Nancy A. Melville

While nearly a quarter of patients with schizophrenia are reported to have primary treatment resistance, clozapine, known as the most effective antipsychotic for treatment-resistant schizophrenia – but burdened by concerns of side effects – remains significantly underprescribed, and when it is used, the drug is often delayed by several crucial years, reducing chances of efficacy.

“Despite being the only pharmacological therapy approved for treatment-resistant schizophrenia, clozapine is underutilized globally, even in developed countries, where only about 30% of patients who would benefit from the drug receive it,” said John M. Kane, MD, of the department of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., in a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.

Clozapine, a tricyclic dibenzodiazepine available in branded and various generic versions, is approved by the U.S. Food and Drug Administration as a third-line therapy for severe, treatment-resistant schizophrenia, with studies showing benefits exceeding those of any other antipsychotics for the indication.

But while recommendations suggest use after a trial of two or more antipsychotics, with at least one being an atypical antipsychotic, one recent review finds delays in clozapine commencement ranging from 19.3 weeks to 5.5 years, and the duration of illness prior to clozapine use ranging from 1.1 to 9.7 years.
 

Blood monitoring, side effects

The key deterrents preventing many clinicians and patients from trying clozapine sooner are the drug’s safety and tolerability profiles, and notably the requirement of regular blood testing due to an increased risk of agranulocytosis.

Specifically, the blood testing is required every week for 6 months, then every other week for the next 6 months, and then once a month after that; however, “many of us think that that’s excessive at this point in time,” Dr. Kane noted.

Various other potential side effects are also of concern, including myocarditis, seizures, constipation, arrhythmia, hypersalivation, pneumonia, and metabolic symptoms including diabetes.

In terms of the common strategies that clinicians turn to when patients fail to respond to their current antipsychotic, including increasing doses, combining agents, or treatment switching, “none of the strategies likely rival clozapine in terms of efficacy,” Dr. Kane said.

Regarding higher dosing: “There is very little data suggesting that higher doses of antipsychotic drugs will work when the moderate or recommended dose has not worked,” he said.

Combination therapy strategies may provide benefits, but “they’re not a substitute for clozapine,” Dr. Kane added, noting that the combinations that do appear to be the most effective involve clozapine.

And regarding drug switching, studies suggest the likelihood of response in switching from one drug to another is “actually very low,” Dr. Kane added.

Clozapine also doesn’t work for all – the response rate runs between about 30% and 60%, Dr. Kane said, but when it is effective, the benefits can be profound.

“There are some patients who have a very pronounced response to clozapine – some patients describe it as life-changing,” he said.
 

Treatment delays reduce efficacy

Importantly, the delays before receiving clozapine are not inconsequential – data show that each outpatient antipsychotic trial prior to clozapine reduces the likelihood of response by 8%-11%, and each hospital admission further reduces the likelihood of response by 4%-8%, underscoring the need to identify treatment resistance as early as possible, Dr. Kane said.

“It’s critically important to try to identify treatment resistance earlier than we usually do because if we can get it under control sooner, we have a better chance of improving the patient’s outcome, and this has been shown in a number of studies,” he said.

“The longer you wait, the less likely you are to see a good response even to clozapine.”

Despite the concerns about clozapine, Dr. Kane notes that even the blood monitoring does not appear to be a big complaint for patients, especially they are improving.

“In our experience, the patients who benefit from clozapine don’t really have a problem with the monitoring,” he said.

“In fact, patients who benefit from clozapine are much more adherent to the medication than other patients that we see, which is understandable, because if you feel you’re really getting a benefit from medicine, you’re going to be much more motivated to take it even if it has side effects.”

A recent systematic review of 13 studies and 1,487 patients backs that up, concluding that “patients generally have a favorable experience when being treated with clozapine,” with the caveat that “conclusions are limited by the risk of bias, particularly survivorship bias.”

Preference for clozapine over other antipsychotic medications was reported by 54%-86% of patients in the review, with specific improvements in mood (11%-78%) and cognition (5%-68%).
 

Clinicians the biggest ‘obstacle’

Dr. Kane notes that an important factor in underutilization could indeed be the manner in which clinicians discuss clozapine with their patients – often opening the discussion by focusing on the negative aspects that, without the context of the potential benefits, can be deal-breakers for patient from the start.

“The clinicians in my opinion are really the obstacle,” Dr. Kane said. “What we always hear from clinicians is ‘I can’t do it because the patient refuses, or the patient doesn’t like the side effects’.”

Dr. Kane notes that most side effects can indeed be managed – regarding the risk for metabolic syndrome, for instance, he recommends that patients should be given metformin from the beginning when they’re started on clozapine.

He adds that in most cases, a 3-month trial is enough to answer the question of whether clozapine is working or not.

“Three months is a good trial, but it may not even tell you the total response to clozapine because that may actually accrue over time,” he said. “We’ve seen patients who actually get better and better beyond 3 months.”

Not offering the drug to patients, however, is doing them a serious disservice, Dr. Kane added.

“What I tell patients and families is that it would be a shame to miss this opportunity for a potential treatment that could be life-changing,” he said. “Does it have potential side effects? Yes. Do you have to get blood tests? Yes. And I can’t tell by evaluating a patient’s history or examining that patient whether or not they’re going to be a good responder. But would you really want to miss an opportunity to find that out?”

“To me the argument is – let’s try this drug for 3 months and see what effect it has, and at that point you’ll be in a much better position to make a decision about the benefits versus risk,” Dr. Kane said.
 

The only FDA-approved drug for treatment-resistant schizophrenia

Remarkably, clozapine isn’t just the only drug to currently have approval from the FDA for treatment-resistant schizophrenia – it has been for the last 3 decades.

“There have been attempts to develop medications with similar efficacy, but they have not succeeded,” Dr. Kane said in an interview. “We are still uncertain as to what accounts for clozapine’s unique qualities.”

Yet, with treatment-resistant schizophrenia patients representing some of the most dire mental illness cases clinicians may face, the need for better treatment decisions – and additional options – is pressing, Dr. Kane said.

“[The lack of any other drugs] is a big embarrassment to our field, in my opinion,” he said. “I’m a big proponent of clozapine, but we should have found another substance by now that could substitute for clozapine, which obviously has a lot of side effects and is not the easiest drug to use.”

Dr. Kane reported relationships either as a speaker or consultant/advisory board member and/or receives research grant support from Alkermes, Allergan, Click Therapeutics, Dainippon Sumitomo, H. Lundbeck, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Neumora Therapeutics, Novartis Pharmaceuticals, Otsuka, Reviva, Roche, Saladax, Sunovion, Takeda, and Teva. Dr. Kane receives non-mutual funds stock ownership/stock options from LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics, and receives patent holder/royalties paid by UpToDate.

The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.

While nearly a quarter of patients with schizophrenia are reported to have primary treatment resistance, clozapine, known as the most effective antipsychotic for treatment-resistant schizophrenia – but burdened by concerns of side effects – remains significantly underprescribed, and when it is used, the drug is often delayed by several crucial years, reducing chances of efficacy.

“Despite being the only pharmacological therapy approved for treatment-resistant schizophrenia, clozapine is underutilized globally, even in developed countries, where only about 30% of patients who would benefit from the drug receive it,” said John M. Kane, MD, of the department of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., in a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.

Clozapine, a tricyclic dibenzodiazepine available in branded and various generic versions, is approved by the U.S. Food and Drug Administration as a third-line therapy for severe, treatment-resistant schizophrenia, with studies showing benefits exceeding those of any other antipsychotics for the indication.

But while recommendations suggest use after a trial of two or more antipsychotics, with at least one being an atypical antipsychotic, one recent review finds delays in clozapine commencement ranging from 19.3 weeks to 5.5 years, and the duration of illness prior to clozapine use ranging from 1.1 to 9.7 years.
 

Blood monitoring, side effects

The key deterrents preventing many clinicians and patients from trying clozapine sooner are the drug’s safety and tolerability profiles, and notably the requirement of regular blood testing due to an increased risk of agranulocytosis.

Specifically, the blood testing is required every week for 6 months, then every other week for the next 6 months, and then once a month after that; however, “many of us think that that’s excessive at this point in time,” Dr. Kane noted.

Various other potential side effects are also of concern, including myocarditis, seizures, constipation, arrhythmia, hypersalivation, pneumonia, and metabolic symptoms including diabetes.

In terms of the common strategies that clinicians turn to when patients fail to respond to their current antipsychotic, including increasing doses, combining agents, or treatment switching, “none of the strategies likely rival clozapine in terms of efficacy,” Dr. Kane said.

Regarding higher dosing: “There is very little data suggesting that higher doses of antipsychotic drugs will work when the moderate or recommended dose has not worked,” he said.

Combination therapy strategies may provide benefits, but “they’re not a substitute for clozapine,” Dr. Kane added, noting that the combinations that do appear to be the most effective involve clozapine.

And regarding drug switching, studies suggest the likelihood of response in switching from one drug to another is “actually very low,” Dr. Kane added.

Clozapine also doesn’t work for all – the response rate runs between about 30% and 60%, Dr. Kane said, but when it is effective, the benefits can be profound.

“There are some patients who have a very pronounced response to clozapine – some patients describe it as life-changing,” he said.
 

Treatment delays reduce efficacy

Importantly, the delays before receiving clozapine are not inconsequential – data show that each outpatient antipsychotic trial prior to clozapine reduces the likelihood of response by 8%-11%, and each hospital admission further reduces the likelihood of response by 4%-8%, underscoring the need to identify treatment resistance as early as possible, Dr. Kane said.

“It’s critically important to try to identify treatment resistance earlier than we usually do because if we can get it under control sooner, we have a better chance of improving the patient’s outcome, and this has been shown in a number of studies,” he said.

“The longer you wait, the less likely you are to see a good response even to clozapine.”

Despite the concerns about clozapine, Dr. Kane notes that even the blood monitoring does not appear to be a big complaint for patients, especially they are improving.

“In our experience, the patients who benefit from clozapine don’t really have a problem with the monitoring,” he said.

“In fact, patients who benefit from clozapine are much more adherent to the medication than other patients that we see, which is understandable, because if you feel you’re really getting a benefit from medicine, you’re going to be much more motivated to take it even if it has side effects.”

A recent systematic review of 13 studies and 1,487 patients backs that up, concluding that “patients generally have a favorable experience when being treated with clozapine,” with the caveat that “conclusions are limited by the risk of bias, particularly survivorship bias.”

Preference for clozapine over other antipsychotic medications was reported by 54%-86% of patients in the review, with specific improvements in mood (11%-78%) and cognition (5%-68%).
 

Clinicians the biggest ‘obstacle’

Dr. Kane notes that an important factor in underutilization could indeed be the manner in which clinicians discuss clozapine with their patients – often opening the discussion by focusing on the negative aspects that, without the context of the potential benefits, can be deal-breakers for patient from the start.

“The clinicians in my opinion are really the obstacle,” Dr. Kane said. “What we always hear from clinicians is ‘I can’t do it because the patient refuses, or the patient doesn’t like the side effects’.”

Dr. Kane notes that most side effects can indeed be managed – regarding the risk for metabolic syndrome, for instance, he recommends that patients should be given metformin from the beginning when they’re started on clozapine.

He adds that in most cases, a 3-month trial is enough to answer the question of whether clozapine is working or not.

“Three months is a good trial, but it may not even tell you the total response to clozapine because that may actually accrue over time,” he said. “We’ve seen patients who actually get better and better beyond 3 months.”

Not offering the drug to patients, however, is doing them a serious disservice, Dr. Kane added.

“What I tell patients and families is that it would be a shame to miss this opportunity for a potential treatment that could be life-changing,” he said. “Does it have potential side effects? Yes. Do you have to get blood tests? Yes. And I can’t tell by evaluating a patient’s history or examining that patient whether or not they’re going to be a good responder. But would you really want to miss an opportunity to find that out?”

“To me the argument is – let’s try this drug for 3 months and see what effect it has, and at that point you’ll be in a much better position to make a decision about the benefits versus risk,” Dr. Kane said.
 

The only FDA-approved drug for treatment-resistant schizophrenia

Remarkably, clozapine isn’t just the only drug to currently have approval from the FDA for treatment-resistant schizophrenia – it has been for the last 3 decades.

“There have been attempts to develop medications with similar efficacy, but they have not succeeded,” Dr. Kane said in an interview. “We are still uncertain as to what accounts for clozapine’s unique qualities.”

Yet, with treatment-resistant schizophrenia patients representing some of the most dire mental illness cases clinicians may face, the need for better treatment decisions – and additional options – is pressing, Dr. Kane said.

“[The lack of any other drugs] is a big embarrassment to our field, in my opinion,” he said. “I’m a big proponent of clozapine, but we should have found another substance by now that could substitute for clozapine, which obviously has a lot of side effects and is not the easiest drug to use.”

Dr. Kane reported relationships either as a speaker or consultant/advisory board member and/or receives research grant support from Alkermes, Allergan, Click Therapeutics, Dainippon Sumitomo, H. Lundbeck, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Neumora Therapeutics, Novartis Pharmaceuticals, Otsuka, Reviva, Roche, Saladax, Sunovion, Takeda, and Teva. Dr. Kane receives non-mutual funds stock ownership/stock options from LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics, and receives patent holder/royalties paid by UpToDate.

The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.

While nearly a quarter of patients with schizophrenia are reported to have primary treatment resistance, clozapine, known as the most effective antipsychotic for treatment-resistant schizophrenia – but burdened by concerns of side effects – remains significantly underprescribed, and when it is used, the drug is often delayed by several crucial years, reducing chances of efficacy.

“Despite being the only pharmacological therapy approved for treatment-resistant schizophrenia, clozapine is underutilized globally, even in developed countries, where only about 30% of patients who would benefit from the drug receive it,” said John M. Kane, MD, of the department of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., in a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.

Clozapine, a tricyclic dibenzodiazepine available in branded and various generic versions, is approved by the U.S. Food and Drug Administration as a third-line therapy for severe, treatment-resistant schizophrenia, with studies showing benefits exceeding those of any other antipsychotics for the indication.

But while recommendations suggest use after a trial of two or more antipsychotics, with at least one being an atypical antipsychotic, one recent review finds delays in clozapine commencement ranging from 19.3 weeks to 5.5 years, and the duration of illness prior to clozapine use ranging from 1.1 to 9.7 years.
 

Blood monitoring, side effects

The key deterrents preventing many clinicians and patients from trying clozapine sooner are the drug’s safety and tolerability profiles, and notably the requirement of regular blood testing due to an increased risk of agranulocytosis.

Specifically, the blood testing is required every week for 6 months, then every other week for the next 6 months, and then once a month after that; however, “many of us think that that’s excessive at this point in time,” Dr. Kane noted.

Various other potential side effects are also of concern, including myocarditis, seizures, constipation, arrhythmia, hypersalivation, pneumonia, and metabolic symptoms including diabetes.

In terms of the common strategies that clinicians turn to when patients fail to respond to their current antipsychotic, including increasing doses, combining agents, or treatment switching, “none of the strategies likely rival clozapine in terms of efficacy,” Dr. Kane said.

Regarding higher dosing: “There is very little data suggesting that higher doses of antipsychotic drugs will work when the moderate or recommended dose has not worked,” he said.

Combination therapy strategies may provide benefits, but “they’re not a substitute for clozapine,” Dr. Kane added, noting that the combinations that do appear to be the most effective involve clozapine.

And regarding drug switching, studies suggest the likelihood of response in switching from one drug to another is “actually very low,” Dr. Kane added.

Clozapine also doesn’t work for all – the response rate runs between about 30% and 60%, Dr. Kane said, but when it is effective, the benefits can be profound.

“There are some patients who have a very pronounced response to clozapine – some patients describe it as life-changing,” he said.
 

Treatment delays reduce efficacy

Importantly, the delays before receiving clozapine are not inconsequential – data show that each outpatient antipsychotic trial prior to clozapine reduces the likelihood of response by 8%-11%, and each hospital admission further reduces the likelihood of response by 4%-8%, underscoring the need to identify treatment resistance as early as possible, Dr. Kane said.

“It’s critically important to try to identify treatment resistance earlier than we usually do because if we can get it under control sooner, we have a better chance of improving the patient’s outcome, and this has been shown in a number of studies,” he said.

“The longer you wait, the less likely you are to see a good response even to clozapine.”

Despite the concerns about clozapine, Dr. Kane notes that even the blood monitoring does not appear to be a big complaint for patients, especially they are improving.

“In our experience, the patients who benefit from clozapine don’t really have a problem with the monitoring,” he said.

“In fact, patients who benefit from clozapine are much more adherent to the medication than other patients that we see, which is understandable, because if you feel you’re really getting a benefit from medicine, you’re going to be much more motivated to take it even if it has side effects.”

A recent systematic review of 13 studies and 1,487 patients backs that up, concluding that “patients generally have a favorable experience when being treated with clozapine,” with the caveat that “conclusions are limited by the risk of bias, particularly survivorship bias.”

Preference for clozapine over other antipsychotic medications was reported by 54%-86% of patients in the review, with specific improvements in mood (11%-78%) and cognition (5%-68%).
 

Clinicians the biggest ‘obstacle’

Dr. Kane notes that an important factor in underutilization could indeed be the manner in which clinicians discuss clozapine with their patients – often opening the discussion by focusing on the negative aspects that, without the context of the potential benefits, can be deal-breakers for patient from the start.

“The clinicians in my opinion are really the obstacle,” Dr. Kane said. “What we always hear from clinicians is ‘I can’t do it because the patient refuses, or the patient doesn’t like the side effects’.”

Dr. Kane notes that most side effects can indeed be managed – regarding the risk for metabolic syndrome, for instance, he recommends that patients should be given metformin from the beginning when they’re started on clozapine.

He adds that in most cases, a 3-month trial is enough to answer the question of whether clozapine is working or not.

“Three months is a good trial, but it may not even tell you the total response to clozapine because that may actually accrue over time,” he said. “We’ve seen patients who actually get better and better beyond 3 months.”

Not offering the drug to patients, however, is doing them a serious disservice, Dr. Kane added.

“What I tell patients and families is that it would be a shame to miss this opportunity for a potential treatment that could be life-changing,” he said. “Does it have potential side effects? Yes. Do you have to get blood tests? Yes. And I can’t tell by evaluating a patient’s history or examining that patient whether or not they’re going to be a good responder. But would you really want to miss an opportunity to find that out?”

“To me the argument is – let’s try this drug for 3 months and see what effect it has, and at that point you’ll be in a much better position to make a decision about the benefits versus risk,” Dr. Kane said.
 

The only FDA-approved drug for treatment-resistant schizophrenia

Remarkably, clozapine isn’t just the only drug to currently have approval from the FDA for treatment-resistant schizophrenia – it has been for the last 3 decades.

“There have been attempts to develop medications with similar efficacy, but they have not succeeded,” Dr. Kane said in an interview. “We are still uncertain as to what accounts for clozapine’s unique qualities.”

Yet, with treatment-resistant schizophrenia patients representing some of the most dire mental illness cases clinicians may face, the need for better treatment decisions – and additional options – is pressing, Dr. Kane said.

“[The lack of any other drugs] is a big embarrassment to our field, in my opinion,” he said. “I’m a big proponent of clozapine, but we should have found another substance by now that could substitute for clozapine, which obviously has a lot of side effects and is not the easiest drug to use.”

Dr. Kane reported relationships either as a speaker or consultant/advisory board member and/or receives research grant support from Alkermes, Allergan, Click Therapeutics, Dainippon Sumitomo, H. Lundbeck, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Neumora Therapeutics, Novartis Pharmaceuticals, Otsuka, Reviva, Roche, Saladax, Sunovion, Takeda, and Teva. Dr. Kane receives non-mutual funds stock ownership/stock options from LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics, and receives patent holder/royalties paid by UpToDate.

The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.

MONTREAL – In the treatment of thyroid nodules with radiofrequency ablation (RFA), the amount of energy delivered per unit volume of the nodule strongly correlates with the extent of nodule volume reduction after 6 and 12 months, suggesting an important indicator of treatment success.

The findings “provide an objective measure or goal energy input to achieve during the [RFA] procedure rather than relying only on the subjective judgment of sonographic changes, and in turn, produce more reliable outcomes for our patients,” first author Samantha A. Wolfe, MD, said in an interview.

Dr. Wolfe, of the department of otolaryngology – head and neck surgery at Johns Hopkins University, Baltimore, presented the findings at the American Thyroid Association annual meeting.

Commenting on the study, Insoo Suh, MD, an associate professor and associate vice chair of Surgical Innovation at New York University Langone Health, agreed that “an accounting of the total amount of energy delivered can be a useful additional data point for the operator when they are determining whether an ablation is successful.”

He noted, however, that the location of a nodule can be an important factor when deciding upon amounts of RF energy.

“Some target areas are too close for comfort to critical structures, such as the trachea or the recurrent laryngeal nerve, so sound judgment would dictate that the energy be dialed down in those areas, even if the price you pay is a slightly lower volume reduction,” he explained. 
 

Analysis of patients given RFA at Johns Hopkins

RFA utilizes RF energy for the reduction of nodule compression and aesthetic symptoms, avoiding the need for thyroid hormone replacement or surgery.

And while decisions regarding RFA treatment location and duration are commonly guided by the operator’s judgment of sonographic changes, those assessments can potentially result in inconsistent outcomes.

In observing a relationship between higher amounts of RF energy and nodule volume reduction, Dr. Wolfe and associates conducted their prospective study of nodules treated by two experienced endocrine surgeons at Johns Hopkins between June 2019 and May 2022 at 6 and 12 months in relation to the amount of total energy delivered during the treatment.

The analysis included 101 nodules, which had a median initial volume of 12.9 mL.

After 6 months, the median volume reduction ratio was 60%, and at 12 months, the median reduction was 64%.

In terms of the goal of achieving 50% or more volume reduction at 6 months, the median energy delivered was significantly higher for nodules that did reach that goal compared with those that had a volume reduction of less than 50% (2,317 vs. 1,912 J/mL, respectively; P = .01).

The figures were similar at 12 months (2,031 vs. 1254 J/mL; P < .01).

In a logistic regression analysis, the amount of energy delivered strongly increased the odds of obtaining a volume reduction ratio of at least 50% (odds ratio, 2.58; P = .048).

“Every twofold increase in energy delivered increases the odds of achieving a 50% volume ratio reduction by 2.58 times,” Dr. Wolfe explained.

Likewise, the same twofold increase in energy delivered also increased the odds of achieving a greater than 80% volume ratio reduction by 2.55 times (OR, 2.55; P = .038), she added.
 

Information may help to decide who needs multiple ablations

Of note, the effect was stronger with smaller nodules. Those with an initial volume of less than 20 mL had a significantly greater volume ratio reduction than nodules that were 20 mL or larger (61% vs. 48%, respectively; P = .05).

The initial volume of nodules that did, and did not, achieve a 50% volume ratio reduction at 6 months were 10.9 mL versus 19.1 mL, and the initial volumes of those that did, and did not, have at least a 50% reduction at 12 months were 10.5 mL and 41.5 mL.

“At 6 and 12 months, the successfully treated nodules had a significantly smaller immediate initial volume than those that did not,” Dr. Wolfe said.

“This information may aid in identifying patients with large nodules that are less likely to achieve a greater than 50% volume reduction ratio and may require multiple treatments,” she added.

Other factors – including the probe tip size and total energy delivered – did not significantly correlate with volume ratio reduction at 6 or 12 months.

There was also no significant difference in terms of thyroid-stimulating hormone levels among nodules that achieved at least a 50% volume reduction and those that did not.

Nodules that did not have a satisfactory volume reduction at 12 months had a relatively large median total energy value delivered during ablation (103,463 J, compared with 25,969 J among those achieving more than 50% volume ratio reduction), which Dr. Wolfe said likely reflects that those nodules had a large initial volume.

“This speaks to the importance of describing the energy utilized per unit of nodule volume rather than just a gross measurement,” she said during her presentation.

Dr. Wolfe added that in terms of strategies for getting more energy into the nodule, a key approach is time.

“Sometimes you will see sonographic changes very quickly in the nodule, and it could be tempting to consider that area ablated and move on if you only rely on sonographic changes,” she said in an interview. “However, our research shows that, by spending more time, and thus inputting more energy into the nodule, we had better volume reduction.”

Dr. Wolfe and Dr. Suh reported no relevant financial relationships.

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

MONTREAL – In the treatment of thyroid nodules with radiofrequency ablation (RFA), the amount of energy delivered per unit volume of the nodule strongly correlates with the extent of nodule volume reduction after 6 and 12 months, suggesting an important indicator of treatment success.

The findings “provide an objective measure or goal energy input to achieve during the [RFA] procedure rather than relying only on the subjective judgment of sonographic changes, and in turn, produce more reliable outcomes for our patients,” first author Samantha A. Wolfe, MD, said in an interview.

Dr. Wolfe, of the department of otolaryngology – head and neck surgery at Johns Hopkins University, Baltimore, presented the findings at the American Thyroid Association annual meeting.

Commenting on the study, Insoo Suh, MD, an associate professor and associate vice chair of Surgical Innovation at New York University Langone Health, agreed that “an accounting of the total amount of energy delivered can be a useful additional data point for the operator when they are determining whether an ablation is successful.”

He noted, however, that the location of a nodule can be an important factor when deciding upon amounts of RF energy.

“Some target areas are too close for comfort to critical structures, such as the trachea or the recurrent laryngeal nerve, so sound judgment would dictate that the energy be dialed down in those areas, even if the price you pay is a slightly lower volume reduction,” he explained. 
 

Analysis of patients given RFA at Johns Hopkins

RFA utilizes RF energy for the reduction of nodule compression and aesthetic symptoms, avoiding the need for thyroid hormone replacement or surgery.

And while decisions regarding RFA treatment location and duration are commonly guided by the operator’s judgment of sonographic changes, those assessments can potentially result in inconsistent outcomes.

In observing a relationship between higher amounts of RF energy and nodule volume reduction, Dr. Wolfe and associates conducted their prospective study of nodules treated by two experienced endocrine surgeons at Johns Hopkins between June 2019 and May 2022 at 6 and 12 months in relation to the amount of total energy delivered during the treatment.

The analysis included 101 nodules, which had a median initial volume of 12.9 mL.

After 6 months, the median volume reduction ratio was 60%, and at 12 months, the median reduction was 64%.

In terms of the goal of achieving 50% or more volume reduction at 6 months, the median energy delivered was significantly higher for nodules that did reach that goal compared with those that had a volume reduction of less than 50% (2,317 vs. 1,912 J/mL, respectively; P = .01).

The figures were similar at 12 months (2,031 vs. 1254 J/mL; P < .01).

In a logistic regression analysis, the amount of energy delivered strongly increased the odds of obtaining a volume reduction ratio of at least 50% (odds ratio, 2.58; P = .048).

“Every twofold increase in energy delivered increases the odds of achieving a 50% volume ratio reduction by 2.58 times,” Dr. Wolfe explained.

Likewise, the same twofold increase in energy delivered also increased the odds of achieving a greater than 80% volume ratio reduction by 2.55 times (OR, 2.55; P = .038), she added.
 

Information may help to decide who needs multiple ablations

Of note, the effect was stronger with smaller nodules. Those with an initial volume of less than 20 mL had a significantly greater volume ratio reduction than nodules that were 20 mL or larger (61% vs. 48%, respectively; P = .05).

The initial volume of nodules that did, and did not, achieve a 50% volume ratio reduction at 6 months were 10.9 mL versus 19.1 mL, and the initial volumes of those that did, and did not, have at least a 50% reduction at 12 months were 10.5 mL and 41.5 mL.

“At 6 and 12 months, the successfully treated nodules had a significantly smaller immediate initial volume than those that did not,” Dr. Wolfe said.

“This information may aid in identifying patients with large nodules that are less likely to achieve a greater than 50% volume reduction ratio and may require multiple treatments,” she added.

Other factors – including the probe tip size and total energy delivered – did not significantly correlate with volume ratio reduction at 6 or 12 months.

There was also no significant difference in terms of thyroid-stimulating hormone levels among nodules that achieved at least a 50% volume reduction and those that did not.

Nodules that did not have a satisfactory volume reduction at 12 months had a relatively large median total energy value delivered during ablation (103,463 J, compared with 25,969 J among those achieving more than 50% volume ratio reduction), which Dr. Wolfe said likely reflects that those nodules had a large initial volume.

“This speaks to the importance of describing the energy utilized per unit of nodule volume rather than just a gross measurement,” she said during her presentation.

Dr. Wolfe added that in terms of strategies for getting more energy into the nodule, a key approach is time.

“Sometimes you will see sonographic changes very quickly in the nodule, and it could be tempting to consider that area ablated and move on if you only rely on sonographic changes,” she said in an interview. “However, our research shows that, by spending more time, and thus inputting more energy into the nodule, we had better volume reduction.”

Dr. Wolfe and Dr. Suh reported no relevant financial relationships.

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

MONTREAL – In the treatment of thyroid nodules with radiofrequency ablation (RFA), the amount of energy delivered per unit volume of the nodule strongly correlates with the extent of nodule volume reduction after 6 and 12 months, suggesting an important indicator of treatment success.

The findings “provide an objective measure or goal energy input to achieve during the [RFA] procedure rather than relying only on the subjective judgment of sonographic changes, and in turn, produce more reliable outcomes for our patients,” first author Samantha A. Wolfe, MD, said in an interview.

Dr. Wolfe, of the department of otolaryngology – head and neck surgery at Johns Hopkins University, Baltimore, presented the findings at the American Thyroid Association annual meeting.

Commenting on the study, Insoo Suh, MD, an associate professor and associate vice chair of Surgical Innovation at New York University Langone Health, agreed that “an accounting of the total amount of energy delivered can be a useful additional data point for the operator when they are determining whether an ablation is successful.”

He noted, however, that the location of a nodule can be an important factor when deciding upon amounts of RF energy.

“Some target areas are too close for comfort to critical structures, such as the trachea or the recurrent laryngeal nerve, so sound judgment would dictate that the energy be dialed down in those areas, even if the price you pay is a slightly lower volume reduction,” he explained. 
 

Analysis of patients given RFA at Johns Hopkins

RFA utilizes RF energy for the reduction of nodule compression and aesthetic symptoms, avoiding the need for thyroid hormone replacement or surgery.

And while decisions regarding RFA treatment location and duration are commonly guided by the operator’s judgment of sonographic changes, those assessments can potentially result in inconsistent outcomes.

In observing a relationship between higher amounts of RF energy and nodule volume reduction, Dr. Wolfe and associates conducted their prospective study of nodules treated by two experienced endocrine surgeons at Johns Hopkins between June 2019 and May 2022 at 6 and 12 months in relation to the amount of total energy delivered during the treatment.

The analysis included 101 nodules, which had a median initial volume of 12.9 mL.

After 6 months, the median volume reduction ratio was 60%, and at 12 months, the median reduction was 64%.

In terms of the goal of achieving 50% or more volume reduction at 6 months, the median energy delivered was significantly higher for nodules that did reach that goal compared with those that had a volume reduction of less than 50% (2,317 vs. 1,912 J/mL, respectively; P = .01).

The figures were similar at 12 months (2,031 vs. 1254 J/mL; P < .01).

In a logistic regression analysis, the amount of energy delivered strongly increased the odds of obtaining a volume reduction ratio of at least 50% (odds ratio, 2.58; P = .048).

“Every twofold increase in energy delivered increases the odds of achieving a 50% volume ratio reduction by 2.58 times,” Dr. Wolfe explained.

Likewise, the same twofold increase in energy delivered also increased the odds of achieving a greater than 80% volume ratio reduction by 2.55 times (OR, 2.55; P = .038), she added.
 

Information may help to decide who needs multiple ablations

Of note, the effect was stronger with smaller nodules. Those with an initial volume of less than 20 mL had a significantly greater volume ratio reduction than nodules that were 20 mL or larger (61% vs. 48%, respectively; P = .05).

The initial volume of nodules that did, and did not, achieve a 50% volume ratio reduction at 6 months were 10.9 mL versus 19.1 mL, and the initial volumes of those that did, and did not, have at least a 50% reduction at 12 months were 10.5 mL and 41.5 mL.

“At 6 and 12 months, the successfully treated nodules had a significantly smaller immediate initial volume than those that did not,” Dr. Wolfe said.

“This information may aid in identifying patients with large nodules that are less likely to achieve a greater than 50% volume reduction ratio and may require multiple treatments,” she added.

Other factors – including the probe tip size and total energy delivered – did not significantly correlate with volume ratio reduction at 6 or 12 months.

There was also no significant difference in terms of thyroid-stimulating hormone levels among nodules that achieved at least a 50% volume reduction and those that did not.

Nodules that did not have a satisfactory volume reduction at 12 months had a relatively large median total energy value delivered during ablation (103,463 J, compared with 25,969 J among those achieving more than 50% volume ratio reduction), which Dr. Wolfe said likely reflects that those nodules had a large initial volume.

“This speaks to the importance of describing the energy utilized per unit of nodule volume rather than just a gross measurement,” she said during her presentation.

Dr. Wolfe added that in terms of strategies for getting more energy into the nodule, a key approach is time.

“Sometimes you will see sonographic changes very quickly in the nodule, and it could be tempting to consider that area ablated and move on if you only rely on sonographic changes,” she said in an interview. “However, our research shows that, by spending more time, and thus inputting more energy into the nodule, we had better volume reduction.”

Dr. Wolfe and Dr. Suh reported no relevant financial relationships.

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

MONTREAL – Patients hospitalized with severe COVID-19 and no prior history of thyroid dysfunction show signs of thyroiditis that, although asymptomatic, continue to persist for up to a year after infection, according to research that adds to evidence on the complex involvement of the thyroid in COVID-19.

“To our knowledge these findings are novel,” first author Ilaria Muller, MD, PhD, an assistant professor in endocrinology in the department of clinical sciences and community health, University of Milan, told this news organization.

“Little has been written about the long-term follow-up of thyroid function after severe COVID-19 disease, and we have followed patients up to 1 year after infection.”

The effects are seen in about 10%-15% of patients, and “[while] the thyroid dysfunction is transient, ultrasound areas of thyroiditis may persist after 1 year, even if they progressively shrink,” said Dr. Muller, who presented the findings at the American Thyroid Association annual meeting.
 

Immunological scars? Clinical implications unclear

The nature and implications of the persistent thyroiditis areas are uncertain, Dr. Muller noted. “These areas of thyroiditis are likely a sort of ‘immunologic scar’ of the previous SARS-CoV-2 infection,” she explained. “We still don’t know if there are clinical implications, even if they seem unlikely.”

Of note, increases in autoimmune processes or a higher incidence of thyroid dysfunction after COVID-19 have not been observed, and the shrinkage of the areas of thyroiditis over time is encouraging, she said.

The reasons why some patients develop atypical thyroiditis and others don’t are also unclear, with Dr. Muller’s team investigating further. Importantly, similar effects have been associated with other severe infections, not just COVID-19. “It is well known that in classic subacute thyroiditis due to other viral infections, the areas of thyroiditis persist for months, so this phenomenon might not be unique to COVID-19,” she explained.

Commenting on the story, Jeffrey R. Garber, MD, also noted that such thyroiditis areas stemming from other types of infection may persist – but go unnoticed.

“Resolution is the clinical rule, [and] we generally do not restudy in detail those who clinically recover,” he said in an interview. “However, there is evidence of impaired thyroid reserve in those who recover from viral thyroiditis due to other sources.”

“Thyroid symptoms are often not specific, so ‘atypical’ [cases] are common, [and] resolution with restoring thyroid status to normal is mixed,” noted Dr. Garber, an associate professor of medicine at Harvard Medical School and chief of the division of endocrinology at Atrius Health, Boston.

In terms of clinical practice, while such issues should be kept in mind when evaluating abnormal thyroid tests during severe COVID-19, “it is not a call for routinely checking it in the absence of clinical suspicion,” he observed.
 

Study details

Dr. Muller and her team previously observed that patients hospitalized in intensive care with COVID-19 often had low or suppressed serum thyroid-stimulating hormone (TSH) levels, with and without elevated free thyroxine (FT₄) concentrations, suggestive of thyrotoxicosis.

Upon investigating those cases, they found, as in their previous study reported by this news organization, that a painless, atypical thyroiditis occurs with nonthyroidal illness syndrome among patients hospitalized with severe COVID-19. The atypical thyroiditis was slightly more common in men and was associated with lymphopenia.

To further investigate those cases and follow patients up to 1 year, the team conducted a longitudinal study of 183 patients hospitalized with severe COVID-19 in Italy. The patients, who had no known prior history of thyroid dysfunction, were assessed for serum thyroid function, autoantibodies, and inflammatory markers.

At baseline, 10% of the patients were found to have thyrotoxicosis, and ultrasound performed within 2-3 months postinfection on 65 patients showed that 18 (28%) had areas of thyroiditis.

Importantly, 60% of those patients with the areas of thyroiditis had low TSH levels, while 25% had normal TSH levels (P = .034).

In addition, those showing the presence of thyroiditis on ultrasound at 23 months were more likely to have elevated serum concentrations of FT₄ (P = .018) and higher levels of interleukin-26 (P = .016), compared with those with normal ultrasound readings.

In a longitudinal analysis further following patients post infection, among 15 patients who were evaluated at 6 months, most, 13 (87%), still had areas of thyroiditis, and 6 of 12 (50%) had thyroiditis areas that, though reduced in size, still persisted even at 12 months.

In terms of thyroid uptake, at 3 months, 14 of 17 patients (82%) had diffused or focal areas of a reduction of uptake. After 6 months, there was a recovery, with a median of 28% of thyroid uptake recovered, however, 67% of patients still had some focal or diffused reduction in thyroid uptake.

Of note, the indications of thyroiditis on imaging persisted even though patients’ TSH levels had quickly normalized at the end of infection and remained normal up to 1 year of follow-up.

The patients showed no apparent development of thyroglobulin antibody, thyroid peroxidase antibodies, or TSH receptor antibodies.

A further fine needle aspiration analysis of eight patients with atypical thyroiditis at 3 months after infection showed that those patients had tissue resident memory T cells (CD4+/CD8+/CD103+/CD69+) within the thyroid, but not in the blood as expected.

Additional assessments at 8 months after infection showed those tissue resident memory T cells continued to be present on imaging.

The results showed “SARS-CoV-2–specific T cells were enriched within the thyroid compared with the blood, many with a tissue resident phenotype,” Dr. Muller explained.

The findings are notable in that “such an in-depth characterization of areas of thyroiditis triggered by SARS-CoV-2 infection combining ultrasound, scintigraphy, and immunological phenotyping has not been performed so far,” she said.

“In particular, SARS-CoV-2–specific tissue-resident memory T lymphocytes have not been described before in the thyroid gland.”

Dr. Muller and Dr. Garber have reported no relevant financial relationships.

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

MONTREAL – Patients hospitalized with severe COVID-19 and no prior history of thyroid dysfunction show signs of thyroiditis that, although asymptomatic, continue to persist for up to a year after infection, according to research that adds to evidence on the complex involvement of the thyroid in COVID-19.

“To our knowledge these findings are novel,” first author Ilaria Muller, MD, PhD, an assistant professor in endocrinology in the department of clinical sciences and community health, University of Milan, told this news organization.

“Little has been written about the long-term follow-up of thyroid function after severe COVID-19 disease, and we have followed patients up to 1 year after infection.”

The effects are seen in about 10%-15% of patients, and “[while] the thyroid dysfunction is transient, ultrasound areas of thyroiditis may persist after 1 year, even if they progressively shrink,” said Dr. Muller, who presented the findings at the American Thyroid Association annual meeting.
 

Immunological scars? Clinical implications unclear

The nature and implications of the persistent thyroiditis areas are uncertain, Dr. Muller noted. “These areas of thyroiditis are likely a sort of ‘immunologic scar’ of the previous SARS-CoV-2 infection,” she explained. “We still don’t know if there are clinical implications, even if they seem unlikely.”

Of note, increases in autoimmune processes or a higher incidence of thyroid dysfunction after COVID-19 have not been observed, and the shrinkage of the areas of thyroiditis over time is encouraging, she said.

The reasons why some patients develop atypical thyroiditis and others don’t are also unclear, with Dr. Muller’s team investigating further. Importantly, similar effects have been associated with other severe infections, not just COVID-19. “It is well known that in classic subacute thyroiditis due to other viral infections, the areas of thyroiditis persist for months, so this phenomenon might not be unique to COVID-19,” she explained.

Commenting on the story, Jeffrey R. Garber, MD, also noted that such thyroiditis areas stemming from other types of infection may persist – but go unnoticed.

“Resolution is the clinical rule, [and] we generally do not restudy in detail those who clinically recover,” he said in an interview. “However, there is evidence of impaired thyroid reserve in those who recover from viral thyroiditis due to other sources.”

“Thyroid symptoms are often not specific, so ‘atypical’ [cases] are common, [and] resolution with restoring thyroid status to normal is mixed,” noted Dr. Garber, an associate professor of medicine at Harvard Medical School and chief of the division of endocrinology at Atrius Health, Boston.

In terms of clinical practice, while such issues should be kept in mind when evaluating abnormal thyroid tests during severe COVID-19, “it is not a call for routinely checking it in the absence of clinical suspicion,” he observed.
 

Study details

Dr. Muller and her team previously observed that patients hospitalized in intensive care with COVID-19 often had low or suppressed serum thyroid-stimulating hormone (TSH) levels, with and without elevated free thyroxine (FT₄) concentrations, suggestive of thyrotoxicosis.

Upon investigating those cases, they found, as in their previous study reported by this news organization, that a painless, atypical thyroiditis occurs with nonthyroidal illness syndrome among patients hospitalized with severe COVID-19. The atypical thyroiditis was slightly more common in men and was associated with lymphopenia.

To further investigate those cases and follow patients up to 1 year, the team conducted a longitudinal study of 183 patients hospitalized with severe COVID-19 in Italy. The patients, who had no known prior history of thyroid dysfunction, were assessed for serum thyroid function, autoantibodies, and inflammatory markers.

At baseline, 10% of the patients were found to have thyrotoxicosis, and ultrasound performed within 2-3 months postinfection on 65 patients showed that 18 (28%) had areas of thyroiditis.

Importantly, 60% of those patients with the areas of thyroiditis had low TSH levels, while 25% had normal TSH levels (P = .034).

In addition, those showing the presence of thyroiditis on ultrasound at 23 months were more likely to have elevated serum concentrations of FT₄ (P = .018) and higher levels of interleukin-26 (P = .016), compared with those with normal ultrasound readings.

In a longitudinal analysis further following patients post infection, among 15 patients who were evaluated at 6 months, most, 13 (87%), still had areas of thyroiditis, and 6 of 12 (50%) had thyroiditis areas that, though reduced in size, still persisted even at 12 months.

In terms of thyroid uptake, at 3 months, 14 of 17 patients (82%) had diffused or focal areas of a reduction of uptake. After 6 months, there was a recovery, with a median of 28% of thyroid uptake recovered, however, 67% of patients still had some focal or diffused reduction in thyroid uptake.

Of note, the indications of thyroiditis on imaging persisted even though patients’ TSH levels had quickly normalized at the end of infection and remained normal up to 1 year of follow-up.

The patients showed no apparent development of thyroglobulin antibody, thyroid peroxidase antibodies, or TSH receptor antibodies.

A further fine needle aspiration analysis of eight patients with atypical thyroiditis at 3 months after infection showed that those patients had tissue resident memory T cells (CD4+/CD8+/CD103+/CD69+) within the thyroid, but not in the blood as expected.

Additional assessments at 8 months after infection showed those tissue resident memory T cells continued to be present on imaging.

The results showed “SARS-CoV-2–specific T cells were enriched within the thyroid compared with the blood, many with a tissue resident phenotype,” Dr. Muller explained.

The findings are notable in that “such an in-depth characterization of areas of thyroiditis triggered by SARS-CoV-2 infection combining ultrasound, scintigraphy, and immunological phenotyping has not been performed so far,” she said.

“In particular, SARS-CoV-2–specific tissue-resident memory T lymphocytes have not been described before in the thyroid gland.”

Dr. Muller and Dr. Garber have reported no relevant financial relationships.

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

MONTREAL – Patients hospitalized with severe COVID-19 and no prior history of thyroid dysfunction show signs of thyroiditis that, although asymptomatic, continue to persist for up to a year after infection, according to research that adds to evidence on the complex involvement of the thyroid in COVID-19.

“To our knowledge these findings are novel,” first author Ilaria Muller, MD, PhD, an assistant professor in endocrinology in the department of clinical sciences and community health, University of Milan, told this news organization.

“Little has been written about the long-term follow-up of thyroid function after severe COVID-19 disease, and we have followed patients up to 1 year after infection.”

The effects are seen in about 10%-15% of patients, and “[while] the thyroid dysfunction is transient, ultrasound areas of thyroiditis may persist after 1 year, even if they progressively shrink,” said Dr. Muller, who presented the findings at the American Thyroid Association annual meeting.
 

Immunological scars? Clinical implications unclear

The nature and implications of the persistent thyroiditis areas are uncertain, Dr. Muller noted. “These areas of thyroiditis are likely a sort of ‘immunologic scar’ of the previous SARS-CoV-2 infection,” she explained. “We still don’t know if there are clinical implications, even if they seem unlikely.”

Of note, increases in autoimmune processes or a higher incidence of thyroid dysfunction after COVID-19 have not been observed, and the shrinkage of the areas of thyroiditis over time is encouraging, she said.

The reasons why some patients develop atypical thyroiditis and others don’t are also unclear, with Dr. Muller’s team investigating further. Importantly, similar effects have been associated with other severe infections, not just COVID-19. “It is well known that in classic subacute thyroiditis due to other viral infections, the areas of thyroiditis persist for months, so this phenomenon might not be unique to COVID-19,” she explained.

Commenting on the story, Jeffrey R. Garber, MD, also noted that such thyroiditis areas stemming from other types of infection may persist – but go unnoticed.

“Resolution is the clinical rule, [and] we generally do not restudy in detail those who clinically recover,” he said in an interview. “However, there is evidence of impaired thyroid reserve in those who recover from viral thyroiditis due to other sources.”

“Thyroid symptoms are often not specific, so ‘atypical’ [cases] are common, [and] resolution with restoring thyroid status to normal is mixed,” noted Dr. Garber, an associate professor of medicine at Harvard Medical School and chief of the division of endocrinology at Atrius Health, Boston.

In terms of clinical practice, while such issues should be kept in mind when evaluating abnormal thyroid tests during severe COVID-19, “it is not a call for routinely checking it in the absence of clinical suspicion,” he observed.
 

Study details

Dr. Muller and her team previously observed that patients hospitalized in intensive care with COVID-19 often had low or suppressed serum thyroid-stimulating hormone (TSH) levels, with and without elevated free thyroxine (FT₄) concentrations, suggestive of thyrotoxicosis.

Upon investigating those cases, they found, as in their previous study reported by this news organization, that a painless, atypical thyroiditis occurs with nonthyroidal illness syndrome among patients hospitalized with severe COVID-19. The atypical thyroiditis was slightly more common in men and was associated with lymphopenia.

To further investigate those cases and follow patients up to 1 year, the team conducted a longitudinal study of 183 patients hospitalized with severe COVID-19 in Italy. The patients, who had no known prior history of thyroid dysfunction, were assessed for serum thyroid function, autoantibodies, and inflammatory markers.

At baseline, 10% of the patients were found to have thyrotoxicosis, and ultrasound performed within 2-3 months postinfection on 65 patients showed that 18 (28%) had areas of thyroiditis.

Importantly, 60% of those patients with the areas of thyroiditis had low TSH levels, while 25% had normal TSH levels (P = .034).

In addition, those showing the presence of thyroiditis on ultrasound at 23 months were more likely to have elevated serum concentrations of FT₄ (P = .018) and higher levels of interleukin-26 (P = .016), compared with those with normal ultrasound readings.

In a longitudinal analysis further following patients post infection, among 15 patients who were evaluated at 6 months, most, 13 (87%), still had areas of thyroiditis, and 6 of 12 (50%) had thyroiditis areas that, though reduced in size, still persisted even at 12 months.

In terms of thyroid uptake, at 3 months, 14 of 17 patients (82%) had diffused or focal areas of a reduction of uptake. After 6 months, there was a recovery, with a median of 28% of thyroid uptake recovered, however, 67% of patients still had some focal or diffused reduction in thyroid uptake.

Of note, the indications of thyroiditis on imaging persisted even though patients’ TSH levels had quickly normalized at the end of infection and remained normal up to 1 year of follow-up.

The patients showed no apparent development of thyroglobulin antibody, thyroid peroxidase antibodies, or TSH receptor antibodies.

A further fine needle aspiration analysis of eight patients with atypical thyroiditis at 3 months after infection showed that those patients had tissue resident memory T cells (CD4+/CD8+/CD103+/CD69+) within the thyroid, but not in the blood as expected.

Additional assessments at 8 months after infection showed those tissue resident memory T cells continued to be present on imaging.

The results showed “SARS-CoV-2–specific T cells were enriched within the thyroid compared with the blood, many with a tissue resident phenotype,” Dr. Muller explained.

The findings are notable in that “such an in-depth characterization of areas of thyroiditis triggered by SARS-CoV-2 infection combining ultrasound, scintigraphy, and immunological phenotyping has not been performed so far,” she said.

“In particular, SARS-CoV-2–specific tissue-resident memory T lymphocytes have not been described before in the thyroid gland.”

Dr. Muller and Dr. Garber have reported no relevant financial relationships.

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

Expanding eligibility for active surveillance in low-risk papillary thyroid cancer appears to be safe, a new prospective trial indicates.

Researchers found that doubling the limits for tumor size to 2 cm and nearly doubling the limits for tumor growth in low-risk papillary thyroid cancer showed no increased risk of adverse outcomes or mortality for patients undergoing active surveillance versus surgery.

“The results of this nonrandomized controlled trial suggest the basis of a more permissive strategy for thyroid cancer management, strengthening the evidence for active surveillance and broadening potential candidacy to most diagnosed thyroid cancers,” the authors conclude. “By extending [tumor] size/growth limits, these study results potentially broaden the potential candidacy for active surveillance and reduce the likelihood of surgery by lengthening the window of observation.”

However, “the expanded parameters are quite controversial,” first author Allen S. Ho, MD, of Cedars-Sinai Medical Center, Los Angeles, told this news organization. Prior studies have only examined tumor size limits up to 1 cm and “clinicians rarely recommend active surveillance up to 2 cm,” Dr. Ho noted. “As far as we know, Cedars-Sinai is the only place that will consider it.”

In addition, the ultimate decision surrounding active surveillance versus surgery may depend on the patient’s level of anxiety, researchers found.

The research was published in JAMA Oncology.

The potential to expand criteria for thyroid cancer active surveillance comes amid ongoing concerns surrounding overtreatment. Advances in technology have led to increased detection of small, often indolent thyroid cancers that can likely be monitored safely through active surveillance but may present decision-making challenges for clinicians about whether to treat or watch and wait.

Similar challenges in prostate cancer have been addressed with tiered risk stratification, but such guidelines have not been as firmly established in thyroid cancer.

Guidelines from the American Thyroid Association in 2015 suggest active surveillance as an alternative for very low-risk tumors; however, studies in general have recommended the approach for initial tumor sizes of only up to 1 cm and with growth of less than 3 mm. And overall, active surveillance has not been broadly adopted as an option in thyroid cancer, the authors explained.

To determine if criteria for active surveillance can be safely expanded to tumors up to 2 cm and for those with growth up to 5 mm, Dr. Ho and colleagues compared outcomes among 222 patients with Bethesda 5 or 6 nodules of 2 cm or smaller who received either active surveillance or immediate surgery.

The patients were recruited from Cedars-Sinai Medical Center between 2014 and 2021. Patients were a median 46.8 years old; 76% were female.

The median size of tumors was 11 mm, with about 60% representing larger tumors (10.1 to 20 mm) and 20.6% measuring 15.1 to 20 mm.

About half of patients (n = 112) chose active surveillance. The median size of tumors in this group was smaller than those in the surgery group (10.1 mm vs. 12 mm). Tumor growth exceeded 5 mm in 3.6% of cases, and tumor volume increases of more than 100% occurred in 7% of cases.

With a mean follow-up of 37 months, 90% (101) of those on active surveillance continued with that approach. Notably, 41% of these patients demonstrated a decrease in tumor size, and no cases of metastatic lymph nodes or distant metastases emerged.

Of the 110 patients who elected to undergo immediate surgery, 19% (21) had equivocal-risk or undetermined features on final pathology, but the disease severity for these patients remained classified as stage I thyroid cancer.

The disease-specific survival and overall survival rates were the same in both groups, at 100%.

Although a general concern is that larger tumors may be more likely to grow, it’s important to note that “papillary thyroid cancer exists in a spectrum,” Dr. Ho explained. What that means is “some smaller cancers grow quickly, while some larger cancers are stable for decades.”

“We believe that a 1 cm cutoff is arbitrary,” Dr. Ho said, adding that 2 cm cancers that grow will still be within the therapeutic window for safe surgery.

However, a key factor in treatment decisions is patient fear. The authors also looked at the anxiety levels in both groups, using the 18-item Thyroid Cancer Modified Anxiety Scale.

Among the 59 patients who participated, those who chose immediate surgery had significantly higher baseline anxiety levels, compared with those who opted for active surveillance. Notably, these higher rates of anxiety endured over time, including after the intervention.

“It is unsurprising that patients choosing surgery possess a higher baseline level of worry,” Dr. Ho said. “However, we were astonished to find that such patients retained high levels of worry, even after surgery and presumed cure of their cancer.”

The role of the anxiety, however, underscores the need for clinicians to be mindful of the often profound psychological impacts of cancer, even low-risk disease.

“We always encourage clinicians to educate patients on active surveillance, especially as it gets highlighted more in official guidelines,” Dr. Ho noted. “However, we certainly acknowledge that cancer is a life-changing diagnosis, and the term can carry enormous psychological weight.”

The authors also acknowledged several study limitations, including the single-center, nonrandomized design and small sample size, and urge follow-up analyses to “independently verify our findings.”

In an accompanying editorial, Andrea L. Merrill, MD, from Boston Medical Center, and Priya H. Dedhia, MD, PhD, with Ohio State University Wexner Medical Center, said the findings have important clinical implications.

“This provocative study not only lays the groundwork for expanding active surveillance criteria for low-risk papillary thyroid cancer but may also improve use of current American Thyroid Association guidelines for active surveillance by demonstrating that use of active surveillance for Bethesda 5 or 6 nodules 20 mm or smaller was not associated with an increase in staging or disease-specific mortality,” they write.

The study is also notable for being among the first to assess the role of patient anxiety in the selection of immediate surgery versus active surveillance, Dr. Merrill and Dr. Dedhia added.

“These findings imply that patient anxiety should be an essential component of shared decision-making and selection of strategies for low-risk papillary thyroid cancer,” they say.

The study authors and editorial authors report no relevant financial relationships.

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

Expanding eligibility for active surveillance in low-risk papillary thyroid cancer appears to be safe, a new prospective trial indicates.

Researchers found that doubling the limits for tumor size to 2 cm and nearly doubling the limits for tumor growth in low-risk papillary thyroid cancer showed no increased risk of adverse outcomes or mortality for patients undergoing active surveillance versus surgery.

“The results of this nonrandomized controlled trial suggest the basis of a more permissive strategy for thyroid cancer management, strengthening the evidence for active surveillance and broadening potential candidacy to most diagnosed thyroid cancers,” the authors conclude. “By extending [tumor] size/growth limits, these study results potentially broaden the potential candidacy for active surveillance and reduce the likelihood of surgery by lengthening the window of observation.”

However, “the expanded parameters are quite controversial,” first author Allen S. Ho, MD, of Cedars-Sinai Medical Center, Los Angeles, told this news organization. Prior studies have only examined tumor size limits up to 1 cm and “clinicians rarely recommend active surveillance up to 2 cm,” Dr. Ho noted. “As far as we know, Cedars-Sinai is the only place that will consider it.”

In addition, the ultimate decision surrounding active surveillance versus surgery may depend on the patient’s level of anxiety, researchers found.

The research was published in JAMA Oncology.

The potential to expand criteria for thyroid cancer active surveillance comes amid ongoing concerns surrounding overtreatment. Advances in technology have led to increased detection of small, often indolent thyroid cancers that can likely be monitored safely through active surveillance but may present decision-making challenges for clinicians about whether to treat or watch and wait.

Similar challenges in prostate cancer have been addressed with tiered risk stratification, but such guidelines have not been as firmly established in thyroid cancer.

Guidelines from the American Thyroid Association in 2015 suggest active surveillance as an alternative for very low-risk tumors; however, studies in general have recommended the approach for initial tumor sizes of only up to 1 cm and with growth of less than 3 mm. And overall, active surveillance has not been broadly adopted as an option in thyroid cancer, the authors explained.

To determine if criteria for active surveillance can be safely expanded to tumors up to 2 cm and for those with growth up to 5 mm, Dr. Ho and colleagues compared outcomes among 222 patients with Bethesda 5 or 6 nodules of 2 cm or smaller who received either active surveillance or immediate surgery.

The patients were recruited from Cedars-Sinai Medical Center between 2014 and 2021. Patients were a median 46.8 years old; 76% were female.

The median size of tumors was 11 mm, with about 60% representing larger tumors (10.1 to 20 mm) and 20.6% measuring 15.1 to 20 mm.

About half of patients (n = 112) chose active surveillance. The median size of tumors in this group was smaller than those in the surgery group (10.1 mm vs. 12 mm). Tumor growth exceeded 5 mm in 3.6% of cases, and tumor volume increases of more than 100% occurred in 7% of cases.

With a mean follow-up of 37 months, 90% (101) of those on active surveillance continued with that approach. Notably, 41% of these patients demonstrated a decrease in tumor size, and no cases of metastatic lymph nodes or distant metastases emerged.

Of the 110 patients who elected to undergo immediate surgery, 19% (21) had equivocal-risk or undetermined features on final pathology, but the disease severity for these patients remained classified as stage I thyroid cancer.

The disease-specific survival and overall survival rates were the same in both groups, at 100%.

Although a general concern is that larger tumors may be more likely to grow, it’s important to note that “papillary thyroid cancer exists in a spectrum,” Dr. Ho explained. What that means is “some smaller cancers grow quickly, while some larger cancers are stable for decades.”

“We believe that a 1 cm cutoff is arbitrary,” Dr. Ho said, adding that 2 cm cancers that grow will still be within the therapeutic window for safe surgery.

However, a key factor in treatment decisions is patient fear. The authors also looked at the anxiety levels in both groups, using the 18-item Thyroid Cancer Modified Anxiety Scale.

Among the 59 patients who participated, those who chose immediate surgery had significantly higher baseline anxiety levels, compared with those who opted for active surveillance. Notably, these higher rates of anxiety endured over time, including after the intervention.

“It is unsurprising that patients choosing surgery possess a higher baseline level of worry,” Dr. Ho said. “However, we were astonished to find that such patients retained high levels of worry, even after surgery and presumed cure of their cancer.”

The role of the anxiety, however, underscores the need for clinicians to be mindful of the often profound psychological impacts of cancer, even low-risk disease.

“We always encourage clinicians to educate patients on active surveillance, especially as it gets highlighted more in official guidelines,” Dr. Ho noted. “However, we certainly acknowledge that cancer is a life-changing diagnosis, and the term can carry enormous psychological weight.”

The authors also acknowledged several study limitations, including the single-center, nonrandomized design and small sample size, and urge follow-up analyses to “independently verify our findings.”

In an accompanying editorial, Andrea L. Merrill, MD, from Boston Medical Center, and Priya H. Dedhia, MD, PhD, with Ohio State University Wexner Medical Center, said the findings have important clinical implications.

“This provocative study not only lays the groundwork for expanding active surveillance criteria for low-risk papillary thyroid cancer but may also improve use of current American Thyroid Association guidelines for active surveillance by demonstrating that use of active surveillance for Bethesda 5 or 6 nodules 20 mm or smaller was not associated with an increase in staging or disease-specific mortality,” they write.

The study is also notable for being among the first to assess the role of patient anxiety in the selection of immediate surgery versus active surveillance, Dr. Merrill and Dr. Dedhia added.

“These findings imply that patient anxiety should be an essential component of shared decision-making and selection of strategies for low-risk papillary thyroid cancer,” they say.

The study authors and editorial authors report no relevant financial relationships.

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

Expanding eligibility for active surveillance in low-risk papillary thyroid cancer appears to be safe, a new prospective trial indicates.

Researchers found that doubling the limits for tumor size to 2 cm and nearly doubling the limits for tumor growth in low-risk papillary thyroid cancer showed no increased risk of adverse outcomes or mortality for patients undergoing active surveillance versus surgery.

“The results of this nonrandomized controlled trial suggest the basis of a more permissive strategy for thyroid cancer management, strengthening the evidence for active surveillance and broadening potential candidacy to most diagnosed thyroid cancers,” the authors conclude. “By extending [tumor] size/growth limits, these study results potentially broaden the potential candidacy for active surveillance and reduce the likelihood of surgery by lengthening the window of observation.”

However, “the expanded parameters are quite controversial,” first author Allen S. Ho, MD, of Cedars-Sinai Medical Center, Los Angeles, told this news organization. Prior studies have only examined tumor size limits up to 1 cm and “clinicians rarely recommend active surveillance up to 2 cm,” Dr. Ho noted. “As far as we know, Cedars-Sinai is the only place that will consider it.”

In addition, the ultimate decision surrounding active surveillance versus surgery may depend on the patient’s level of anxiety, researchers found.

The research was published in JAMA Oncology.

The potential to expand criteria for thyroid cancer active surveillance comes amid ongoing concerns surrounding overtreatment. Advances in technology have led to increased detection of small, often indolent thyroid cancers that can likely be monitored safely through active surveillance but may present decision-making challenges for clinicians about whether to treat or watch and wait.

Similar challenges in prostate cancer have been addressed with tiered risk stratification, but such guidelines have not been as firmly established in thyroid cancer.

Guidelines from the American Thyroid Association in 2015 suggest active surveillance as an alternative for very low-risk tumors; however, studies in general have recommended the approach for initial tumor sizes of only up to 1 cm and with growth of less than 3 mm. And overall, active surveillance has not been broadly adopted as an option in thyroid cancer, the authors explained.

To determine if criteria for active surveillance can be safely expanded to tumors up to 2 cm and for those with growth up to 5 mm, Dr. Ho and colleagues compared outcomes among 222 patients with Bethesda 5 or 6 nodules of 2 cm or smaller who received either active surveillance or immediate surgery.

The patients were recruited from Cedars-Sinai Medical Center between 2014 and 2021. Patients were a median 46.8 years old; 76% were female.

The median size of tumors was 11 mm, with about 60% representing larger tumors (10.1 to 20 mm) and 20.6% measuring 15.1 to 20 mm.

About half of patients (n = 112) chose active surveillance. The median size of tumors in this group was smaller than those in the surgery group (10.1 mm vs. 12 mm). Tumor growth exceeded 5 mm in 3.6% of cases, and tumor volume increases of more than 100% occurred in 7% of cases.

With a mean follow-up of 37 months, 90% (101) of those on active surveillance continued with that approach. Notably, 41% of these patients demonstrated a decrease in tumor size, and no cases of metastatic lymph nodes or distant metastases emerged.

Of the 110 patients who elected to undergo immediate surgery, 19% (21) had equivocal-risk or undetermined features on final pathology, but the disease severity for these patients remained classified as stage I thyroid cancer.

The disease-specific survival and overall survival rates were the same in both groups, at 100%.

Although a general concern is that larger tumors may be more likely to grow, it’s important to note that “papillary thyroid cancer exists in a spectrum,” Dr. Ho explained. What that means is “some smaller cancers grow quickly, while some larger cancers are stable for decades.”

“We believe that a 1 cm cutoff is arbitrary,” Dr. Ho said, adding that 2 cm cancers that grow will still be within the therapeutic window for safe surgery.

However, a key factor in treatment decisions is patient fear. The authors also looked at the anxiety levels in both groups, using the 18-item Thyroid Cancer Modified Anxiety Scale.

Among the 59 patients who participated, those who chose immediate surgery had significantly higher baseline anxiety levels, compared with those who opted for active surveillance. Notably, these higher rates of anxiety endured over time, including after the intervention.

“It is unsurprising that patients choosing surgery possess a higher baseline level of worry,” Dr. Ho said. “However, we were astonished to find that such patients retained high levels of worry, even after surgery and presumed cure of their cancer.”

The role of the anxiety, however, underscores the need for clinicians to be mindful of the often profound psychological impacts of cancer, even low-risk disease.

“We always encourage clinicians to educate patients on active surveillance, especially as it gets highlighted more in official guidelines,” Dr. Ho noted. “However, we certainly acknowledge that cancer is a life-changing diagnosis, and the term can carry enormous psychological weight.”

The authors also acknowledged several study limitations, including the single-center, nonrandomized design and small sample size, and urge follow-up analyses to “independently verify our findings.”

In an accompanying editorial, Andrea L. Merrill, MD, from Boston Medical Center, and Priya H. Dedhia, MD, PhD, with Ohio State University Wexner Medical Center, said the findings have important clinical implications.

“This provocative study not only lays the groundwork for expanding active surveillance criteria for low-risk papillary thyroid cancer but may also improve use of current American Thyroid Association guidelines for active surveillance by demonstrating that use of active surveillance for Bethesda 5 or 6 nodules 20 mm or smaller was not associated with an increase in staging or disease-specific mortality,” they write.

The study is also notable for being among the first to assess the role of patient anxiety in the selection of immediate surgery versus active surveillance, Dr. Merrill and Dr. Dedhia added.

“These findings imply that patient anxiety should be an essential component of shared decision-making and selection of strategies for low-risk papillary thyroid cancer,” they say.

The study authors and editorial authors report no relevant financial relationships.

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

MONTREAL – Pediatric patients with low-risk differentiated thyroid cancer (DTC) who are spared radioactive iodine (RAI) therapy show no increases in the risk of remission, compared with those who do receive it, supporting guidelines that recommend against use of RAI in such patients.

“In 2015, when the American Thyroid Association [ATA] created their pediatric guidelines [on RAI therapy in DTC], they were taking a leap of faith that these [pediatric DTC] patients would be able to achieve remission without RAI,” said first author Mya Bojarsky, Children’s Hospital of Philadelphia (CHOP), when presenting the findings at the American Thyroid Association annual meeting.

“This is the first study to validate those guidelines and support the sentiment that for ATA low-risk pediatric thyroid cancer patients, withholding RAI therapy is clinically beneficial as it reduces exposure to radiation while having no negative impact on remission,” she said.

Prior to 2015, thyroidectomy in combination with RAI was the standard treatment for DTC in pediatric patients. However, data showing that radiation exposure in children increases the risk of secondary hematologic malignancies by 51% and solid malignancies by 23% over a lifetime raised concerns and led to a push to change the treatment approach.

In response, the 2015 ATA pediatric guidelines recommended that patients not receive RAI for the treatment of DTC that was mostly confined to the thyroid (N0 or minimal N1a disease).

Senior author Andrew J. Bauer, MD, noted that, in addition to being the first study to confirm that withholding RAI in low-risk patients is associated with the same rate of achieving remission as patients treated with RAI, the study also endorses that assessments at 1 year can be reliable predictors of remission.

“For these patients, the 1-year mark post-initial treatment (thyroidectomy) is an early and accurate time point for initial assessment of remission, with increasing rates of remission with continued surveillance (at last clinical follow-up) of approximately 90% 2 years post initial treatment,” said Dr. Bauer, medical director, CHOP, and professor of pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

“This approach has recently been validated through a prospective study in adult patients,” he added. A large recent study of 730 patients, published in the New England Journal of Medicine, supported the omission of RAI in low-risk DTC in adults, showing that, compared with those who received RAI, the no-RAI group was noninferior in the occurrence of functional, structural, and biologic events at 3 years.
 

Safe to eliminate RAI therapy in low-risk DTC in children

With limited data on how or if the change in treatment had an impact on rates of remission in pediatric patients, Ms. Bojarsky and colleagues conducted a retrospective cohort study of patients under the age of 19 years with ATA low-risk DTC who had undergone a total thyroidectomy at CHOP between 2010 and 2020.

Overall, they identified 95 patients, including 50 who had been treated with RAI in addition to thyroidectomy and 45 who did not receive RAI. Among those who did receive RAI, 31 were treated prior to 2015, and 19 were treated after 2019.

For the study, remission was defined as having undetectable thyroglobulin levels as well as no evidence of disease by ultrasound, Ms. Bojarsky said.

“This is important to show, because we want to ensure that as we are reducing our RAI use in the pediatric population, we were not negatively impacting their ability to achieve remission,” she explained.

The percentage of low-risk pediatric patients with DTC treated with RAI had already dropped from 100% in 2010 down to 38% by 2015 when the guidelines were issued, and after a slight rise to 50% by 2018, the practice plummeted to 0% by 2020, the study shows.

In terms of remission, at 1 year post-treatment, 80% of patients who received RAI were in remission, and the rate was even slightly higher, at 84%, among those who did not receive RAI, for a difference that was not significant.

Further looking at disease status as of the last clinical evaluation, 90% in the group treated with RAI had no evidence of disease at a median of 4.9 years of follow-up, and the rate was 87% in the group not receiving RAI, which had a median of 2.7 years of follow-up.

“In ATA low-risk patients, there is no detriment in achieving remission if RAI therapy is withheld,” say investigators.   

The median tumor size in the RAI group was larger (19.5 mm vs. 12.0 mm; P < .001), and the primary tumor was T1 in 44% of the RAI group but 82% in the no-RAI group (P < .001).

The lymph node status was N0 in 72% of those receiving RAI and 76% in the no RAI group, which was not significantly different.

The leading risk factors associated with treatment with RAI included larger primary tumor size (OR, 1.07; P = .003), lymph node metastasis (OR, 3.72; P = .036), and surgery pre-2015 (OR, 9.83; P < .001).

RAI administration, N1a disease, and surgery prior to 2015 were not independent risk factors for evidence of persistent disease or indeterminate status.

Ms. Bojarsky has reported no relevant financial relationships.

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

MONTREAL – Pediatric patients with low-risk differentiated thyroid cancer (DTC) who are spared radioactive iodine (RAI) therapy show no increases in the risk of remission, compared with those who do receive it, supporting guidelines that recommend against use of RAI in such patients.

“In 2015, when the American Thyroid Association [ATA] created their pediatric guidelines [on RAI therapy in DTC], they were taking a leap of faith that these [pediatric DTC] patients would be able to achieve remission without RAI,” said first author Mya Bojarsky, Children’s Hospital of Philadelphia (CHOP), when presenting the findings at the American Thyroid Association annual meeting.

“This is the first study to validate those guidelines and support the sentiment that for ATA low-risk pediatric thyroid cancer patients, withholding RAI therapy is clinically beneficial as it reduces exposure to radiation while having no negative impact on remission,” she said.

Prior to 2015, thyroidectomy in combination with RAI was the standard treatment for DTC in pediatric patients. However, data showing that radiation exposure in children increases the risk of secondary hematologic malignancies by 51% and solid malignancies by 23% over a lifetime raised concerns and led to a push to change the treatment approach.

In response, the 2015 ATA pediatric guidelines recommended that patients not receive RAI for the treatment of DTC that was mostly confined to the thyroid (N0 or minimal N1a disease).

Senior author Andrew J. Bauer, MD, noted that, in addition to being the first study to confirm that withholding RAI in low-risk patients is associated with the same rate of achieving remission as patients treated with RAI, the study also endorses that assessments at 1 year can be reliable predictors of remission.

“For these patients, the 1-year mark post-initial treatment (thyroidectomy) is an early and accurate time point for initial assessment of remission, with increasing rates of remission with continued surveillance (at last clinical follow-up) of approximately 90% 2 years post initial treatment,” said Dr. Bauer, medical director, CHOP, and professor of pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

“This approach has recently been validated through a prospective study in adult patients,” he added. A large recent study of 730 patients, published in the New England Journal of Medicine, supported the omission of RAI in low-risk DTC in adults, showing that, compared with those who received RAI, the no-RAI group was noninferior in the occurrence of functional, structural, and biologic events at 3 years.
 

Safe to eliminate RAI therapy in low-risk DTC in children

With limited data on how or if the change in treatment had an impact on rates of remission in pediatric patients, Ms. Bojarsky and colleagues conducted a retrospective cohort study of patients under the age of 19 years with ATA low-risk DTC who had undergone a total thyroidectomy at CHOP between 2010 and 2020.

Overall, they identified 95 patients, including 50 who had been treated with RAI in addition to thyroidectomy and 45 who did not receive RAI. Among those who did receive RAI, 31 were treated prior to 2015, and 19 were treated after 2019.

For the study, remission was defined as having undetectable thyroglobulin levels as well as no evidence of disease by ultrasound, Ms. Bojarsky said.

“This is important to show, because we want to ensure that as we are reducing our RAI use in the pediatric population, we were not negatively impacting their ability to achieve remission,” she explained.

The percentage of low-risk pediatric patients with DTC treated with RAI had already dropped from 100% in 2010 down to 38% by 2015 when the guidelines were issued, and after a slight rise to 50% by 2018, the practice plummeted to 0% by 2020, the study shows.

In terms of remission, at 1 year post-treatment, 80% of patients who received RAI were in remission, and the rate was even slightly higher, at 84%, among those who did not receive RAI, for a difference that was not significant.

Further looking at disease status as of the last clinical evaluation, 90% in the group treated with RAI had no evidence of disease at a median of 4.9 years of follow-up, and the rate was 87% in the group not receiving RAI, which had a median of 2.7 years of follow-up.

“In ATA low-risk patients, there is no detriment in achieving remission if RAI therapy is withheld,” say investigators.   

The median tumor size in the RAI group was larger (19.5 mm vs. 12.0 mm; P < .001), and the primary tumor was T1 in 44% of the RAI group but 82% in the no-RAI group (P < .001).

The lymph node status was N0 in 72% of those receiving RAI and 76% in the no RAI group, which was not significantly different.

The leading risk factors associated with treatment with RAI included larger primary tumor size (OR, 1.07; P = .003), lymph node metastasis (OR, 3.72; P = .036), and surgery pre-2015 (OR, 9.83; P < .001).

RAI administration, N1a disease, and surgery prior to 2015 were not independent risk factors for evidence of persistent disease or indeterminate status.

Ms. Bojarsky has reported no relevant financial relationships.

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

MONTREAL – Pediatric patients with low-risk differentiated thyroid cancer (DTC) who are spared radioactive iodine (RAI) therapy show no increases in the risk of remission, compared with those who do receive it, supporting guidelines that recommend against use of RAI in such patients.

“In 2015, when the American Thyroid Association [ATA] created their pediatric guidelines [on RAI therapy in DTC], they were taking a leap of faith that these [pediatric DTC] patients would be able to achieve remission without RAI,” said first author Mya Bojarsky, Children’s Hospital of Philadelphia (CHOP), when presenting the findings at the American Thyroid Association annual meeting.

“This is the first study to validate those guidelines and support the sentiment that for ATA low-risk pediatric thyroid cancer patients, withholding RAI therapy is clinically beneficial as it reduces exposure to radiation while having no negative impact on remission,” she said.

Prior to 2015, thyroidectomy in combination with RAI was the standard treatment for DTC in pediatric patients. However, data showing that radiation exposure in children increases the risk of secondary hematologic malignancies by 51% and solid malignancies by 23% over a lifetime raised concerns and led to a push to change the treatment approach.

In response, the 2015 ATA pediatric guidelines recommended that patients not receive RAI for the treatment of DTC that was mostly confined to the thyroid (N0 or minimal N1a disease).

Senior author Andrew J. Bauer, MD, noted that, in addition to being the first study to confirm that withholding RAI in low-risk patients is associated with the same rate of achieving remission as patients treated with RAI, the study also endorses that assessments at 1 year can be reliable predictors of remission.

“For these patients, the 1-year mark post-initial treatment (thyroidectomy) is an early and accurate time point for initial assessment of remission, with increasing rates of remission with continued surveillance (at last clinical follow-up) of approximately 90% 2 years post initial treatment,” said Dr. Bauer, medical director, CHOP, and professor of pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

“This approach has recently been validated through a prospective study in adult patients,” he added. A large recent study of 730 patients, published in the New England Journal of Medicine, supported the omission of RAI in low-risk DTC in adults, showing that, compared with those who received RAI, the no-RAI group was noninferior in the occurrence of functional, structural, and biologic events at 3 years.
 

Safe to eliminate RAI therapy in low-risk DTC in children

With limited data on how or if the change in treatment had an impact on rates of remission in pediatric patients, Ms. Bojarsky and colleagues conducted a retrospective cohort study of patients under the age of 19 years with ATA low-risk DTC who had undergone a total thyroidectomy at CHOP between 2010 and 2020.

Overall, they identified 95 patients, including 50 who had been treated with RAI in addition to thyroidectomy and 45 who did not receive RAI. Among those who did receive RAI, 31 were treated prior to 2015, and 19 were treated after 2019.

For the study, remission was defined as having undetectable thyroglobulin levels as well as no evidence of disease by ultrasound, Ms. Bojarsky said.

“This is important to show, because we want to ensure that as we are reducing our RAI use in the pediatric population, we were not negatively impacting their ability to achieve remission,” she explained.

The percentage of low-risk pediatric patients with DTC treated with RAI had already dropped from 100% in 2010 down to 38% by 2015 when the guidelines were issued, and after a slight rise to 50% by 2018, the practice plummeted to 0% by 2020, the study shows.

In terms of remission, at 1 year post-treatment, 80% of patients who received RAI were in remission, and the rate was even slightly higher, at 84%, among those who did not receive RAI, for a difference that was not significant.

Further looking at disease status as of the last clinical evaluation, 90% in the group treated with RAI had no evidence of disease at a median of 4.9 years of follow-up, and the rate was 87% in the group not receiving RAI, which had a median of 2.7 years of follow-up.

“In ATA low-risk patients, there is no detriment in achieving remission if RAI therapy is withheld,” say investigators.   

The median tumor size in the RAI group was larger (19.5 mm vs. 12.0 mm; P < .001), and the primary tumor was T1 in 44% of the RAI group but 82% in the no-RAI group (P < .001).

The lymph node status was N0 in 72% of those receiving RAI and 76% in the no RAI group, which was not significantly different.

The leading risk factors associated with treatment with RAI included larger primary tumor size (OR, 1.07; P = .003), lymph node metastasis (OR, 3.72; P = .036), and surgery pre-2015 (OR, 9.83; P < .001).

RAI administration, N1a disease, and surgery prior to 2015 were not independent risk factors for evidence of persistent disease or indeterminate status.

Ms. Bojarsky has reported no relevant financial relationships.

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

MONTREAL – Patients who discontinue levothyroxine for subclinical hypothyroidism may gravitate towards becoming mildly hypothyroid again, but they importantly show no differences in terms of symptoms and quality of life – and sometimes show even improvement – compared with those who continue treatment, new research shows.

“Our results show feasibility of patient enrollment and safety of discontinuing levothyroxine in patients with subclinical hypothyroidism,” said first author Spyridoula Maraka, MD, when presenting the findings at the American Thyroid Association annual meeting.

Recommendations against levothyroxine for subclinical hypothyroidism

Subclinical hypothyroidism is commonly over-diagnosed, and treatment with thyroid hormone replacement, levothyroxine, has been shown to provide little, if any, benefit in terms of quality of life or relief of thyroid-related symptoms for these patients.

The treatment is meanwhile associated with burdens including cost and lifestyle adjustments, and one guideline panel recently issued a strong recommendation against routine levothyroxine use in most adults with subclinical hypothyroidism.

Nevertheless, levothyroxine treatment has soared in popularity and become one of the most commonly prescribed drugs in the United States.

With research lacking on one key solution of discontinuation of the therapy, Dr. Maraka, who is part of the Division of Endocrinology and Metabolism at the University of Arkansas for Medical Sciences, Little Rock, and colleagues conducted a double-blind, placebo-controlled trial at the Central Arkansas Veterans Healthcare System. In total, 50 patients treated for subclinical hypothyroidism were randomized 1:1 to continue receiving levothyroxine (25-75 mcg daily) or to discontinue treatment and receive a placebo instead, with a planned 6-month follow-up.

In the current interim analysis, Dr. Maraka reported results for the first 40 patients, including 20 randomized to levothyroxine and 20 to discontinuation.

There were no significant differences between the discontinuation and levothyroxine groups at baseline, which were of a similar age (66.2 vs. 70.8 years) and gender (75% women vs. 85% men).

The groups had similar baseline thyroid-stimulating hormone (TSH) levels (3.0 vs. 2.6 mIU/L), free T4 (both 0.9 ng/dL), thyroid peroxidase antibody positivity (17% vs. 11%), and similar clinical symptoms. All patients had at least one elevated TSH reading prior to starting levothyroxine.

With a follow-up of 6-8 weeks, 36.8% of patients in the discontinuation group had subclinical hypothyroidism, compared with 10% of patients who remained on levothyroxine (P = .0648), TSH levels were 5.5 versus 2.7 mIU/L (P = .001) and free T4 levels were 0.8 versus 0.9 ng/dL (P = .011).
 

No differences in symptoms, quality of life between groups

Importantly, there were no significant differences between the discontinuation versus levothyroxine groups in terms of symptoms, and even some improvements with discontinuation, including Thyroid-Specific Quality of Life Patient-Reported Outcome (ThyPRO)-Hypothyroid Symptoms score (4.6 reduction vs. 2.2 increase), tiredness (2.6 reduction vs. 1.1 increase), and EuroQoL 5-Dimension Self-Report Questionnaire (EQ-5D) quality of life score, for which there were no differences between groups.

There were no reports of overt hypothyroidism; hyperthyroidism; cardiovascular events including atrial fibrillation, stroke, or heart failure; osteoporotic fractures; or deaths.

One patient in the discontinuation group had a TSH level of 11 mIU/L at 6-8 weeks and switched to open-label levothyroxine 75 mcg daily. Another patient in the discontinuation group switched to open-label levothyroxine 75 mcg daily at 10 weeks due to fatigue; however, the patient was diagnosed with metastatic colon cancer 1 month later.

The finding that only about a third of patients who discontinued levothyroxine developed subclinical hypothyroidism was lower than expected, Dr. Maraka noted.

“This was ... unexpected ... for us,” she said. “We were expecting a larger number of patients to develop hypothyroidism, but to our surprise, that was not the case.”

“But what is more important is that there was no difference in the quality of life measures,” she added. “If anything, the placebo group was a little better, though the [differences] were not statistically significant.”

Dr. Maraka also noted that in further research and a final 6-month analysis, the authors will look at factors associated with developing subclinical hypothyroidism after treatment discontinuation, among other issues.
 

Discontinuation of levothyroxine is manageable

The results are encouraging, as they provide assurance that discontinuation of levothyroxine is manageable.

“This research will pave the way for initiatives to promote levothyroxine deprescription and implementation of evidence-based care for patients with subclinical hypothyroidism,” she said.

In further comments, Dr. Hennessey noted that the dilemma of having patients on levothyroxine who may not be benefitting from treatment is “significant,” with patients sometimes reluctant to discontinue treatment due to concerns of developing hypothyroidism-associated symptoms such as brain fog and weight gain.

He noted, however, that “many with mildly elevated TSH actually go on to normalize with time, so they are not really hypothyroid, [and] if we remove thyroxine from people with normal thyroid function, they will remain normal.”

Dr. Maraka has reported no relevant financial relationships. Dr. Hennessey has reported consulting for pharmaceutical companies to design clinical studies for thyroid medications.

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

MONTREAL – Patients who discontinue levothyroxine for subclinical hypothyroidism may gravitate towards becoming mildly hypothyroid again, but they importantly show no differences in terms of symptoms and quality of life – and sometimes show even improvement – compared with those who continue treatment, new research shows.

“Our results show feasibility of patient enrollment and safety of discontinuing levothyroxine in patients with subclinical hypothyroidism,” said first author Spyridoula Maraka, MD, when presenting the findings at the American Thyroid Association annual meeting.

Recommendations against levothyroxine for subclinical hypothyroidism

Subclinical hypothyroidism is commonly over-diagnosed, and treatment with thyroid hormone replacement, levothyroxine, has been shown to provide little, if any, benefit in terms of quality of life or relief of thyroid-related symptoms for these patients.

The treatment is meanwhile associated with burdens including cost and lifestyle adjustments, and one guideline panel recently issued a strong recommendation against routine levothyroxine use in most adults with subclinical hypothyroidism.

Nevertheless, levothyroxine treatment has soared in popularity and become one of the most commonly prescribed drugs in the United States.

With research lacking on one key solution of discontinuation of the therapy, Dr. Maraka, who is part of the Division of Endocrinology and Metabolism at the University of Arkansas for Medical Sciences, Little Rock, and colleagues conducted a double-blind, placebo-controlled trial at the Central Arkansas Veterans Healthcare System. In total, 50 patients treated for subclinical hypothyroidism were randomized 1:1 to continue receiving levothyroxine (25-75 mcg daily) or to discontinue treatment and receive a placebo instead, with a planned 6-month follow-up.

In the current interim analysis, Dr. Maraka reported results for the first 40 patients, including 20 randomized to levothyroxine and 20 to discontinuation.

There were no significant differences between the discontinuation and levothyroxine groups at baseline, which were of a similar age (66.2 vs. 70.8 years) and gender (75% women vs. 85% men).

The groups had similar baseline thyroid-stimulating hormone (TSH) levels (3.0 vs. 2.6 mIU/L), free T4 (both 0.9 ng/dL), thyroid peroxidase antibody positivity (17% vs. 11%), and similar clinical symptoms. All patients had at least one elevated TSH reading prior to starting levothyroxine.

With a follow-up of 6-8 weeks, 36.8% of patients in the discontinuation group had subclinical hypothyroidism, compared with 10% of patients who remained on levothyroxine (P = .0648), TSH levels were 5.5 versus 2.7 mIU/L (P = .001) and free T4 levels were 0.8 versus 0.9 ng/dL (P = .011).
 

No differences in symptoms, quality of life between groups

Importantly, there were no significant differences between the discontinuation versus levothyroxine groups in terms of symptoms, and even some improvements with discontinuation, including Thyroid-Specific Quality of Life Patient-Reported Outcome (ThyPRO)-Hypothyroid Symptoms score (4.6 reduction vs. 2.2 increase), tiredness (2.6 reduction vs. 1.1 increase), and EuroQoL 5-Dimension Self-Report Questionnaire (EQ-5D) quality of life score, for which there were no differences between groups.

There were no reports of overt hypothyroidism; hyperthyroidism; cardiovascular events including atrial fibrillation, stroke, or heart failure; osteoporotic fractures; or deaths.

One patient in the discontinuation group had a TSH level of 11 mIU/L at 6-8 weeks and switched to open-label levothyroxine 75 mcg daily. Another patient in the discontinuation group switched to open-label levothyroxine 75 mcg daily at 10 weeks due to fatigue; however, the patient was diagnosed with metastatic colon cancer 1 month later.

The finding that only about a third of patients who discontinued levothyroxine developed subclinical hypothyroidism was lower than expected, Dr. Maraka noted.

“This was ... unexpected ... for us,” she said. “We were expecting a larger number of patients to develop hypothyroidism, but to our surprise, that was not the case.”

“But what is more important is that there was no difference in the quality of life measures,” she added. “If anything, the placebo group was a little better, though the [differences] were not statistically significant.”

Dr. Maraka also noted that in further research and a final 6-month analysis, the authors will look at factors associated with developing subclinical hypothyroidism after treatment discontinuation, among other issues.
 

Discontinuation of levothyroxine is manageable

The results are encouraging, as they provide assurance that discontinuation of levothyroxine is manageable.

“This research will pave the way for initiatives to promote levothyroxine deprescription and implementation of evidence-based care for patients with subclinical hypothyroidism,” she said.

In further comments, Dr. Hennessey noted that the dilemma of having patients on levothyroxine who may not be benefitting from treatment is “significant,” with patients sometimes reluctant to discontinue treatment due to concerns of developing hypothyroidism-associated symptoms such as brain fog and weight gain.

He noted, however, that “many with mildly elevated TSH actually go on to normalize with time, so they are not really hypothyroid, [and] if we remove thyroxine from people with normal thyroid function, they will remain normal.”

Dr. Maraka has reported no relevant financial relationships. Dr. Hennessey has reported consulting for pharmaceutical companies to design clinical studies for thyroid medications.

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

MONTREAL – Patients who discontinue levothyroxine for subclinical hypothyroidism may gravitate towards becoming mildly hypothyroid again, but they importantly show no differences in terms of symptoms and quality of life – and sometimes show even improvement – compared with those who continue treatment, new research shows.

“Our results show feasibility of patient enrollment and safety of discontinuing levothyroxine in patients with subclinical hypothyroidism,” said first author Spyridoula Maraka, MD, when presenting the findings at the American Thyroid Association annual meeting.

Recommendations against levothyroxine for subclinical hypothyroidism

Subclinical hypothyroidism is commonly over-diagnosed, and treatment with thyroid hormone replacement, levothyroxine, has been shown to provide little, if any, benefit in terms of quality of life or relief of thyroid-related symptoms for these patients.

The treatment is meanwhile associated with burdens including cost and lifestyle adjustments, and one guideline panel recently issued a strong recommendation against routine levothyroxine use in most adults with subclinical hypothyroidism.

Nevertheless, levothyroxine treatment has soared in popularity and become one of the most commonly prescribed drugs in the United States.

With research lacking on one key solution of discontinuation of the therapy, Dr. Maraka, who is part of the Division of Endocrinology and Metabolism at the University of Arkansas for Medical Sciences, Little Rock, and colleagues conducted a double-blind, placebo-controlled trial at the Central Arkansas Veterans Healthcare System. In total, 50 patients treated for subclinical hypothyroidism were randomized 1:1 to continue receiving levothyroxine (25-75 mcg daily) or to discontinue treatment and receive a placebo instead, with a planned 6-month follow-up.

In the current interim analysis, Dr. Maraka reported results for the first 40 patients, including 20 randomized to levothyroxine and 20 to discontinuation.

There were no significant differences between the discontinuation and levothyroxine groups at baseline, which were of a similar age (66.2 vs. 70.8 years) and gender (75% women vs. 85% men).

The groups had similar baseline thyroid-stimulating hormone (TSH) levels (3.0 vs. 2.6 mIU/L), free T4 (both 0.9 ng/dL), thyroid peroxidase antibody positivity (17% vs. 11%), and similar clinical symptoms. All patients had at least one elevated TSH reading prior to starting levothyroxine.

With a follow-up of 6-8 weeks, 36.8% of patients in the discontinuation group had subclinical hypothyroidism, compared with 10% of patients who remained on levothyroxine (P = .0648), TSH levels were 5.5 versus 2.7 mIU/L (P = .001) and free T4 levels were 0.8 versus 0.9 ng/dL (P = .011).
 

No differences in symptoms, quality of life between groups

Importantly, there were no significant differences between the discontinuation versus levothyroxine groups in terms of symptoms, and even some improvements with discontinuation, including Thyroid-Specific Quality of Life Patient-Reported Outcome (ThyPRO)-Hypothyroid Symptoms score (4.6 reduction vs. 2.2 increase), tiredness (2.6 reduction vs. 1.1 increase), and EuroQoL 5-Dimension Self-Report Questionnaire (EQ-5D) quality of life score, for which there were no differences between groups.

There were no reports of overt hypothyroidism; hyperthyroidism; cardiovascular events including atrial fibrillation, stroke, or heart failure; osteoporotic fractures; or deaths.

One patient in the discontinuation group had a TSH level of 11 mIU/L at 6-8 weeks and switched to open-label levothyroxine 75 mcg daily. Another patient in the discontinuation group switched to open-label levothyroxine 75 mcg daily at 10 weeks due to fatigue; however, the patient was diagnosed with metastatic colon cancer 1 month later.

The finding that only about a third of patients who discontinued levothyroxine developed subclinical hypothyroidism was lower than expected, Dr. Maraka noted.

“This was ... unexpected ... for us,” she said. “We were expecting a larger number of patients to develop hypothyroidism, but to our surprise, that was not the case.”

“But what is more important is that there was no difference in the quality of life measures,” she added. “If anything, the placebo group was a little better, though the [differences] were not statistically significant.”

Dr. Maraka also noted that in further research and a final 6-month analysis, the authors will look at factors associated with developing subclinical hypothyroidism after treatment discontinuation, among other issues.
 

Discontinuation of levothyroxine is manageable

The results are encouraging, as they provide assurance that discontinuation of levothyroxine is manageable.

“This research will pave the way for initiatives to promote levothyroxine deprescription and implementation of evidence-based care for patients with subclinical hypothyroidism,” she said.

In further comments, Dr. Hennessey noted that the dilemma of having patients on levothyroxine who may not be benefitting from treatment is “significant,” with patients sometimes reluctant to discontinue treatment due to concerns of developing hypothyroidism-associated symptoms such as brain fog and weight gain.

He noted, however, that “many with mildly elevated TSH actually go on to normalize with time, so they are not really hypothyroid, [and] if we remove thyroxine from people with normal thyroid function, they will remain normal.”

Dr. Maraka has reported no relevant financial relationships. Dr. Hennessey has reported consulting for pharmaceutical companies to design clinical studies for thyroid medications.

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

MONTREAL – Amid common patient concerns about weight gain in the treatment of hyperthyroidism, findings from a large study suggest the therapy with the most favorable survival rate – radioiodine – is not associated with an increased risk of weight gain or obesity.

“EGRET is the first large study using population-based linked community and hospital data to elucidate the long-term consequences of treatment modalities for hyperthyroidism,” said co-author Kristien Boelaert, MD, PhD, while presenting the research at the American Thyroid Association annual meeting.

“The administration of [radioiodine] for hyperthyroidism is associated with a survival benefit for patients with hyperthyroidism and is not associated with increased risks of becoming obese,” Dr. Boelaert, a professor of endocrinology and consultant endocrinologist with the Institute of Applied Health Research, University of Birmingham, England, told this news organization.

However, “overall, there was a nearly 10% risk of major adverse cardiac events [MACE] in patients with hyperthyroidism regardless of the treatment modality used,” she noted.

Commenting on the findings, Jonathon O. Russell, MD, said the study offers surprising – but encouraging – results.

The discovery that radioiodine shows no increase in weight gain “contradicts numerous previous studies which have consistently demonstrated weight gain following definitive radioiodine,” Dr. Russell told this news organization.

Overall, however, “these findings reinforce our knowledge that definitive treatment of an overactive thyroid leads to a longer life – even if there is some weight gain,” added Dr. Russell, who is chief of the Division of Head and Neck Endocrine Surgery at Johns Hopkins, Baltimore.
 

Hyperthyroidism associated with serious long-term cardiometabolic issues

Hyperthyroidism is associated with serious long-term cardiovascular and metabolic morbidity and mortality, and treatment is therefore essential. However, the swing to hypothyroidism that often occurs afterward commonly results in regaining the weight lost due to the hyperthyroidism, if not more, potentially leading to obesity and its attendant health risks.

To investigate those risks in relation to the three key hyperthyroidism treatments, the authors conducted the EGRET trial. They identified 62,474 patients in the United Kingdom population-based electronic health record database who had newly diagnosed hyperthyroidism and were treated with antithyroid drugs (73.4%), radioiodine (19.5%), or thyroidectomy (7.1%) between April 1997 and December 2015.

Exclusion criteria included those with less than 6 months of antithyroid drugs as the only form of treatment, thyroid cancer, or pregnancy during the first episode.

With a median follow-up of about 8 years, those who were treated with thyroidectomy had a significantly increased risk of gaining weight, compared with the general population (P < .001), and of developing obesity (body mass index > 30 kg/m2; P = .003), while the corresponding increases with antithyroid drugs and radioiodine were not significantly different, compared with the general population over the same period.

In terms of survival, with an average follow-up of about 11 years per person, about 14% of the cohort died, with rates of 14.4% in the antithyroid drug group, 15.8% in the radioiodine group, and 9.2% in the thyroidectomy group.

Mortality rates were further assessed based on an average treatment effects analysis in which the average change was estimated, compared with the index of antithyroid drugs – for instance, if all were treated instead with radioiodine. In that extension of life analysis, those treated with radioiodine could be expected to die, on average, 1.2 years later than those taking antithyroid drugs (P < .001), while those treated with thyroidectomy would be expected to die 0.6 years later, which was not statistically significant.

Using the same average treatment effects analysis, Dr. Boelaert noted, “we found a slightly increased risk of major adverse cardiovascular events following radioiodine, compared with antithyroid drugs; [however], the risk was very small and may not be clinically relevant.”

“Previous data from our and other groups have shown reduced risks of mortality and cardiovascular death following radioiodine-induced hypothyroidism, although this is not confirmed in all studies.”
 

Weight gain after hyperthyroid treatment drives concerns

The findings are important because weight gain associated with hyperthyroidism treatment is no small matter for many patients, even prompting a lack of adherence to therapy for some, despite its importance, Dr. Boelaert noted.

“Since the majority of patients lose weight as a consequence of being hyperthyroid, it can be expected that they will at least regain the lost weight and possibly even have a weight overshoot,” she explained. “Indeed, many patients are reluctant to accept definitive treatment with surgery or radioiodine out of fear of weight gain.”

“This may cause difficulties to some patients who occasionally may even stop taking antithyroid drugs to prevent this weight regain. Such lack of adherence may have dire consequences and is likely a contributing factor to the increased mortality in these patients,” she observed.

In a previous study of 1,373 patients, Dr. Boelaert and colleagues found that men treated for hyperthyroidism gained an average of 8.0 kg (17.6 lb), and women gained an average of 5.5 kg (12.1 lb).

Compared with the background population, men were significantly more likely to gain weight over the study period (odds ratio, 1.7; P < .001) as were women (OR, 1.3; P < .001). Also in that study, radioiodine was associated with greater weight gain (0.6 kg; P < .001), compared with antithyroid drug treatment alone.

Dr. Russell added that even when weight gain does occur, the payoff of having treated the potentially serious state of hyperthyroidism is a highly beneficial trade-off.

Ultimately, “the goal of treating any patient with Graves’ should be to get them to become hypothyroid as quickly as possible,” he said. “Patients have options, and all of these options can be safe in the right situation.”

“It is unrealistic to think that going from a hyperthyroid state to a low thyroid state will not result in weight gain for many patients,” Dr. Russell added. “But the key point is that overall health is better despite this weight gain.”

Dr. Boelaert has disclosed consulting fees paid to the University of Birmingham by Lilly and Eisai. Dr. Russell has reported no relevant financial relationships.

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

MONTREAL – Amid common patient concerns about weight gain in the treatment of hyperthyroidism, findings from a large study suggest the therapy with the most favorable survival rate – radioiodine – is not associated with an increased risk of weight gain or obesity.

“EGRET is the first large study using population-based linked community and hospital data to elucidate the long-term consequences of treatment modalities for hyperthyroidism,” said co-author Kristien Boelaert, MD, PhD, while presenting the research at the American Thyroid Association annual meeting.

“The administration of [radioiodine] for hyperthyroidism is associated with a survival benefit for patients with hyperthyroidism and is not associated with increased risks of becoming obese,” Dr. Boelaert, a professor of endocrinology and consultant endocrinologist with the Institute of Applied Health Research, University of Birmingham, England, told this news organization.

However, “overall, there was a nearly 10% risk of major adverse cardiac events [MACE] in patients with hyperthyroidism regardless of the treatment modality used,” she noted.

Commenting on the findings, Jonathon O. Russell, MD, said the study offers surprising – but encouraging – results.

The discovery that radioiodine shows no increase in weight gain “contradicts numerous previous studies which have consistently demonstrated weight gain following definitive radioiodine,” Dr. Russell told this news organization.

Overall, however, “these findings reinforce our knowledge that definitive treatment of an overactive thyroid leads to a longer life – even if there is some weight gain,” added Dr. Russell, who is chief of the Division of Head and Neck Endocrine Surgery at Johns Hopkins, Baltimore.
 

Hyperthyroidism associated with serious long-term cardiometabolic issues

Hyperthyroidism is associated with serious long-term cardiovascular and metabolic morbidity and mortality, and treatment is therefore essential. However, the swing to hypothyroidism that often occurs afterward commonly results in regaining the weight lost due to the hyperthyroidism, if not more, potentially leading to obesity and its attendant health risks.

To investigate those risks in relation to the three key hyperthyroidism treatments, the authors conducted the EGRET trial. They identified 62,474 patients in the United Kingdom population-based electronic health record database who had newly diagnosed hyperthyroidism and were treated with antithyroid drugs (73.4%), radioiodine (19.5%), or thyroidectomy (7.1%) between April 1997 and December 2015.

Exclusion criteria included those with less than 6 months of antithyroid drugs as the only form of treatment, thyroid cancer, or pregnancy during the first episode.

With a median follow-up of about 8 years, those who were treated with thyroidectomy had a significantly increased risk of gaining weight, compared with the general population (P < .001), and of developing obesity (body mass index > 30 kg/m2; P = .003), while the corresponding increases with antithyroid drugs and radioiodine were not significantly different, compared with the general population over the same period.

In terms of survival, with an average follow-up of about 11 years per person, about 14% of the cohort died, with rates of 14.4% in the antithyroid drug group, 15.8% in the radioiodine group, and 9.2% in the thyroidectomy group.

Mortality rates were further assessed based on an average treatment effects analysis in which the average change was estimated, compared with the index of antithyroid drugs – for instance, if all were treated instead with radioiodine. In that extension of life analysis, those treated with radioiodine could be expected to die, on average, 1.2 years later than those taking antithyroid drugs (P < .001), while those treated with thyroidectomy would be expected to die 0.6 years later, which was not statistically significant.

Using the same average treatment effects analysis, Dr. Boelaert noted, “we found a slightly increased risk of major adverse cardiovascular events following radioiodine, compared with antithyroid drugs; [however], the risk was very small and may not be clinically relevant.”

“Previous data from our and other groups have shown reduced risks of mortality and cardiovascular death following radioiodine-induced hypothyroidism, although this is not confirmed in all studies.”
 

Weight gain after hyperthyroid treatment drives concerns

The findings are important because weight gain associated with hyperthyroidism treatment is no small matter for many patients, even prompting a lack of adherence to therapy for some, despite its importance, Dr. Boelaert noted.

“Since the majority of patients lose weight as a consequence of being hyperthyroid, it can be expected that they will at least regain the lost weight and possibly even have a weight overshoot,” she explained. “Indeed, many patients are reluctant to accept definitive treatment with surgery or radioiodine out of fear of weight gain.”

“This may cause difficulties to some patients who occasionally may even stop taking antithyroid drugs to prevent this weight regain. Such lack of adherence may have dire consequences and is likely a contributing factor to the increased mortality in these patients,” she observed.

In a previous study of 1,373 patients, Dr. Boelaert and colleagues found that men treated for hyperthyroidism gained an average of 8.0 kg (17.6 lb), and women gained an average of 5.5 kg (12.1 lb).

Compared with the background population, men were significantly more likely to gain weight over the study period (odds ratio, 1.7; P < .001) as were women (OR, 1.3; P < .001). Also in that study, radioiodine was associated with greater weight gain (0.6 kg; P < .001), compared with antithyroid drug treatment alone.

Dr. Russell added that even when weight gain does occur, the payoff of having treated the potentially serious state of hyperthyroidism is a highly beneficial trade-off.

Ultimately, “the goal of treating any patient with Graves’ should be to get them to become hypothyroid as quickly as possible,” he said. “Patients have options, and all of these options can be safe in the right situation.”

“It is unrealistic to think that going from a hyperthyroid state to a low thyroid state will not result in weight gain for many patients,” Dr. Russell added. “But the key point is that overall health is better despite this weight gain.”

Dr. Boelaert has disclosed consulting fees paid to the University of Birmingham by Lilly and Eisai. Dr. Russell has reported no relevant financial relationships.

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

MONTREAL – Amid common patient concerns about weight gain in the treatment of hyperthyroidism, findings from a large study suggest the therapy with the most favorable survival rate – radioiodine – is not associated with an increased risk of weight gain or obesity.

“EGRET is the first large study using population-based linked community and hospital data to elucidate the long-term consequences of treatment modalities for hyperthyroidism,” said co-author Kristien Boelaert, MD, PhD, while presenting the research at the American Thyroid Association annual meeting.

“The administration of [radioiodine] for hyperthyroidism is associated with a survival benefit for patients with hyperthyroidism and is not associated with increased risks of becoming obese,” Dr. Boelaert, a professor of endocrinology and consultant endocrinologist with the Institute of Applied Health Research, University of Birmingham, England, told this news organization.

However, “overall, there was a nearly 10% risk of major adverse cardiac events [MACE] in patients with hyperthyroidism regardless of the treatment modality used,” she noted.

Commenting on the findings, Jonathon O. Russell, MD, said the study offers surprising – but encouraging – results.

The discovery that radioiodine shows no increase in weight gain “contradicts numerous previous studies which have consistently demonstrated weight gain following definitive radioiodine,” Dr. Russell told this news organization.

Overall, however, “these findings reinforce our knowledge that definitive treatment of an overactive thyroid leads to a longer life – even if there is some weight gain,” added Dr. Russell, who is chief of the Division of Head and Neck Endocrine Surgery at Johns Hopkins, Baltimore.
 

Hyperthyroidism associated with serious long-term cardiometabolic issues

Hyperthyroidism is associated with serious long-term cardiovascular and metabolic morbidity and mortality, and treatment is therefore essential. However, the swing to hypothyroidism that often occurs afterward commonly results in regaining the weight lost due to the hyperthyroidism, if not more, potentially leading to obesity and its attendant health risks.

To investigate those risks in relation to the three key hyperthyroidism treatments, the authors conducted the EGRET trial. They identified 62,474 patients in the United Kingdom population-based electronic health record database who had newly diagnosed hyperthyroidism and were treated with antithyroid drugs (73.4%), radioiodine (19.5%), or thyroidectomy (7.1%) between April 1997 and December 2015.

Exclusion criteria included those with less than 6 months of antithyroid drugs as the only form of treatment, thyroid cancer, or pregnancy during the first episode.

With a median follow-up of about 8 years, those who were treated with thyroidectomy had a significantly increased risk of gaining weight, compared with the general population (P < .001), and of developing obesity (body mass index > 30 kg/m2; P = .003), while the corresponding increases with antithyroid drugs and radioiodine were not significantly different, compared with the general population over the same period.

In terms of survival, with an average follow-up of about 11 years per person, about 14% of the cohort died, with rates of 14.4% in the antithyroid drug group, 15.8% in the radioiodine group, and 9.2% in the thyroidectomy group.

Mortality rates were further assessed based on an average treatment effects analysis in which the average change was estimated, compared with the index of antithyroid drugs – for instance, if all were treated instead with radioiodine. In that extension of life analysis, those treated with radioiodine could be expected to die, on average, 1.2 years later than those taking antithyroid drugs (P < .001), while those treated with thyroidectomy would be expected to die 0.6 years later, which was not statistically significant.

Using the same average treatment effects analysis, Dr. Boelaert noted, “we found a slightly increased risk of major adverse cardiovascular events following radioiodine, compared with antithyroid drugs; [however], the risk was very small and may not be clinically relevant.”

“Previous data from our and other groups have shown reduced risks of mortality and cardiovascular death following radioiodine-induced hypothyroidism, although this is not confirmed in all studies.”
 

Weight gain after hyperthyroid treatment drives concerns

The findings are important because weight gain associated with hyperthyroidism treatment is no small matter for many patients, even prompting a lack of adherence to therapy for some, despite its importance, Dr. Boelaert noted.

“Since the majority of patients lose weight as a consequence of being hyperthyroid, it can be expected that they will at least regain the lost weight and possibly even have a weight overshoot,” she explained. “Indeed, many patients are reluctant to accept definitive treatment with surgery or radioiodine out of fear of weight gain.”

“This may cause difficulties to some patients who occasionally may even stop taking antithyroid drugs to prevent this weight regain. Such lack of adherence may have dire consequences and is likely a contributing factor to the increased mortality in these patients,” she observed.

In a previous study of 1,373 patients, Dr. Boelaert and colleagues found that men treated for hyperthyroidism gained an average of 8.0 kg (17.6 lb), and women gained an average of 5.5 kg (12.1 lb).

Compared with the background population, men were significantly more likely to gain weight over the study period (odds ratio, 1.7; P < .001) as were women (OR, 1.3; P < .001). Also in that study, radioiodine was associated with greater weight gain (0.6 kg; P < .001), compared with antithyroid drug treatment alone.

Dr. Russell added that even when weight gain does occur, the payoff of having treated the potentially serious state of hyperthyroidism is a highly beneficial trade-off.

Ultimately, “the goal of treating any patient with Graves’ should be to get them to become hypothyroid as quickly as possible,” he said. “Patients have options, and all of these options can be safe in the right situation.”

“It is unrealistic to think that going from a hyperthyroid state to a low thyroid state will not result in weight gain for many patients,” Dr. Russell added. “But the key point is that overall health is better despite this weight gain.”

Dr. Boelaert has disclosed consulting fees paid to the University of Birmingham by Lilly and Eisai. Dr. Russell has reported no relevant financial relationships.

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

Older adults who take part in regular weight lifting – either with or without moderate to vigorous aerobic activity – show significant reductions in all-cause and cardiovascular disease (CVD) mortality, with the strongest effects observed when the two types of exercise are combined, new research shows.

“The novel finding from our study is that weight lifting is independently associated with lower all-cause and CVD-specific mortality, regardless of aerobic activity,” first author Jessica Gorzelitz, PhD, said in an interview.

Wavebreakmedia/Getty Images

“What’s less surprising – but consistent and nonetheless noteworthy – is that weight lifting in combination with aerobic exercise provides the lowest...risk for mortality in older adults,” added Dr. Gorzelitz, an assistant professor of health promotion in the department of health and human physiology at the University of Iowa, Iowa City.

Those who undertook weight lifting and aerobic exercise in combination had around a 40% lower risk of death than those who reported no moderate to vigorous aerobic activity or weight lifting. The findings were recently published online in the British Journal of Sports Medicine.

Physical activity guidelines generally recommend regular moderate to vigorous aerobic physical activity, in addition to at least 2 days per week of muscle-strengthening exercise for all major muscle groups for adults to improve health and boost longevity.

However, few observational studies have examined the association between muscle strengthening and mortality, and even fewer have looked specifically at the benefits of weight lifting, Dr. Gorzelitz said.
 

Benefit of weight lifting stronger in women than men

To investigate, Dr. Gorzelitz and coauthors evaluated data on participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which, initiated in 1993, and involved adults aged 55-74 at 10 U.S. cancer centers.

Thirteen years into the trial, in 2006, participants completed follow-up questionnaires that included an assessment of weight lifting (not included in a baseline survey).

Among 99,713 participants involved in the current analysis, the mean age at the time of the follow-up questionnaire was 71.3 years. Participants had a mean body mass index of 27.8 kg/m² and 52.6% were women.

Only about a quarter of adults (23%) reported any weight lifting activity within the previous 12 months, with fewer, at 16%, reporting regular weight lifting of between one and six times per week.

Participants’ physical aerobic activity was also assessed. Physical activity guidelines (2018) recommend at least 150-300 minutes per week of moderate-intensity aerobic physical activity or 75-150 minutes per week of vigorous intensity aerobic activity or an equal combination of the two. Overall, 23.6% of participants reported activity that met the guideline for moderate to vigorous physical activity, and 8% exceeded it.

Over a median follow-up of about 9 years, 28,477 deaths occurred.

Those reporting weight lifting had a 9% lower risk of combined all-cause mortality and CVD mortality, after adjustment for any moderate to vigorous physical activity (each hazard ratio, 0.91).

Adults who met aerobic activity recommendations but did not weight lift had a 32% lower risk of all-cause mortality (HR, 0.68), while those who also reported weight lifting 1-2 times per week in addition to the aerobic activity had as much as a 41% lower risk of death (HR, 0.59), compared with adults reporting no moderate to vigorous aerobic activity or weight lifting.

The benefit of weight lifting in terms of cancer mortality was only observed without adjustment for moderate to vigorous physical activity, and was therefore considered null, which Dr. Gorzelitz said was somewhat surprising. “We will examine this association further because there could still be a signal there,” she said, noting other studies have shown that muscle strengthening activity is associated with lower cancer-specific mortality.

Of note, the benefit of weight lifting appeared stronger in women versus men, Dr. Gorzelitz said.
 

What are the mechanisms?

Underscoring that the results show only associations and not causation, Dr. Gorzelitz speculated that mechanisms behind a mortality benefit could include known favorable physiological changes of weight lifting.

“If people are weight lifting [to a degree] to reap strength benefits, we generally see improvement in body composition, including reductions in fat and improvements in lean tissue, and we know that those changes are associated with mortality, so it could be that the weight lifting is driving the strength or body composition,” she said.

The full body response involved in weight lifting could also play a key role, she noted.

With weight lifting, “the muscles have to redirect more blood flow, the heart is pumping harder, the lungs breathe more and when the muscles are worked in that fashion, there could be other system-wide adaptations,” she said.

Furthermore, social aspects could play a role, Dr. Gorzelitz observed.

“Unlike muscle strengthening [activities] that can be done in the home setting, weight lifting typically has to be done in recreational facilities or other community centers, and considering that this is an older adult population, that social interaction could be very key for preventing isolation.”

Important limitations include that the study did not determine the nature of the weight lifting, including the duration of the weight lifting sessions or type of weight, which could feasibly range from small hand-held weights to heavier weight lifting.

The study also couldn’t show how long participants had engaged in weight lifting in terms of months or years, hence, the duration needed to see a mortality benefit was not established.

Nevertheless, the study’s finding that the group with the lowest benefits was the one reporting no aerobic or weight lifting exercise underscores the benefits of even small amounts of exercise.

“I think it’s really important to promote the importance of adding muscle strengthening, but also of any physical activity,” Dr. Gorzelitz said. “Start small, but something is better than nothing.”

The authors reported no relevant financial relationships.

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

Older adults who take part in regular weight lifting – either with or without moderate to vigorous aerobic activity – show significant reductions in all-cause and cardiovascular disease (CVD) mortality, with the strongest effects observed when the two types of exercise are combined, new research shows.

“The novel finding from our study is that weight lifting is independently associated with lower all-cause and CVD-specific mortality, regardless of aerobic activity,” first author Jessica Gorzelitz, PhD, said in an interview.

Wavebreakmedia/Getty Images

“What’s less surprising – but consistent and nonetheless noteworthy – is that weight lifting in combination with aerobic exercise provides the lowest...risk for mortality in older adults,” added Dr. Gorzelitz, an assistant professor of health promotion in the department of health and human physiology at the University of Iowa, Iowa City.

Those who undertook weight lifting and aerobic exercise in combination had around a 40% lower risk of death than those who reported no moderate to vigorous aerobic activity or weight lifting. The findings were recently published online in the British Journal of Sports Medicine.

Physical activity guidelines generally recommend regular moderate to vigorous aerobic physical activity, in addition to at least 2 days per week of muscle-strengthening exercise for all major muscle groups for adults to improve health and boost longevity.

However, few observational studies have examined the association between muscle strengthening and mortality, and even fewer have looked specifically at the benefits of weight lifting, Dr. Gorzelitz said.
 

Benefit of weight lifting stronger in women than men

To investigate, Dr. Gorzelitz and coauthors evaluated data on participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which, initiated in 1993, and involved adults aged 55-74 at 10 U.S. cancer centers.

Thirteen years into the trial, in 2006, participants completed follow-up questionnaires that included an assessment of weight lifting (not included in a baseline survey).

Among 99,713 participants involved in the current analysis, the mean age at the time of the follow-up questionnaire was 71.3 years. Participants had a mean body mass index of 27.8 kg/m² and 52.6% were women.

Only about a quarter of adults (23%) reported any weight lifting activity within the previous 12 months, with fewer, at 16%, reporting regular weight lifting of between one and six times per week.

Participants’ physical aerobic activity was also assessed. Physical activity guidelines (2018) recommend at least 150-300 minutes per week of moderate-intensity aerobic physical activity or 75-150 minutes per week of vigorous intensity aerobic activity or an equal combination of the two. Overall, 23.6% of participants reported activity that met the guideline for moderate to vigorous physical activity, and 8% exceeded it.

Over a median follow-up of about 9 years, 28,477 deaths occurred.

Those reporting weight lifting had a 9% lower risk of combined all-cause mortality and CVD mortality, after adjustment for any moderate to vigorous physical activity (each hazard ratio, 0.91).

Adults who met aerobic activity recommendations but did not weight lift had a 32% lower risk of all-cause mortality (HR, 0.68), while those who also reported weight lifting 1-2 times per week in addition to the aerobic activity had as much as a 41% lower risk of death (HR, 0.59), compared with adults reporting no moderate to vigorous aerobic activity or weight lifting.

The benefit of weight lifting in terms of cancer mortality was only observed without adjustment for moderate to vigorous physical activity, and was therefore considered null, which Dr. Gorzelitz said was somewhat surprising. “We will examine this association further because there could still be a signal there,” she said, noting other studies have shown that muscle strengthening activity is associated with lower cancer-specific mortality.

Of note, the benefit of weight lifting appeared stronger in women versus men, Dr. Gorzelitz said.
 

What are the mechanisms?

Underscoring that the results show only associations and not causation, Dr. Gorzelitz speculated that mechanisms behind a mortality benefit could include known favorable physiological changes of weight lifting.

“If people are weight lifting [to a degree] to reap strength benefits, we generally see improvement in body composition, including reductions in fat and improvements in lean tissue, and we know that those changes are associated with mortality, so it could be that the weight lifting is driving the strength or body composition,” she said.

The full body response involved in weight lifting could also play a key role, she noted.

With weight lifting, “the muscles have to redirect more blood flow, the heart is pumping harder, the lungs breathe more and when the muscles are worked in that fashion, there could be other system-wide adaptations,” she said.

Furthermore, social aspects could play a role, Dr. Gorzelitz observed.

“Unlike muscle strengthening [activities] that can be done in the home setting, weight lifting typically has to be done in recreational facilities or other community centers, and considering that this is an older adult population, that social interaction could be very key for preventing isolation.”

Important limitations include that the study did not determine the nature of the weight lifting, including the duration of the weight lifting sessions or type of weight, which could feasibly range from small hand-held weights to heavier weight lifting.

The study also couldn’t show how long participants had engaged in weight lifting in terms of months or years, hence, the duration needed to see a mortality benefit was not established.

Nevertheless, the study’s finding that the group with the lowest benefits was the one reporting no aerobic or weight lifting exercise underscores the benefits of even small amounts of exercise.

“I think it’s really important to promote the importance of adding muscle strengthening, but also of any physical activity,” Dr. Gorzelitz said. “Start small, but something is better than nothing.”

The authors reported no relevant financial relationships.

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

Older adults who take part in regular weight lifting – either with or without moderate to vigorous aerobic activity – show significant reductions in all-cause and cardiovascular disease (CVD) mortality, with the strongest effects observed when the two types of exercise are combined, new research shows.

“The novel finding from our study is that weight lifting is independently associated with lower all-cause and CVD-specific mortality, regardless of aerobic activity,” first author Jessica Gorzelitz, PhD, said in an interview.

Wavebreakmedia/Getty Images

“What’s less surprising – but consistent and nonetheless noteworthy – is that weight lifting in combination with aerobic exercise provides the lowest...risk for mortality in older adults,” added Dr. Gorzelitz, an assistant professor of health promotion in the department of health and human physiology at the University of Iowa, Iowa City.

Those who undertook weight lifting and aerobic exercise in combination had around a 40% lower risk of death than those who reported no moderate to vigorous aerobic activity or weight lifting. The findings were recently published online in the British Journal of Sports Medicine.

Physical activity guidelines generally recommend regular moderate to vigorous aerobic physical activity, in addition to at least 2 days per week of muscle-strengthening exercise for all major muscle groups for adults to improve health and boost longevity.

However, few observational studies have examined the association between muscle strengthening and mortality, and even fewer have looked specifically at the benefits of weight lifting, Dr. Gorzelitz said.
 

Benefit of weight lifting stronger in women than men

To investigate, Dr. Gorzelitz and coauthors evaluated data on participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which, initiated in 1993, and involved adults aged 55-74 at 10 U.S. cancer centers.

Thirteen years into the trial, in 2006, participants completed follow-up questionnaires that included an assessment of weight lifting (not included in a baseline survey).

Among 99,713 participants involved in the current analysis, the mean age at the time of the follow-up questionnaire was 71.3 years. Participants had a mean body mass index of 27.8 kg/m² and 52.6% were women.

Only about a quarter of adults (23%) reported any weight lifting activity within the previous 12 months, with fewer, at 16%, reporting regular weight lifting of between one and six times per week.

Participants’ physical aerobic activity was also assessed. Physical activity guidelines (2018) recommend at least 150-300 minutes per week of moderate-intensity aerobic physical activity or 75-150 minutes per week of vigorous intensity aerobic activity or an equal combination of the two. Overall, 23.6% of participants reported activity that met the guideline for moderate to vigorous physical activity, and 8% exceeded it.

Over a median follow-up of about 9 years, 28,477 deaths occurred.

Those reporting weight lifting had a 9% lower risk of combined all-cause mortality and CVD mortality, after adjustment for any moderate to vigorous physical activity (each hazard ratio, 0.91).

Adults who met aerobic activity recommendations but did not weight lift had a 32% lower risk of all-cause mortality (HR, 0.68), while those who also reported weight lifting 1-2 times per week in addition to the aerobic activity had as much as a 41% lower risk of death (HR, 0.59), compared with adults reporting no moderate to vigorous aerobic activity or weight lifting.

The benefit of weight lifting in terms of cancer mortality was only observed without adjustment for moderate to vigorous physical activity, and was therefore considered null, which Dr. Gorzelitz said was somewhat surprising. “We will examine this association further because there could still be a signal there,” she said, noting other studies have shown that muscle strengthening activity is associated with lower cancer-specific mortality.

Of note, the benefit of weight lifting appeared stronger in women versus men, Dr. Gorzelitz said.
 

What are the mechanisms?

Underscoring that the results show only associations and not causation, Dr. Gorzelitz speculated that mechanisms behind a mortality benefit could include known favorable physiological changes of weight lifting.

“If people are weight lifting [to a degree] to reap strength benefits, we generally see improvement in body composition, including reductions in fat and improvements in lean tissue, and we know that those changes are associated with mortality, so it could be that the weight lifting is driving the strength or body composition,” she said.

The full body response involved in weight lifting could also play a key role, she noted.

With weight lifting, “the muscles have to redirect more blood flow, the heart is pumping harder, the lungs breathe more and when the muscles are worked in that fashion, there could be other system-wide adaptations,” she said.

Furthermore, social aspects could play a role, Dr. Gorzelitz observed.

“Unlike muscle strengthening [activities] that can be done in the home setting, weight lifting typically has to be done in recreational facilities or other community centers, and considering that this is an older adult population, that social interaction could be very key for preventing isolation.”

Important limitations include that the study did not determine the nature of the weight lifting, including the duration of the weight lifting sessions or type of weight, which could feasibly range from small hand-held weights to heavier weight lifting.

The study also couldn’t show how long participants had engaged in weight lifting in terms of months or years, hence, the duration needed to see a mortality benefit was not established.

Nevertheless, the study’s finding that the group with the lowest benefits was the one reporting no aerobic or weight lifting exercise underscores the benefits of even small amounts of exercise.

“I think it’s really important to promote the importance of adding muscle strengthening, but also of any physical activity,” Dr. Gorzelitz said. “Start small, but something is better than nothing.”

The authors reported no relevant financial relationships.

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

Patients undergoing chimeric antigen receptor (CAR) T-cell therapy who develop potentially serious neurotoxicity from the therapy show elevated plasma levels of neurofilament light chain (NfL) prior to the treatment, suggesting a possibly important predictor of risk for the side effect.

“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.

“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.

CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.

Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.

NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.

To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.

The patients had a median age of 64 and were 40% female.

Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.

Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.

A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).

Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.

However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.

The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
 

Interest in NfL levels on the rise

NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.

Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.

“Future studies will explore validating NfL for ICANS and additional indications,” he said.

ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.

The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.

Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.

“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
 

Limitations: Validation, preventive measures needed

Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.

“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.

The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.

“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”

A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.

“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”

Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.

Patients undergoing chimeric antigen receptor (CAR) T-cell therapy who develop potentially serious neurotoxicity from the therapy show elevated plasma levels of neurofilament light chain (NfL) prior to the treatment, suggesting a possibly important predictor of risk for the side effect.

“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.

“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.

CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.

Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.

NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.

To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.

The patients had a median age of 64 and were 40% female.

Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.

Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.

A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).

Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.

However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.

The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
 

Interest in NfL levels on the rise

NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.

Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.

“Future studies will explore validating NfL for ICANS and additional indications,” he said.

ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.

The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.

Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.

“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
 

Limitations: Validation, preventive measures needed

Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.

“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.

The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.

“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”

A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.

“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”

Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.

Patients undergoing chimeric antigen receptor (CAR) T-cell therapy who develop potentially serious neurotoxicity from the therapy show elevated plasma levels of neurofilament light chain (NfL) prior to the treatment, suggesting a possibly important predictor of risk for the side effect.

“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.

“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.

CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.

Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.

NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.

To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.

The patients had a median age of 64 and were 40% female.

Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.

Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.

A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).

Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.

However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.

The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
 

Interest in NfL levels on the rise

NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.

Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.

“Future studies will explore validating NfL for ICANS and additional indications,” he said.

ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.

The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.

Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.

“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
 

Limitations: Validation, preventive measures needed

Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.

“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.

The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.

“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”

A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.

“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”

Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.

In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.

“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.

The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.

Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.

“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.

Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.

The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.

Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.

Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).

Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.

“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.

Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.

With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).

The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.

“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.

While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.

“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.

The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.

“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
 

Case suggests ‘hope’ for relapsing patients

Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.

“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.

But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.

“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”

Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
 

Approach may help address unmet need

Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.

“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”

Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.

Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.

Dr. Lagana and associates are doing just that.

“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.

Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.

In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.

“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.

The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.

Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.

“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.

Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.

The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.

Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.

Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).

Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.

“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.

Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.

With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).

The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.

“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.

While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.

“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.

The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.

“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
 

Case suggests ‘hope’ for relapsing patients

Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.

“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.

But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.

“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”

Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
 

Approach may help address unmet need

Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.

“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”

Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.

Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.

Dr. Lagana and associates are doing just that.

“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.

Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.

In a case that researchers hope might pave the way for similar responses, a hospice-bound relapsed/refractory multiple myeloma (RRMM) patient who relapsed after chimeric antigen receptor (CAR) T-cell therapy was brought back into remission with the help of next-generation genomic sequencing, targeted molecular analysis and a novel combination of MAP kinase (MAPK)–inhibiting drugs.

“We have shown that comprehensive molecular profiling of advanced myeloma patients may provide critical information to guide treatment beyond standard of care,” senior author Alessandro Lagana, PhD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“This represents proof of concept that, while not curative, targeted molecules may serve as potential bridging therapies to clinical trial enrollment,” the authors further report in the case study, published recently in the Journal of Hematology & Oncology.

The use of B-cell maturation antigen (BCMA) CAR T-cell therapy approaches has transformed the treatment of multiple myeloma and leukemias, resulting in high response rates. However, most patients ultimately relapse, and no clear treatment options beyond CAR T therapy are established.

Such was the case for a 61-year old patient described in the study, who had relapsed 6 months after undergoing anti-BCMA CAR T-cell therapy and progressed after being salvaged for a short period with autologous stem cell transplantation. The patient had developed skin extramedullary disease, manifested as subcutaneous nodules.

“The subcutaneous skin lesions in lower extremities made him [ineligible] for another clinical trial and left him with no options,” Dr. Lagana said.

Using next-generation whole-exome sequencing, Dr. Lagana and colleagues had observed that a previously identified BRAF V600E–dominant subclone had persisted, despite the CAR T-cell treatment, in the patient’s bone marrow and cutaneous plasmacytoma.

The finding was not uncommon. More than half of RRMM patients (about 53%) show emerging clones with mutations within the MAPK signaling pathway, and in about 7% of patients, those include BRAF V600E, which can be targeted, the authors noted.

Further assessment of the patient’s CD138-positive MM cells using western blot signaling pathway analysis looking at DNA and RNA markers did indeed show an increase in MAPK signaling as a consequence of the mutation. This suggested a potential benefit of triple MAPK inhibition, compared with standard strategies.

Based on that information and on insights the researchers had gained from previous research, they implemented the novel, orally administered triple-combination treatment strategy, consisting of monomeric inhibition of BRAF dabrafenib (100 mg, twice daily), as well as dimeric inhibition with the multi–kinase inhibitor regorafenib (40 mg, once daily) and a MEK inhibitor (trametinib, 1.5 mg, for 21/28 days daily).

Of note, previous efforts using only monomeric inhibition of BRAF have not shown much success, but early data has shown some potential, with the inclusion of dimeric inhibition.

“Monomeric inhibition of BRAF has been attempted in patients with V600E, but the efficacy has been limited, likely due to feedback activation of the MAPK pathway via induction of BRAF dimer formation,” Dr. Lagana explained.

Meanwhile, “previous in vitro data from our colleagues at Mount Sinai has shown that inhibition of both monomeric and dimeric forms of BRAF in combination with MEK inhibition can overcome the negative feedback and lead to more efficacious and tolerable treatment,” he said.

With the treatment, the patient achieved a very good partial response for 110 days, with prompt reduction of the subcutaneous skin lesions and an 80% reduction in lambda free light chain (27.5 mg/L).

The triple-drug combination was well tolerated with minimal side effects, primarily involving grade 1 fatigue, and the patient was able to carry out activities of daily living and return to work.

“The triple inhibition allowed us to use less of each drug, which resulted in a well-tolerated regimen without any significant side effects,” Dr. Lagana said.

While the patient relapsed about 3 months later, there was, importantly, no recurrence of the subcutaneous nodules.

“We believe that the triple MAPK inhibition completely eradicated the disease clones driving the extramedullary disease,” Dr. Lagana said.

The therapy meanwhile enabled the patient to bridge to a new clinical trial, where he went into complete remission, and still was as of Sept. 29.

“To our knowledge, this was the first reported successful case of this treatment in an RRMM patient,” Dr. Lagana explained.
 

Case suggests ‘hope’ for relapsing patients

Importantly, currently many patients in the same position may wind up going to hospice, until such targeted medicine gains momentum, coauthor Samir Parekh, MD, a professor of hematology-oncology at the Hess Center for Science and Medicine, Icahn School of Medicine at Mount Sinai, said in an interview.

“As precision medicine is in its infancy in myeloma, these patients are not routinely sequenced for drug options that may be identified by next-generation sequencing,” said Dr. Parekh.

But for clinicians, the message of this case should be that “there is hope for patients relapsing after CAR T,” he added.

“Precision medicine approaches may be applicable even for this relapsed patient population,” he added. “MAP kinase mutations are common and drugs targeting them may be useful in myeloma.”

Noting that “the infrastructure to test and guide application of these therapies needs to be developed for myeloma, Dr. Parekh predicted that, “in the future, more effective MAPK inhibitors and other mutation or RNA-seq guided therapies will be applicable and hopefully provide more durable remissions.”
 

Approach may help address unmet need

Until then, however, treatment for patients who relapse after CAR-T and BCMA-targeted therapies has emerged as a significant unmet need. Therefore, this case highlights an important potential strategy, said Hans Lee, MD, an associate professor in the department of lymphoma/myeloma, division of cancer medicine, University of Texas MD Anderson Cancer Center, Houston, commenting on the study.

“This case report provides impetus for oncologists to strongly consider performing next-generation sequencing on myeloma tumor samples to look for potential actionable mutations, such as those in the MAPK pathway – which are common in myeloma,” he said. “With limited treatment options in the post–CAR T and post-BCMA setting, identifying such actional mutations may at least provide a bridge to other effective therapies available through clinical trials such as this patient’s case.”

Dr. Lee noted that key caveats include the fact that most physicians currently don’t have access to the type of next-generation sequencing and drug sensitivity testing used in the study.

Nevertheless, considering the limited options in the post–CAR T and post-BCMA setting, “the successful use of triple MAPK pathway inhibition through monomeric and dimeric inhibition of BRAF and MEK inhibition warrants further study in multiple myeloma in a clinical trial,” he said.

Dr. Lagana and associates are doing just that.

“We are about to launch the clinical trial, where we will match advanced RRMM patients with potential targeted treatments using different DNA and RNA markers,” Dr. Lagana said.

Dr. Lagana and Dr. Parekh had no disclosures to report. Three study coauthors reported receiving research grants or consulting fees from numerous pharmaceutical companies.