psoriasis,” Matthias Augustin, MD, and colleagues wrote in the study, published recently in the British Journal of Dermatology. “Dose optimization may be highly beneficial for patients with higher body weight,” they noted, adding that their study supports previous study findings and pharmacokinetic/pharmacodynamic modelling data, showing that secukinumab dosed every 2 weeks “leads to a clinically and statistically significant advantage in PASI 90 response,” compared with standard dosing every 4 weeks in patients who weight 90 kg (about 198 pounds) or more, after 16 weeks of treatment, which was maintained until week 52.

For the study, Dr. Augustin, of the Institute for Health Services Research in Dermatology and Nursing at University Medical Center Hamburg-Eppendorf (Germany), and colleagues randomized 331 patients with moderate to severe chronic plaque psoriasis who weighed 90 kg or more to receive secukinumab 300 mg every 2 weeks, or secukinumab 300 mg every 4 weeks. The mean age of the patients was 47 years, 75% were male, 92% were White, and their mean body weight was 111.1 kg, with a mean body mass index of 36.1 kg/m².

Patients who did not achieve a Psoriasis Area and Severity Index (PASI) 90 at week 16 on the monthly regimen (Q4W) either remained on that regimen or were up-titrated to dosing every 2 weeks (Q2W). Of the 331 patients, 165 received Q2W dosing and 166 received Q4W dosing. The researchers found that, at 16 weeks, patients in the Q2W dosing group had significantly higher PASI 90 responses, compared with those in the Q4W group (73.2% vs. 55.5%, respectively; P = .0003; odds ratio estimate, 2.3).

At 52 weeks, a greater proportion of patients in the Q2W group maintained responses to several outcome measures, compared with those in the Q4W group, including PASI 75 (88.9% vs. 74.8%), PASI 90 (76.4% vs. 52.4%), and PASI 100 (46.7% vs. 27.3%) scores; Investigator’s Global Assessment score of 0 or 1 (75.9% vs. 55.6%); and Dermatology Life Quality Index scores of 0 or 1 (66.1% vs. 48.8%).

In addition, those who had not had a PASI 90 response at week 16 who were up-titrated to Q2W dosing demonstrated higher efficacy responses at week 32, compared with those who remained on the Q4W regimen, with PASI 90 scores of 37.7% versus 16.5%, respectively.

Both regimens were well-tolerated, consistent with the known secukinumab safety profile; safety was comparable in the treatment arms, and there was “no clear dose-response relationship seen” for the incidence of overall adverse events, serious AEs, and AEs leading to discontinuation of the study treatment, “or AEs related to the identified risks” of infections, hypersensitivity, neutropenia and potential risk of major adverse cardiovascular events, the authors wrote.

“Despite more frequent dosing, the incidence of Candida infections was numerically lower in the Q2W group versus the Q4W group,” although there were not many cases, three patients versus six patients, respectively.

 

Need for individualized treatment

“Despite a decades-long revolution in development of highly efficacious biologic treatments for psoriasis, we are only in the early stages of developing personalized clinical approaches,” said Raj Chovatiya, MD, PhD, a dermatologist at Northwestern University, Chicago, who was asked to comment on the study. “The need for individualized treatment in psoriasis is very real; not every patient may respond to therapy in the same way. Obesity is one important comorbidity of psoriasis, and increased body mass index may be associated with variable treatment outcomes with systemic therapy.”

The data from this study, he added, “suggest that dose optimization may be an important strategy to enhance psoriasis clearance in patients with suboptimal treatment outcomes on standard dosing, including those with increased weight. Future studies should examine optimal regimen of biologic therapy across a variety of patient factors.”

The study was funded by Novartis, the manufacturer of secukinumab (Cosentyx); several authors were company employees. Dr. Augustin disclosed that he has served as a consultant for or has been a paid speaker for clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Medac, Merck, MSD, Novartis, Pfizer, UCB, and Xenoport. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, and/or a member of the advisory board for AbbVie, Arcutis, Arena, Incyte, Pfizer, Regeneron, and Sanofi Genzyme.

Over the period of 1 year, secukinumab 300 mg every 2 weeks demonstrated superior efficacy compared with secukinumab 300 mg every 4 weeks in overweight patients with moderate to severe plaque psoriasis, results from a multicenter, double-blind, parallel-group trial showed.

The more frequent dosing was also associated with comparable safety, consistent with the established secukinumab safety profile.

“Weight may have an impact on pharmacokinetics and, therefore, on the clinical outcome of biologic treatment for psoriasis,” Matthias Augustin, MD, and colleagues wrote in the study, published recently in the British Journal of Dermatology. “Dose optimization may be highly beneficial for patients with higher body weight,” they noted, adding that their study supports previous study findings and pharmacokinetic/pharmacodynamic modelling data, showing that secukinumab dosed every 2 weeks “leads to a clinically and statistically significant advantage in PASI 90 response,” compared with standard dosing every 4 weeks in patients who weight 90 kg (about 198 pounds) or more, after 16 weeks of treatment, which was maintained until week 52.

For the study, Dr. Augustin, of the Institute for Health Services Research in Dermatology and Nursing at University Medical Center Hamburg-Eppendorf (Germany), and colleagues randomized 331 patients with moderate to severe chronic plaque psoriasis who weighed 90 kg or more to receive secukinumab 300 mg every 2 weeks, or secukinumab 300 mg every 4 weeks. The mean age of the patients was 47 years, 75% were male, 92% were White, and their mean body weight was 111.1 kg, with a mean body mass index of 36.1 kg/m².

Patients who did not achieve a Psoriasis Area and Severity Index (PASI) 90 at week 16 on the monthly regimen (Q4W) either remained on that regimen or were up-titrated to dosing every 2 weeks (Q2W). Of the 331 patients, 165 received Q2W dosing and 166 received Q4W dosing. The researchers found that, at 16 weeks, patients in the Q2W dosing group had significantly higher PASI 90 responses, compared with those in the Q4W group (73.2% vs. 55.5%, respectively; P = .0003; odds ratio estimate, 2.3).

At 52 weeks, a greater proportion of patients in the Q2W group maintained responses to several outcome measures, compared with those in the Q4W group, including PASI 75 (88.9% vs. 74.8%), PASI 90 (76.4% vs. 52.4%), and PASI 100 (46.7% vs. 27.3%) scores; Investigator’s Global Assessment score of 0 or 1 (75.9% vs. 55.6%); and Dermatology Life Quality Index scores of 0 or 1 (66.1% vs. 48.8%).

In addition, those who had not had a PASI 90 response at week 16 who were up-titrated to Q2W dosing demonstrated higher efficacy responses at week 32, compared with those who remained on the Q4W regimen, with PASI 90 scores of 37.7% versus 16.5%, respectively.

Both regimens were well-tolerated, consistent with the known secukinumab safety profile; safety was comparable in the treatment arms, and there was “no clear dose-response relationship seen” for the incidence of overall adverse events, serious AEs, and AEs leading to discontinuation of the study treatment, “or AEs related to the identified risks” of infections, hypersensitivity, neutropenia and potential risk of major adverse cardiovascular events, the authors wrote.

“Despite more frequent dosing, the incidence of Candida infections was numerically lower in the Q2W group versus the Q4W group,” although there were not many cases, three patients versus six patients, respectively.

 

Need for individualized treatment

“Despite a decades-long revolution in development of highly efficacious biologic treatments for psoriasis, we are only in the early stages of developing personalized clinical approaches,” said Raj Chovatiya, MD, PhD, a dermatologist at Northwestern University, Chicago, who was asked to comment on the study. “The need for individualized treatment in psoriasis is very real; not every patient may respond to therapy in the same way. Obesity is one important comorbidity of psoriasis, and increased body mass index may be associated with variable treatment outcomes with systemic therapy.”

The data from this study, he added, “suggest that dose optimization may be an important strategy to enhance psoriasis clearance in patients with suboptimal treatment outcomes on standard dosing, including those with increased weight. Future studies should examine optimal regimen of biologic therapy across a variety of patient factors.”

The study was funded by Novartis, the manufacturer of secukinumab (Cosentyx); several authors were company employees. Dr. Augustin disclosed that he has served as a consultant for or has been a paid speaker for clinical trials sponsored by companies that manufacture drugs used for the treatment of psoriasis, including AbbVie, Almirall, Amgen, Biogen, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Medac, Merck, MSD, Novartis, Pfizer, UCB, and Xenoport. Dr. Chovatiya disclosed that he is a consultant to, a speaker for, and/or a member of the advisory board for AbbVie, Arcutis, Arena, Incyte, Pfizer, Regeneron, and Sanofi Genzyme.

Chinese researchers reporting at the 2022 Gastrointestinal Cancers Symposium shared new results from a phase 1b/2 study showing that combination treatment with the antibody AK104 shows promise for patients with gastric and gastroesophageal junction cancer.

“AK-104 plus chemo presents a potential new first line treatment option for these patients,” said Jiafu Ji, MD, PhD, of Peking University Cancer Hospital and Institute Gastrointestinal Cancer Center, Beijing.

AK104 is a PD-1/CTLA4 antibody manufactured by Akeso Biopharma, which in 2020 received fast-track designation for the drug’s use as monotherapy for patients with recurrent or chemotherapy-resistant metastatic squamous cervical cancer.

The new trial was a multicenter, open-label study that combined chemotherapy (XELOX – capecitabine combined with oxaliplatin) with AK104 for use as first-line therapy for patients with gastric and gastroesophageal junction cancer.

Two previous studies showed that combination treatment with an anti–PD-1 and anti-CTLA4 AK104 produced a higher response rate and better long-term overall survival than anti–PD-1 therapy alone, but at a cost of greater toxicity.

“The toxicity can be really significant with the combination ... you see some severe immune related events. So with the bispecific antibody, the hope is that we can minimize that additive toxicity by bringing the CTLA4 inhibitor to antigen-experienced PD-1–positive T cells, and hopefully enhance the effect of blocking CTLA4 at the tumor-immune interface, rather than nonspecifically,” said Katherine Bever, MD, who was asked to comment on the study. Dr. Bever is an assistant professor of oncology at Johns Hopkins University, Baltimore, and moderated the panel where the study was presented.

The new results are encouraging, Dr. Bever said. “The data looks promising in terms of the survival that they reported. It compares very favorably to our other first-line studies. But we need randomized data to show exactly what the contribution of the bispecific antibody is to the chemotherapy that it’s being combined with, and how that compares to combination with anti–PD-1 alone, and also to understand more about what they saw in terms of immune toxicities.”

Dr. Bever said the combination of chemotherapy and the PD-1 inhibitor nivolumab is now a first-line treatment for gastric and gastroesophageal junction cancer based on results from the CheckMate 649 study, but relatively few patients appear to benefit from the PD-1 inhibitor compared to chemotherapy alone.

“I think there’s the potential that by incorporating PD-1 and CTLA4 targeting in the first line, we might further improve outcomes for these patients, but you need randomized data to show that,” she said.

Dr. Ji said that there is an ongoing phase 3 study of AK104 in combination with chemotherapy for first-line treatment of gastric or gastroesophageal junction cancer.

The phase 1b/2 clinical trial included 96 patients (median age, 62.7 years; 70.8% male) who were treated with AK-104 every 2-3 weeks, plus XELOX (capecitabine plus oxaliplatin) or modified XELOX.

After a median follow-up of 9.95 months the overall response rate was 65.9% (2.3% complete, 63.6% partial). The disease control rate was 92.0%. The median duration of response was 6.93 months, the median progression-free survival was 7.10 months, and median overall survival was 17.41 months. Treatment-related adverse events included reductions in platelet count (60.4%), white blood cells (58.3%), and neutrophils (56.3%), anemia (47.9%), nausea (30.2%), vomiting (30.2%), and increase in AST (30.2%); 62.5% had at least one grade 3 or higher TRAE.

The study was funded by Akeso Biopharma. Dr. Ji and Dr. Bever have no relevant financial disclosures.

Chinese researchers reporting at the 2022 Gastrointestinal Cancers Symposium shared new results from a phase 1b/2 study showing that combination treatment with the antibody AK104 shows promise for patients with gastric and gastroesophageal junction cancer.

“AK-104 plus chemo presents a potential new first line treatment option for these patients,” said Jiafu Ji, MD, PhD, of Peking University Cancer Hospital and Institute Gastrointestinal Cancer Center, Beijing.

AK104 is a PD-1/CTLA4 antibody manufactured by Akeso Biopharma, which in 2020 received fast-track designation for the drug’s use as monotherapy for patients with recurrent or chemotherapy-resistant metastatic squamous cervical cancer.

The new trial was a multicenter, open-label study that combined chemotherapy (XELOX – capecitabine combined with oxaliplatin) with AK104 for use as first-line therapy for patients with gastric and gastroesophageal junction cancer.

Two previous studies showed that combination treatment with an anti–PD-1 and anti-CTLA4 AK104 produced a higher response rate and better long-term overall survival than anti–PD-1 therapy alone, but at a cost of greater toxicity.

“The toxicity can be really significant with the combination ... you see some severe immune related events. So with the bispecific antibody, the hope is that we can minimize that additive toxicity by bringing the CTLA4 inhibitor to antigen-experienced PD-1–positive T cells, and hopefully enhance the effect of blocking CTLA4 at the tumor-immune interface, rather than nonspecifically,” said Katherine Bever, MD, who was asked to comment on the study. Dr. Bever is an assistant professor of oncology at Johns Hopkins University, Baltimore, and moderated the panel where the study was presented.

The new results are encouraging, Dr. Bever said. “The data looks promising in terms of the survival that they reported. It compares very favorably to our other first-line studies. But we need randomized data to show exactly what the contribution of the bispecific antibody is to the chemotherapy that it’s being combined with, and how that compares to combination with anti–PD-1 alone, and also to understand more about what they saw in terms of immune toxicities.”

Dr. Bever said the combination of chemotherapy and the PD-1 inhibitor nivolumab is now a first-line treatment for gastric and gastroesophageal junction cancer based on results from the CheckMate 649 study, but relatively few patients appear to benefit from the PD-1 inhibitor compared to chemotherapy alone.

“I think there’s the potential that by incorporating PD-1 and CTLA4 targeting in the first line, we might further improve outcomes for these patients, but you need randomized data to show that,” she said.

Dr. Ji said that there is an ongoing phase 3 study of AK104 in combination with chemotherapy for first-line treatment of gastric or gastroesophageal junction cancer.

The phase 1b/2 clinical trial included 96 patients (median age, 62.7 years; 70.8% male) who were treated with AK-104 every 2-3 weeks, plus XELOX (capecitabine plus oxaliplatin) or modified XELOX.

After a median follow-up of 9.95 months the overall response rate was 65.9% (2.3% complete, 63.6% partial). The disease control rate was 92.0%. The median duration of response was 6.93 months, the median progression-free survival was 7.10 months, and median overall survival was 17.41 months. Treatment-related adverse events included reductions in platelet count (60.4%), white blood cells (58.3%), and neutrophils (56.3%), anemia (47.9%), nausea (30.2%), vomiting (30.2%), and increase in AST (30.2%); 62.5% had at least one grade 3 or higher TRAE.

The study was funded by Akeso Biopharma. Dr. Ji and Dr. Bever have no relevant financial disclosures.

Chinese researchers reporting at the 2022 Gastrointestinal Cancers Symposium shared new results from a phase 1b/2 study showing that combination treatment with the antibody AK104 shows promise for patients with gastric and gastroesophageal junction cancer.

“AK-104 plus chemo presents a potential new first line treatment option for these patients,” said Jiafu Ji, MD, PhD, of Peking University Cancer Hospital and Institute Gastrointestinal Cancer Center, Beijing.

AK104 is a PD-1/CTLA4 antibody manufactured by Akeso Biopharma, which in 2020 received fast-track designation for the drug’s use as monotherapy for patients with recurrent or chemotherapy-resistant metastatic squamous cervical cancer.

The new trial was a multicenter, open-label study that combined chemotherapy (XELOX – capecitabine combined with oxaliplatin) with AK104 for use as first-line therapy for patients with gastric and gastroesophageal junction cancer.

Two previous studies showed that combination treatment with an anti–PD-1 and anti-CTLA4 AK104 produced a higher response rate and better long-term overall survival than anti–PD-1 therapy alone, but at a cost of greater toxicity.

“The toxicity can be really significant with the combination ... you see some severe immune related events. So with the bispecific antibody, the hope is that we can minimize that additive toxicity by bringing the CTLA4 inhibitor to antigen-experienced PD-1–positive T cells, and hopefully enhance the effect of blocking CTLA4 at the tumor-immune interface, rather than nonspecifically,” said Katherine Bever, MD, who was asked to comment on the study. Dr. Bever is an assistant professor of oncology at Johns Hopkins University, Baltimore, and moderated the panel where the study was presented.

The new results are encouraging, Dr. Bever said. “The data looks promising in terms of the survival that they reported. It compares very favorably to our other first-line studies. But we need randomized data to show exactly what the contribution of the bispecific antibody is to the chemotherapy that it’s being combined with, and how that compares to combination with anti–PD-1 alone, and also to understand more about what they saw in terms of immune toxicities.”

Dr. Bever said the combination of chemotherapy and the PD-1 inhibitor nivolumab is now a first-line treatment for gastric and gastroesophageal junction cancer based on results from the CheckMate 649 study, but relatively few patients appear to benefit from the PD-1 inhibitor compared to chemotherapy alone.

“I think there’s the potential that by incorporating PD-1 and CTLA4 targeting in the first line, we might further improve outcomes for these patients, but you need randomized data to show that,” she said.

Dr. Ji said that there is an ongoing phase 3 study of AK104 in combination with chemotherapy for first-line treatment of gastric or gastroesophageal junction cancer.

The phase 1b/2 clinical trial included 96 patients (median age, 62.7 years; 70.8% male) who were treated with AK-104 every 2-3 weeks, plus XELOX (capecitabine plus oxaliplatin) or modified XELOX.

After a median follow-up of 9.95 months the overall response rate was 65.9% (2.3% complete, 63.6% partial). The disease control rate was 92.0%. The median duration of response was 6.93 months, the median progression-free survival was 7.10 months, and median overall survival was 17.41 months. Treatment-related adverse events included reductions in platelet count (60.4%), white blood cells (58.3%), and neutrophils (56.3%), anemia (47.9%), nausea (30.2%), vomiting (30.2%), and increase in AST (30.2%); 62.5% had at least one grade 3 or higher TRAE.

The study was funded by Akeso Biopharma. Dr. Ji and Dr. Bever have no relevant financial disclosures.

Surgeons should perform endoscopic mucosal resection (EMR) for all visible lesions in the presence of neoplasia to make an accurate histopathologic diagnosis of early-stage esophageal cancer, said a physician presenting at the 2022 Gastrointestinal Cancers Symposium.

Vani Konda, MD, a gastroenterologist with Baylor Scott and White Center for Esophageal Diseases, Dallas, participated in an educational session on approaches for treating localized gastroesophageal cancer. In her presentation, she addressed the advantages and disadvantages of EMR and endoscopic submucosal dissection (ESD) for esophageal neoplasia for both diagnosis and treatment.

Esophageal neoplasia therapy includes tissue-acquiring (lesion removal and histopathologic samples) and non–tissue-acquiring therapies (which include radiofrequency ablation, cryotherapy and hybrid-argon plasma coagulation.

The optimal therapy may vary with the esophageal cancer, and the cancer may vary with geography. Worldwide, squamous cell carcinoma is predominant, while in Western countries, esophageal adenocarcinoma is most prevalent. The incidence and mortality of esophageal adenocarcinoma has been rising for several decades, Dr. Konda said.
 

Considering risk factors

Barrett’s esophagus is a known risk factor for esophageal adenocarcinoma. It can be seen endoscopically as salmon-colored lining, and histologically as specialized intestinal metaplasia.

A lesion extending beyond the basement membrane into the lamina propria is an intramucosal carcinoma, or T1a lesion. A lesion extending beyond the muscularis mucosa into the submucosa is a submucosal carcinoma, or T1b tumor, Dr. Konda said.

“The difference between T1a and T1b is important in the selection of treatment approaches due to the risk of [lymph node] metastasis,” she said. She equated a T1a lesion with a 2% or smaller risk of lymph node metastasis, and a T1b tumor with a 20% risk.*

Endoscopic therapy is more reasonable for a T1a lesion, especially since the alternative, esophagectomy, may have a mortality rate of 2% or higher, she said, while for T1b tumors, surgical or systemic treatments are warranted.

A diagnosis of high-grade dysplasia by biopsy is associated with a 40% risk of prevalent cancer, mostly intramucosal carcinoma. On the other hand, submucosal carcinoma is rare in the absence of endoscopically visible lesions. “This risk of prevalent cancer, especially in visible lesions, is the reason that we should address all visible lesions with endoscopic resection, especially in the setting of dysplasia,” Dr. Konda said.

EMR is more accurate than biopsies; diagnoses change up to half the time when EMR is done after a preresection biopsy, and there’s a higher interobserver agreement among pathologists with EMR, she said.

The goal of therapy in Barrett’s esophagus is total Barrett’s eradication to treat not only the known neoplasia, but also the rest of the at-risk epithelium.

Piecemeal EMR for the entire Barrett’s epithelium can bring about a 96% or greater neoplasia eradication rate. But the stricture rate may reach 37%, and bleeding and perforation are also common.

Combining endoscopic mucosal resection for visible lesions with ablation for the rest of the at-risk lining can achieve an eradication rate of 93% with a more favorable complication profile.
 

Weighing the benefits of ESD

In contrast to EMR, ESD has been practiced more frequently in Asia. It provides an en bloc specimen.

A 2014 systematic review of 380 EMR procedures and 333 ESD procedures for Barret’s associated neoplasia indicated that ESD takes longer. The recurrence rate was 0.7% for ESD versus 2.6% for EMR, but this difference fell just short of statistical significance (P = .06). Bleeding and perforation rates were similar, but stricture rates reached 22.3% with wide-field EMR, 3.4% with ESD and 0.7% with focal EMR.

In a 2016 head-to-head trial, researchers assigned 20 patients each to EMR or ESD. They found the procedure longer, but the en bloc resection was higher in ESD. Complete remission of the neoplasia was not statistically different between the two groups, with 15 of 16 patients achieving this goal with ESD and 16 of 17 with EMR. All the patients had complete remission after one retreatment of residual neoplasia. There were two severe adverse events in the ESD group, and none in the EMR group.

Weighing the pros and cons, Dr. Konda concluded that EMR is technically easier and adequate in most cases of Barrett’s esophagus, while ESD may be preferred in select cases with concern for submucosal carcinoma or nonlifting lesions.

She advocated taking patient characteristics, disease characteristics, and available expertise into account.

Dr. Konda reported financial relationships with Ambu, Cernostics, Exact Sciences, Medtronic, and Lucid Sciences. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

*Correction, 1/28/22: An earlier version of this article mischaracterized lymph node metastasis.

Surgeons should perform endoscopic mucosal resection (EMR) for all visible lesions in the presence of neoplasia to make an accurate histopathologic diagnosis of early-stage esophageal cancer, said a physician presenting at the 2022 Gastrointestinal Cancers Symposium.

Vani Konda, MD, a gastroenterologist with Baylor Scott and White Center for Esophageal Diseases, Dallas, participated in an educational session on approaches for treating localized gastroesophageal cancer. In her presentation, she addressed the advantages and disadvantages of EMR and endoscopic submucosal dissection (ESD) for esophageal neoplasia for both diagnosis and treatment.

Esophageal neoplasia therapy includes tissue-acquiring (lesion removal and histopathologic samples) and non–tissue-acquiring therapies (which include radiofrequency ablation, cryotherapy and hybrid-argon plasma coagulation.

The optimal therapy may vary with the esophageal cancer, and the cancer may vary with geography. Worldwide, squamous cell carcinoma is predominant, while in Western countries, esophageal adenocarcinoma is most prevalent. The incidence and mortality of esophageal adenocarcinoma has been rising for several decades, Dr. Konda said.
 

Considering risk factors

Barrett’s esophagus is a known risk factor for esophageal adenocarcinoma. It can be seen endoscopically as salmon-colored lining, and histologically as specialized intestinal metaplasia.

A lesion extending beyond the basement membrane into the lamina propria is an intramucosal carcinoma, or T1a lesion. A lesion extending beyond the muscularis mucosa into the submucosa is a submucosal carcinoma, or T1b tumor, Dr. Konda said.

“The difference between T1a and T1b is important in the selection of treatment approaches due to the risk of [lymph node] metastasis,” she said. She equated a T1a lesion with a 2% or smaller risk of lymph node metastasis, and a T1b tumor with a 20% risk.*

Endoscopic therapy is more reasonable for a T1a lesion, especially since the alternative, esophagectomy, may have a mortality rate of 2% or higher, she said, while for T1b tumors, surgical or systemic treatments are warranted.

A diagnosis of high-grade dysplasia by biopsy is associated with a 40% risk of prevalent cancer, mostly intramucosal carcinoma. On the other hand, submucosal carcinoma is rare in the absence of endoscopically visible lesions. “This risk of prevalent cancer, especially in visible lesions, is the reason that we should address all visible lesions with endoscopic resection, especially in the setting of dysplasia,” Dr. Konda said.

EMR is more accurate than biopsies; diagnoses change up to half the time when EMR is done after a preresection biopsy, and there’s a higher interobserver agreement among pathologists with EMR, she said.

The goal of therapy in Barrett’s esophagus is total Barrett’s eradication to treat not only the known neoplasia, but also the rest of the at-risk epithelium.

Piecemeal EMR for the entire Barrett’s epithelium can bring about a 96% or greater neoplasia eradication rate. But the stricture rate may reach 37%, and bleeding and perforation are also common.

Combining endoscopic mucosal resection for visible lesions with ablation for the rest of the at-risk lining can achieve an eradication rate of 93% with a more favorable complication profile.
 

Weighing the benefits of ESD

In contrast to EMR, ESD has been practiced more frequently in Asia. It provides an en bloc specimen.

A 2014 systematic review of 380 EMR procedures and 333 ESD procedures for Barret’s associated neoplasia indicated that ESD takes longer. The recurrence rate was 0.7% for ESD versus 2.6% for EMR, but this difference fell just short of statistical significance (P = .06). Bleeding and perforation rates were similar, but stricture rates reached 22.3% with wide-field EMR, 3.4% with ESD and 0.7% with focal EMR.

In a 2016 head-to-head trial, researchers assigned 20 patients each to EMR or ESD. They found the procedure longer, but the en bloc resection was higher in ESD. Complete remission of the neoplasia was not statistically different between the two groups, with 15 of 16 patients achieving this goal with ESD and 16 of 17 with EMR. All the patients had complete remission after one retreatment of residual neoplasia. There were two severe adverse events in the ESD group, and none in the EMR group.

Weighing the pros and cons, Dr. Konda concluded that EMR is technically easier and adequate in most cases of Barrett’s esophagus, while ESD may be preferred in select cases with concern for submucosal carcinoma or nonlifting lesions.

She advocated taking patient characteristics, disease characteristics, and available expertise into account.

Dr. Konda reported financial relationships with Ambu, Cernostics, Exact Sciences, Medtronic, and Lucid Sciences. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

*Correction, 1/28/22: An earlier version of this article mischaracterized lymph node metastasis.

Surgeons should perform endoscopic mucosal resection (EMR) for all visible lesions in the presence of neoplasia to make an accurate histopathologic diagnosis of early-stage esophageal cancer, said a physician presenting at the 2022 Gastrointestinal Cancers Symposium.

Vani Konda, MD, a gastroenterologist with Baylor Scott and White Center for Esophageal Diseases, Dallas, participated in an educational session on approaches for treating localized gastroesophageal cancer. In her presentation, she addressed the advantages and disadvantages of EMR and endoscopic submucosal dissection (ESD) for esophageal neoplasia for both diagnosis and treatment.

Esophageal neoplasia therapy includes tissue-acquiring (lesion removal and histopathologic samples) and non–tissue-acquiring therapies (which include radiofrequency ablation, cryotherapy and hybrid-argon plasma coagulation.

The optimal therapy may vary with the esophageal cancer, and the cancer may vary with geography. Worldwide, squamous cell carcinoma is predominant, while in Western countries, esophageal adenocarcinoma is most prevalent. The incidence and mortality of esophageal adenocarcinoma has been rising for several decades, Dr. Konda said.
 

Considering risk factors

Barrett’s esophagus is a known risk factor for esophageal adenocarcinoma. It can be seen endoscopically as salmon-colored lining, and histologically as specialized intestinal metaplasia.

A lesion extending beyond the basement membrane into the lamina propria is an intramucosal carcinoma, or T1a lesion. A lesion extending beyond the muscularis mucosa into the submucosa is a submucosal carcinoma, or T1b tumor, Dr. Konda said.

“The difference between T1a and T1b is important in the selection of treatment approaches due to the risk of [lymph node] metastasis,” she said. She equated a T1a lesion with a 2% or smaller risk of lymph node metastasis, and a T1b tumor with a 20% risk.*

Endoscopic therapy is more reasonable for a T1a lesion, especially since the alternative, esophagectomy, may have a mortality rate of 2% or higher, she said, while for T1b tumors, surgical or systemic treatments are warranted.

A diagnosis of high-grade dysplasia by biopsy is associated with a 40% risk of prevalent cancer, mostly intramucosal carcinoma. On the other hand, submucosal carcinoma is rare in the absence of endoscopically visible lesions. “This risk of prevalent cancer, especially in visible lesions, is the reason that we should address all visible lesions with endoscopic resection, especially in the setting of dysplasia,” Dr. Konda said.

EMR is more accurate than biopsies; diagnoses change up to half the time when EMR is done after a preresection biopsy, and there’s a higher interobserver agreement among pathologists with EMR, she said.

The goal of therapy in Barrett’s esophagus is total Barrett’s eradication to treat not only the known neoplasia, but also the rest of the at-risk epithelium.

Piecemeal EMR for the entire Barrett’s epithelium can bring about a 96% or greater neoplasia eradication rate. But the stricture rate may reach 37%, and bleeding and perforation are also common.

Combining endoscopic mucosal resection for visible lesions with ablation for the rest of the at-risk lining can achieve an eradication rate of 93% with a more favorable complication profile.
 

Weighing the benefits of ESD

In contrast to EMR, ESD has been practiced more frequently in Asia. It provides an en bloc specimen.

A 2014 systematic review of 380 EMR procedures and 333 ESD procedures for Barret’s associated neoplasia indicated that ESD takes longer. The recurrence rate was 0.7% for ESD versus 2.6% for EMR, but this difference fell just short of statistical significance (P = .06). Bleeding and perforation rates were similar, but stricture rates reached 22.3% with wide-field EMR, 3.4% with ESD and 0.7% with focal EMR.

In a 2016 head-to-head trial, researchers assigned 20 patients each to EMR or ESD. They found the procedure longer, but the en bloc resection was higher in ESD. Complete remission of the neoplasia was not statistically different between the two groups, with 15 of 16 patients achieving this goal with ESD and 16 of 17 with EMR. All the patients had complete remission after one retreatment of residual neoplasia. There were two severe adverse events in the ESD group, and none in the EMR group.

Weighing the pros and cons, Dr. Konda concluded that EMR is technically easier and adequate in most cases of Barrett’s esophagus, while ESD may be preferred in select cases with concern for submucosal carcinoma or nonlifting lesions.

She advocated taking patient characteristics, disease characteristics, and available expertise into account.

Dr. Konda reported financial relationships with Ambu, Cernostics, Exact Sciences, Medtronic, and Lucid Sciences. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

*Correction, 1/28/22: An earlier version of this article mischaracterized lymph node metastasis.