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Antidepressant study yields controversial findings
Researchers who conducted the study admit this finding was unexpected, and outside experts say no firm conclusions can be drawn from the research.
“Of course we were surprised by the results,” first author Omar Almohammed, PharmD, PhD, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, told this news organization.
“We were expecting to see some positive impact with the use of antidepressant medications on the HRQoL measures when we compared these patients to patients that did not use antidepressant medications,” Dr. Almohammed said.
The study was published online in PLOS ONE.
Controversial impact on quality of life
Depression is known to harm HRQoL. Despite evidence that antidepressants improve depressed mood, their effect on patients’ overall well-being and HRQoL remains controversial.
The researchers examined the effect of antidepressants on HRQoL in adults with depression using 11 years of data from the U.S. Medical Expenditures Panel Survey (MEPS), a large longitudinal survey that tracks health service use in the United States. HRQoL was measured using the 12-item Short Form Health Survey (SF-12).
On average, about 17.5 million adults were diagnosed with depression each year during the study period (2005-2016). More than half (57.6%) of these patients were treated with antidepressants.
Patients with depression had an average age of 48.3 years. Women made up more than two-thirds of the total sample (68%), and more women than men received antidepressants (61% vs. 52%).
Compared with no antidepressant use, antidepressant use was associated with some improvement on the mental, but not physical, component of the SF-12, the researchers report.
However, difference-in-differences (D-I-D) univariate analysis showed no significant difference between adults using and not using antidepressants in the SF-12 physical (-0.35 vs. -0.34; P = .9,595) or mental component (1.28 vs. 1.13; P = .6,405).
“The multivariate D-I-D analyses ensured the robustness of these results,” the researchers note.
The change in HRQoL observed in patients using antidepressants was not significantly different from that seen among peers not using these drugs, the researchers report.
“We are not saying that antidepressant medications are not helpful at all; HRQoL is only one of many measures intended to assess health outcomes,” Dr. Almohammed told this news organization.
“Based on our research design and data, we can only say that patients who used antidepressant medications did not experience better change in terms of HRQoL compared to patients who did not use antidepressant medications,” he said.
“These patients may have had some improvement on other clinical outcome measures, but that clinical improvement did not have a significant positive impact on HRQoL,” he noted.
“We still recommend that patients continue using their antidepressant medications, but they may want to ask their doctors to provide them with other nonpharmacologic interventions as this may have additional impact on their HRQoL,” Dr. Almohammed said.
Further research is needed to address a “gap in knowledge” about the impact of nondrug interventions – alone or in combination with antidepressant medications – on patients’ HRQoL, Dr. Almohammed added.
Experts weigh in
Several experts weighed in on the study in a statement from the British nonprofit Science Media Center.
Gemma Lewis, PhD, with University College London (UCL), noted that “clinical trials with experimental designs have found that antidepressants improve mental health-related quality of life.”
“In this study, the people who received antidepressants had worse quality of life, and are likely to have been more severely depressed, than those who did not. This type of bias is difficult to eliminate in a naturalistic study like this, which does not involve an experimental design,” Dr. Lewis commented.
Eduard Vieta, PhD, with University of Barcelona, noted the “inability to control for severity of depression between the two different groups is a crucial flaw, and therefore, there is little we can learn from this data.”
Echoing Dr. Vieta, David Curtis, MBBS, MD, PhD, with UCL Genetics Institute, said, “One might well assume that the people who were taking antidepressants had been more severely depressed than those who were not.”
“From this point of view, one could argue that it seems that the antidepressants were effective and that with their use people who had presented with more severe depression did not have markedly reduced quality of life,” Dr. Curtis said.
“However, the reality is that this kind of observational study tells us nothing about causation. For that, clinical trials are required, and numerous such trials have demonstrated that, on average, antidepressants are effective in terms of treating depressive illness and in improving the quality of life of patients with significant depression,” he added.
Michael Sharpe, MD, with University of Oxford, said the study highlights the importance of measuring the long-term outcomes of treatments for depression. “However, this study has no clear implication for the care of patients with depression and certainly should not discourage patients who may benefit from taking these drugs.”
Livia de Picker, MD, PhD, with University of Antwerp, Belgium, said, “What these data do point towards is the persistent treatment gap for depression in the United States, with only 57.6% of patients with major depressive disorder receiving treatment with antidepressants over a 2-year follow-up.”
Funding for the study was provided by King Saud University, Riyadh, Saudi Arabia. Dr. Almohammed, Dr. de Picker, Dr. Curtis, Dr. Lewis, and Dr. Sharpe have disclosed no relevant financial relationships. Dr. Vieta has participated in clinical trials of antidepressants and advisory boards for Angelini, Biogen, Janssen, and Lundbeck.
A version of this article first appeared on Medscape.com.
Researchers who conducted the study admit this finding was unexpected, and outside experts say no firm conclusions can be drawn from the research.
“Of course we were surprised by the results,” first author Omar Almohammed, PharmD, PhD, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, told this news organization.
“We were expecting to see some positive impact with the use of antidepressant medications on the HRQoL measures when we compared these patients to patients that did not use antidepressant medications,” Dr. Almohammed said.
The study was published online in PLOS ONE.
Controversial impact on quality of life
Depression is known to harm HRQoL. Despite evidence that antidepressants improve depressed mood, their effect on patients’ overall well-being and HRQoL remains controversial.
The researchers examined the effect of antidepressants on HRQoL in adults with depression using 11 years of data from the U.S. Medical Expenditures Panel Survey (MEPS), a large longitudinal survey that tracks health service use in the United States. HRQoL was measured using the 12-item Short Form Health Survey (SF-12).
On average, about 17.5 million adults were diagnosed with depression each year during the study period (2005-2016). More than half (57.6%) of these patients were treated with antidepressants.
Patients with depression had an average age of 48.3 years. Women made up more than two-thirds of the total sample (68%), and more women than men received antidepressants (61% vs. 52%).
Compared with no antidepressant use, antidepressant use was associated with some improvement on the mental, but not physical, component of the SF-12, the researchers report.
However, difference-in-differences (D-I-D) univariate analysis showed no significant difference between adults using and not using antidepressants in the SF-12 physical (-0.35 vs. -0.34; P = .9,595) or mental component (1.28 vs. 1.13; P = .6,405).
“The multivariate D-I-D analyses ensured the robustness of these results,” the researchers note.
The change in HRQoL observed in patients using antidepressants was not significantly different from that seen among peers not using these drugs, the researchers report.
“We are not saying that antidepressant medications are not helpful at all; HRQoL is only one of many measures intended to assess health outcomes,” Dr. Almohammed told this news organization.
“Based on our research design and data, we can only say that patients who used antidepressant medications did not experience better change in terms of HRQoL compared to patients who did not use antidepressant medications,” he said.
“These patients may have had some improvement on other clinical outcome measures, but that clinical improvement did not have a significant positive impact on HRQoL,” he noted.
“We still recommend that patients continue using their antidepressant medications, but they may want to ask their doctors to provide them with other nonpharmacologic interventions as this may have additional impact on their HRQoL,” Dr. Almohammed said.
Further research is needed to address a “gap in knowledge” about the impact of nondrug interventions – alone or in combination with antidepressant medications – on patients’ HRQoL, Dr. Almohammed added.
Experts weigh in
Several experts weighed in on the study in a statement from the British nonprofit Science Media Center.
Gemma Lewis, PhD, with University College London (UCL), noted that “clinical trials with experimental designs have found that antidepressants improve mental health-related quality of life.”
“In this study, the people who received antidepressants had worse quality of life, and are likely to have been more severely depressed, than those who did not. This type of bias is difficult to eliminate in a naturalistic study like this, which does not involve an experimental design,” Dr. Lewis commented.
Eduard Vieta, PhD, with University of Barcelona, noted the “inability to control for severity of depression between the two different groups is a crucial flaw, and therefore, there is little we can learn from this data.”
Echoing Dr. Vieta, David Curtis, MBBS, MD, PhD, with UCL Genetics Institute, said, “One might well assume that the people who were taking antidepressants had been more severely depressed than those who were not.”
“From this point of view, one could argue that it seems that the antidepressants were effective and that with their use people who had presented with more severe depression did not have markedly reduced quality of life,” Dr. Curtis said.
“However, the reality is that this kind of observational study tells us nothing about causation. For that, clinical trials are required, and numerous such trials have demonstrated that, on average, antidepressants are effective in terms of treating depressive illness and in improving the quality of life of patients with significant depression,” he added.
Michael Sharpe, MD, with University of Oxford, said the study highlights the importance of measuring the long-term outcomes of treatments for depression. “However, this study has no clear implication for the care of patients with depression and certainly should not discourage patients who may benefit from taking these drugs.”
Livia de Picker, MD, PhD, with University of Antwerp, Belgium, said, “What these data do point towards is the persistent treatment gap for depression in the United States, with only 57.6% of patients with major depressive disorder receiving treatment with antidepressants over a 2-year follow-up.”
Funding for the study was provided by King Saud University, Riyadh, Saudi Arabia. Dr. Almohammed, Dr. de Picker, Dr. Curtis, Dr. Lewis, and Dr. Sharpe have disclosed no relevant financial relationships. Dr. Vieta has participated in clinical trials of antidepressants and advisory boards for Angelini, Biogen, Janssen, and Lundbeck.
A version of this article first appeared on Medscape.com.
Researchers who conducted the study admit this finding was unexpected, and outside experts say no firm conclusions can be drawn from the research.
“Of course we were surprised by the results,” first author Omar Almohammed, PharmD, PhD, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, told this news organization.
“We were expecting to see some positive impact with the use of antidepressant medications on the HRQoL measures when we compared these patients to patients that did not use antidepressant medications,” Dr. Almohammed said.
The study was published online in PLOS ONE.
Controversial impact on quality of life
Depression is known to harm HRQoL. Despite evidence that antidepressants improve depressed mood, their effect on patients’ overall well-being and HRQoL remains controversial.
The researchers examined the effect of antidepressants on HRQoL in adults with depression using 11 years of data from the U.S. Medical Expenditures Panel Survey (MEPS), a large longitudinal survey that tracks health service use in the United States. HRQoL was measured using the 12-item Short Form Health Survey (SF-12).
On average, about 17.5 million adults were diagnosed with depression each year during the study period (2005-2016). More than half (57.6%) of these patients were treated with antidepressants.
Patients with depression had an average age of 48.3 years. Women made up more than two-thirds of the total sample (68%), and more women than men received antidepressants (61% vs. 52%).
Compared with no antidepressant use, antidepressant use was associated with some improvement on the mental, but not physical, component of the SF-12, the researchers report.
However, difference-in-differences (D-I-D) univariate analysis showed no significant difference between adults using and not using antidepressants in the SF-12 physical (-0.35 vs. -0.34; P = .9,595) or mental component (1.28 vs. 1.13; P = .6,405).
“The multivariate D-I-D analyses ensured the robustness of these results,” the researchers note.
The change in HRQoL observed in patients using antidepressants was not significantly different from that seen among peers not using these drugs, the researchers report.
“We are not saying that antidepressant medications are not helpful at all; HRQoL is only one of many measures intended to assess health outcomes,” Dr. Almohammed told this news organization.
“Based on our research design and data, we can only say that patients who used antidepressant medications did not experience better change in terms of HRQoL compared to patients who did not use antidepressant medications,” he said.
“These patients may have had some improvement on other clinical outcome measures, but that clinical improvement did not have a significant positive impact on HRQoL,” he noted.
“We still recommend that patients continue using their antidepressant medications, but they may want to ask their doctors to provide them with other nonpharmacologic interventions as this may have additional impact on their HRQoL,” Dr. Almohammed said.
Further research is needed to address a “gap in knowledge” about the impact of nondrug interventions – alone or in combination with antidepressant medications – on patients’ HRQoL, Dr. Almohammed added.
Experts weigh in
Several experts weighed in on the study in a statement from the British nonprofit Science Media Center.
Gemma Lewis, PhD, with University College London (UCL), noted that “clinical trials with experimental designs have found that antidepressants improve mental health-related quality of life.”
“In this study, the people who received antidepressants had worse quality of life, and are likely to have been more severely depressed, than those who did not. This type of bias is difficult to eliminate in a naturalistic study like this, which does not involve an experimental design,” Dr. Lewis commented.
Eduard Vieta, PhD, with University of Barcelona, noted the “inability to control for severity of depression between the two different groups is a crucial flaw, and therefore, there is little we can learn from this data.”
Echoing Dr. Vieta, David Curtis, MBBS, MD, PhD, with UCL Genetics Institute, said, “One might well assume that the people who were taking antidepressants had been more severely depressed than those who were not.”
“From this point of view, one could argue that it seems that the antidepressants were effective and that with their use people who had presented with more severe depression did not have markedly reduced quality of life,” Dr. Curtis said.
“However, the reality is that this kind of observational study tells us nothing about causation. For that, clinical trials are required, and numerous such trials have demonstrated that, on average, antidepressants are effective in terms of treating depressive illness and in improving the quality of life of patients with significant depression,” he added.
Michael Sharpe, MD, with University of Oxford, said the study highlights the importance of measuring the long-term outcomes of treatments for depression. “However, this study has no clear implication for the care of patients with depression and certainly should not discourage patients who may benefit from taking these drugs.”
Livia de Picker, MD, PhD, with University of Antwerp, Belgium, said, “What these data do point towards is the persistent treatment gap for depression in the United States, with only 57.6% of patients with major depressive disorder receiving treatment with antidepressants over a 2-year follow-up.”
Funding for the study was provided by King Saud University, Riyadh, Saudi Arabia. Dr. Almohammed, Dr. de Picker, Dr. Curtis, Dr. Lewis, and Dr. Sharpe have disclosed no relevant financial relationships. Dr. Vieta has participated in clinical trials of antidepressants and advisory boards for Angelini, Biogen, Janssen, and Lundbeck.
A version of this article first appeared on Medscape.com.
Polypharmacy common among patients aged 65 or older with HIV
People aged 65 or older with human immunodeficiency virus (HIV) receive significantly more nonantiretroviral therapy (non-ART) medications, compared with patients with HIV who are between ages 50 and 64, according to a new study.
Moreover, in a sample of more than 900 patients with HIV, about 60% were taking at least one potentially inappropriate medication (PIM).
“Clinicians looking after persons living with HIV need to provide medication reconciliation with prioritization of medications based on the patients’ wishes and patients’ goals and life expectancy,” lead author Jacqueline McMillan, MD, clinical assistant professor of geriatric medicine at the University of Calgary (Alt.) told this news organization.
The findings were published online in the Canadian Journal of General Internal Medicine.
Examining the pill burden
A geriatrician by training and a clinical researcher with an interest in aging in patients with HIV, Dr. McMillan said she began to observe that many older adults with HIV were on polypharmacy. “There are many other things that aging people with HIV experience, such as frailty, falls, cognitive impairment, medication nonadherence, and mortality, but in this study, we focused just on the polypharmacy,” said Dr. McMillan.
Her aim was to see if there was a way to improve the pill burden in these older adults.
“Do they need to be on all of these medications? Is there anything that we were overprescribing that they no longer needed, or possibly not prescribing and undertreating people because they were older? I wanted to have a better sense that the medications we were prescribing were appropriate and that we minimized the pill burden for older adults,” Dr. McMillan said.
Persons with HIV are at a particularly increased risk of polypharmacy and potential drug-drug interactions because they need antiretroviral therapy medications and medications to treat comorbidities.
“Certainly, when the ARTs were first discovered, sometimes that regimen required several pills a day, but as time has gone on and our retrovirals have gotten better, some of those requirements have narrowed down to one-pill-a-day regimens. We are now replacing that pill burden with non-HIV drugs,” said Dr. McMillan.
The researchers obtained medication reconciliation data for 951 persons with HIV aged 50 or older as of Feb. 1, 2020. The study population was receiving HIV care through the Southern Alberta HIV Clinic in Calgary. The researchers defined polypharmacy as taking five or more non-ART drugs. They defined PIMs according to the 2019 Beers criteria.
In their analysis, the researchers compared patients aged 65 or older with patients aged 50-64, as well as patients with shorter (< 10 years) and longer (> 10 years) duration of HIV infection.
PIM use common
The population’s mean age was 59 years, and 82% were men. The mean time since HIV diagnosis was 17.8 years, and the median time was 17 years. Most (80%) of the patients were aged 50-64 years, and 20% were 65 and older.
The researchers collected sociodemographic, clinical, medication, and laboratory data for all patients at each clinical visit.
The mean number of non-ART medications was 6.7 for the population. Patients aged 65 years or older were taking significantly more non-ART medications than patients aged 50-64 (8.4 vs. 6.3; P < .001).
Similarly, those living with HIV for more than 10 years were taking significantly more non-ART medications (mean, 6.9) than those living with HIV for 10 or fewer years (mean 6.1; P = .0168).
In all, almost 60% of patients were taking at least one PIM. The mean number of PIMs per patient was 1.6.
Patients living with diagnosed HIV infection for more than 10 years were at greater risk of PIMs (1.6 PIMs) than those with shorter duration of HIV diagnosis (1.4 PIMs; P = .06).
Dr. McMillan says she hopes her study reminds clinicians to review patients’ medications at each visit and ensure they are neither over- nor underprescribing.
“From my perspective as a geriatrician, I hope that we do more dedicated medication reconciliation to actually make sure we know what people are taking,” she said. She asks patients to bring all their medications to the office so that they can review which ones match their diagnoses.
“I want to do more patient-centered personalized care for older adults, with a focus on people who are frail and who may have a limited life expectancy, so that we don’t have someone with a short life expectancy still taking 15 medications a day,” said Dr. McMillan.
‘Carefully document medications’
“This study identifies potentially inappropriate medication use in a group of older people living with HIV who are particularly vulnerable to it at an earlier age because of their medical complexity or frailty than perhaps healthy older adults,” Adrian Wagg, MD, professor of healthy aging in the department of medicine at the University of Alberta, Edmonton, told this news organization.
The study emphasizes the importance of careful documentation of medications that the patient is taking at every clinical visit, he said.
“Make sure you carefully document medications which are taken whenever you see the individual. Also try to limit the number of prescribers, because we know multiple prescribers are associated with greater likelihood of inappropriate prescribing,” Dr. Wagg said.
The move to wean patients from inappropriate medications is gaining momentum, he added.
“There is a huge movement now around actively deprescribing medications which are either no longer indicated or potentially of little benefit, given remaining life expectancy,” said Dr. Wagg. Drugs such as proton pump inhibitors, hypnotics, unrequired antidepressants, and benzodiazepines are the first targets for elimination, he concluded.
The study was funded by the University of Calgary. Dr. McMillan and Dr. Wagg reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People aged 65 or older with human immunodeficiency virus (HIV) receive significantly more nonantiretroviral therapy (non-ART) medications, compared with patients with HIV who are between ages 50 and 64, according to a new study.
Moreover, in a sample of more than 900 patients with HIV, about 60% were taking at least one potentially inappropriate medication (PIM).
“Clinicians looking after persons living with HIV need to provide medication reconciliation with prioritization of medications based on the patients’ wishes and patients’ goals and life expectancy,” lead author Jacqueline McMillan, MD, clinical assistant professor of geriatric medicine at the University of Calgary (Alt.) told this news organization.
The findings were published online in the Canadian Journal of General Internal Medicine.
Examining the pill burden
A geriatrician by training and a clinical researcher with an interest in aging in patients with HIV, Dr. McMillan said she began to observe that many older adults with HIV were on polypharmacy. “There are many other things that aging people with HIV experience, such as frailty, falls, cognitive impairment, medication nonadherence, and mortality, but in this study, we focused just on the polypharmacy,” said Dr. McMillan.
Her aim was to see if there was a way to improve the pill burden in these older adults.
“Do they need to be on all of these medications? Is there anything that we were overprescribing that they no longer needed, or possibly not prescribing and undertreating people because they were older? I wanted to have a better sense that the medications we were prescribing were appropriate and that we minimized the pill burden for older adults,” Dr. McMillan said.
Persons with HIV are at a particularly increased risk of polypharmacy and potential drug-drug interactions because they need antiretroviral therapy medications and medications to treat comorbidities.
“Certainly, when the ARTs were first discovered, sometimes that regimen required several pills a day, but as time has gone on and our retrovirals have gotten better, some of those requirements have narrowed down to one-pill-a-day regimens. We are now replacing that pill burden with non-HIV drugs,” said Dr. McMillan.
The researchers obtained medication reconciliation data for 951 persons with HIV aged 50 or older as of Feb. 1, 2020. The study population was receiving HIV care through the Southern Alberta HIV Clinic in Calgary. The researchers defined polypharmacy as taking five or more non-ART drugs. They defined PIMs according to the 2019 Beers criteria.
In their analysis, the researchers compared patients aged 65 or older with patients aged 50-64, as well as patients with shorter (< 10 years) and longer (> 10 years) duration of HIV infection.
PIM use common
The population’s mean age was 59 years, and 82% were men. The mean time since HIV diagnosis was 17.8 years, and the median time was 17 years. Most (80%) of the patients were aged 50-64 years, and 20% were 65 and older.
The researchers collected sociodemographic, clinical, medication, and laboratory data for all patients at each clinical visit.
The mean number of non-ART medications was 6.7 for the population. Patients aged 65 years or older were taking significantly more non-ART medications than patients aged 50-64 (8.4 vs. 6.3; P < .001).
Similarly, those living with HIV for more than 10 years were taking significantly more non-ART medications (mean, 6.9) than those living with HIV for 10 or fewer years (mean 6.1; P = .0168).
In all, almost 60% of patients were taking at least one PIM. The mean number of PIMs per patient was 1.6.
Patients living with diagnosed HIV infection for more than 10 years were at greater risk of PIMs (1.6 PIMs) than those with shorter duration of HIV diagnosis (1.4 PIMs; P = .06).
Dr. McMillan says she hopes her study reminds clinicians to review patients’ medications at each visit and ensure they are neither over- nor underprescribing.
“From my perspective as a geriatrician, I hope that we do more dedicated medication reconciliation to actually make sure we know what people are taking,” she said. She asks patients to bring all their medications to the office so that they can review which ones match their diagnoses.
“I want to do more patient-centered personalized care for older adults, with a focus on people who are frail and who may have a limited life expectancy, so that we don’t have someone with a short life expectancy still taking 15 medications a day,” said Dr. McMillan.
‘Carefully document medications’
“This study identifies potentially inappropriate medication use in a group of older people living with HIV who are particularly vulnerable to it at an earlier age because of their medical complexity or frailty than perhaps healthy older adults,” Adrian Wagg, MD, professor of healthy aging in the department of medicine at the University of Alberta, Edmonton, told this news organization.
The study emphasizes the importance of careful documentation of medications that the patient is taking at every clinical visit, he said.
“Make sure you carefully document medications which are taken whenever you see the individual. Also try to limit the number of prescribers, because we know multiple prescribers are associated with greater likelihood of inappropriate prescribing,” Dr. Wagg said.
The move to wean patients from inappropriate medications is gaining momentum, he added.
“There is a huge movement now around actively deprescribing medications which are either no longer indicated or potentially of little benefit, given remaining life expectancy,” said Dr. Wagg. Drugs such as proton pump inhibitors, hypnotics, unrequired antidepressants, and benzodiazepines are the first targets for elimination, he concluded.
The study was funded by the University of Calgary. Dr. McMillan and Dr. Wagg reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
People aged 65 or older with human immunodeficiency virus (HIV) receive significantly more nonantiretroviral therapy (non-ART) medications, compared with patients with HIV who are between ages 50 and 64, according to a new study.
Moreover, in a sample of more than 900 patients with HIV, about 60% were taking at least one potentially inappropriate medication (PIM).
“Clinicians looking after persons living with HIV need to provide medication reconciliation with prioritization of medications based on the patients’ wishes and patients’ goals and life expectancy,” lead author Jacqueline McMillan, MD, clinical assistant professor of geriatric medicine at the University of Calgary (Alt.) told this news organization.
The findings were published online in the Canadian Journal of General Internal Medicine.
Examining the pill burden
A geriatrician by training and a clinical researcher with an interest in aging in patients with HIV, Dr. McMillan said she began to observe that many older adults with HIV were on polypharmacy. “There are many other things that aging people with HIV experience, such as frailty, falls, cognitive impairment, medication nonadherence, and mortality, but in this study, we focused just on the polypharmacy,” said Dr. McMillan.
Her aim was to see if there was a way to improve the pill burden in these older adults.
“Do they need to be on all of these medications? Is there anything that we were overprescribing that they no longer needed, or possibly not prescribing and undertreating people because they were older? I wanted to have a better sense that the medications we were prescribing were appropriate and that we minimized the pill burden for older adults,” Dr. McMillan said.
Persons with HIV are at a particularly increased risk of polypharmacy and potential drug-drug interactions because they need antiretroviral therapy medications and medications to treat comorbidities.
“Certainly, when the ARTs were first discovered, sometimes that regimen required several pills a day, but as time has gone on and our retrovirals have gotten better, some of those requirements have narrowed down to one-pill-a-day regimens. We are now replacing that pill burden with non-HIV drugs,” said Dr. McMillan.
The researchers obtained medication reconciliation data for 951 persons with HIV aged 50 or older as of Feb. 1, 2020. The study population was receiving HIV care through the Southern Alberta HIV Clinic in Calgary. The researchers defined polypharmacy as taking five or more non-ART drugs. They defined PIMs according to the 2019 Beers criteria.
In their analysis, the researchers compared patients aged 65 or older with patients aged 50-64, as well as patients with shorter (< 10 years) and longer (> 10 years) duration of HIV infection.
PIM use common
The population’s mean age was 59 years, and 82% were men. The mean time since HIV diagnosis was 17.8 years, and the median time was 17 years. Most (80%) of the patients were aged 50-64 years, and 20% were 65 and older.
The researchers collected sociodemographic, clinical, medication, and laboratory data for all patients at each clinical visit.
The mean number of non-ART medications was 6.7 for the population. Patients aged 65 years or older were taking significantly more non-ART medications than patients aged 50-64 (8.4 vs. 6.3; P < .001).
Similarly, those living with HIV for more than 10 years were taking significantly more non-ART medications (mean, 6.9) than those living with HIV for 10 or fewer years (mean 6.1; P = .0168).
In all, almost 60% of patients were taking at least one PIM. The mean number of PIMs per patient was 1.6.
Patients living with diagnosed HIV infection for more than 10 years were at greater risk of PIMs (1.6 PIMs) than those with shorter duration of HIV diagnosis (1.4 PIMs; P = .06).
Dr. McMillan says she hopes her study reminds clinicians to review patients’ medications at each visit and ensure they are neither over- nor underprescribing.
“From my perspective as a geriatrician, I hope that we do more dedicated medication reconciliation to actually make sure we know what people are taking,” she said. She asks patients to bring all their medications to the office so that they can review which ones match their diagnoses.
“I want to do more patient-centered personalized care for older adults, with a focus on people who are frail and who may have a limited life expectancy, so that we don’t have someone with a short life expectancy still taking 15 medications a day,” said Dr. McMillan.
‘Carefully document medications’
“This study identifies potentially inappropriate medication use in a group of older people living with HIV who are particularly vulnerable to it at an earlier age because of their medical complexity or frailty than perhaps healthy older adults,” Adrian Wagg, MD, professor of healthy aging in the department of medicine at the University of Alberta, Edmonton, told this news organization.
The study emphasizes the importance of careful documentation of medications that the patient is taking at every clinical visit, he said.
“Make sure you carefully document medications which are taken whenever you see the individual. Also try to limit the number of prescribers, because we know multiple prescribers are associated with greater likelihood of inappropriate prescribing,” Dr. Wagg said.
The move to wean patients from inappropriate medications is gaining momentum, he added.
“There is a huge movement now around actively deprescribing medications which are either no longer indicated or potentially of little benefit, given remaining life expectancy,” said Dr. Wagg. Drugs such as proton pump inhibitors, hypnotics, unrequired antidepressants, and benzodiazepines are the first targets for elimination, he concluded.
The study was funded by the University of Calgary. Dr. McMillan and Dr. Wagg reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE CANADIAN JOURNAL OF GENERAL INTERNAL MEDICINE
Hair loss: Consider a patient’s supplement use
BOSTON – .
This is an important question because patients consider supplements as “natural and healthy,” not as drugs or chemicals, Wilma F. Bergfeld, MD, said at the annual meeting of the American Academy of Dermatology.
Some of these products contain botanicals, which are not always safe, added Dr. Bergfeld, professor of dermatology and pathology at the Cleveland Clinic. “They have many activities, and they are being touted as having some activity in helping the hair or enhancing hair growth,” including having 5-alpha-reductase inhibitors as an ingredient. “Saw palmetto is probably the most common one, but there are a host of natural ingredients that are being put into these supplements, including those that promote androgen induction, as well as antioxidants and anti-inflammatories.”
In the opinion of Dr. Bergfeld, a nutrition-focused physical assessment should include an examination of the scalp and all hairy areas. “It’s also important to see the symmetry and shape of hair growth or hair loss areas, the distribution, hair color, the thickness and texture of the hair fibers,” she added.
Besides asking about what supplements patients are taking, other questions to ask during the visit include: Are you noticing more hair on your brush, pillow, and shoulders, or in the shower? Do you think your hair is thinning? What are your medical problems? Have you experienced rapid weight loss? Have you started any new medications? What medication(s) are you on? What foods do you eat? Do you have a family history of hair loss?
Possible causes of hair loss or changes include environmental factors, stress, hormonal changes, medications, and nutrition.
Common ingredients contained in healthy hair supplements include biotin, folic acid, L-cysteine, L-methionine, MSM (methylsulfonylmethane), vitamin B complex, and vitamins A, C, D, and E. “Vitamin D and A are associated on the hair follicle receptor sites, and they balance each other, so if one is down the other is usually down,” said Dr. Bergfeld, who directs Cleveland Clinic’s hair disorders clinic and its dermatopathology program. Other important ingredients include iron, zinc, manganese, amino acids including L-Lysine, and fatty acids.
Iron deficiency is a known cause of hair loss. “The absorption of iron relies on vitamin C and sometimes lysine,” she said. Red meat has a high iron content and since many patients are restricting red meat intake, “they do need to think about that.” Zinc deficiency is less common in Western countries, she continued, “but when you find it, it’s revolutionary because if they’re shedding hair and their hair character is changing, often some supplementation will do the trick. But remember: Zinc is not only an anti-inflammatory, it’s also an antiandrogen. It has 5-alpha-reductase inhibitor capabilities.”.
Dr. Bergfeld noted that biotin, also known as vitamin B7 and found in many foods, is used in many vitamin supplements marketed for hair loss. The recommended daily allowance (RDA) is 30 mcg/day in adults but the amount in hair supplements can be up to 650% of RDA. “Biotin at high levels is believed to be safe, but can interfere with troponin and other lab testing,” she cautioned. “This can lead to dangerous false laboratory results.”
To date, insufficient data exist to recommend supplementation with zinc, riboflavin, folic acid, or vitamin B12 for hair loss, “but they may help in cases of deficiency,” said Dr. Bergfeld, a past president of the American Hair Research Society. The use of vitamin E and biotin supplementation is not supported in the literature for treating androgenetic alopecia or telogen effluvium. Excessive vitamin A (not beta carotene) and selenium can contribute to hair loss and studies have shown a relationship between androgenetic alopecia and low vitamin D levels. “Vitamin D should be supplemented if serum levels are low, but more studies are needed to determine the effect of iron and zinc supplementation” in patients with androgenetic alopecia, she said.
While there are not enough data to support a recommendation for supplementation of folic or B12 for alopecia, she said, “vitamin B12 deficiency may occur in androgenetic alopecia patients, associated with pernicious anemia.”
She added that the use biotin supplementation for the treatment of androgenetic alopecia is not supported by available data, and “it is also unclear if selenium plays a role in this disease.”
Dr. Bergfeld reported having no disclosures related to her presentation.
BOSTON – .
This is an important question because patients consider supplements as “natural and healthy,” not as drugs or chemicals, Wilma F. Bergfeld, MD, said at the annual meeting of the American Academy of Dermatology.
Some of these products contain botanicals, which are not always safe, added Dr. Bergfeld, professor of dermatology and pathology at the Cleveland Clinic. “They have many activities, and they are being touted as having some activity in helping the hair or enhancing hair growth,” including having 5-alpha-reductase inhibitors as an ingredient. “Saw palmetto is probably the most common one, but there are a host of natural ingredients that are being put into these supplements, including those that promote androgen induction, as well as antioxidants and anti-inflammatories.”
In the opinion of Dr. Bergfeld, a nutrition-focused physical assessment should include an examination of the scalp and all hairy areas. “It’s also important to see the symmetry and shape of hair growth or hair loss areas, the distribution, hair color, the thickness and texture of the hair fibers,” she added.
Besides asking about what supplements patients are taking, other questions to ask during the visit include: Are you noticing more hair on your brush, pillow, and shoulders, or in the shower? Do you think your hair is thinning? What are your medical problems? Have you experienced rapid weight loss? Have you started any new medications? What medication(s) are you on? What foods do you eat? Do you have a family history of hair loss?
Possible causes of hair loss or changes include environmental factors, stress, hormonal changes, medications, and nutrition.
Common ingredients contained in healthy hair supplements include biotin, folic acid, L-cysteine, L-methionine, MSM (methylsulfonylmethane), vitamin B complex, and vitamins A, C, D, and E. “Vitamin D and A are associated on the hair follicle receptor sites, and they balance each other, so if one is down the other is usually down,” said Dr. Bergfeld, who directs Cleveland Clinic’s hair disorders clinic and its dermatopathology program. Other important ingredients include iron, zinc, manganese, amino acids including L-Lysine, and fatty acids.
Iron deficiency is a known cause of hair loss. “The absorption of iron relies on vitamin C and sometimes lysine,” she said. Red meat has a high iron content and since many patients are restricting red meat intake, “they do need to think about that.” Zinc deficiency is less common in Western countries, she continued, “but when you find it, it’s revolutionary because if they’re shedding hair and their hair character is changing, often some supplementation will do the trick. But remember: Zinc is not only an anti-inflammatory, it’s also an antiandrogen. It has 5-alpha-reductase inhibitor capabilities.”.
Dr. Bergfeld noted that biotin, also known as vitamin B7 and found in many foods, is used in many vitamin supplements marketed for hair loss. The recommended daily allowance (RDA) is 30 mcg/day in adults but the amount in hair supplements can be up to 650% of RDA. “Biotin at high levels is believed to be safe, but can interfere with troponin and other lab testing,” she cautioned. “This can lead to dangerous false laboratory results.”
To date, insufficient data exist to recommend supplementation with zinc, riboflavin, folic acid, or vitamin B12 for hair loss, “but they may help in cases of deficiency,” said Dr. Bergfeld, a past president of the American Hair Research Society. The use of vitamin E and biotin supplementation is not supported in the literature for treating androgenetic alopecia or telogen effluvium. Excessive vitamin A (not beta carotene) and selenium can contribute to hair loss and studies have shown a relationship between androgenetic alopecia and low vitamin D levels. “Vitamin D should be supplemented if serum levels are low, but more studies are needed to determine the effect of iron and zinc supplementation” in patients with androgenetic alopecia, she said.
While there are not enough data to support a recommendation for supplementation of folic or B12 for alopecia, she said, “vitamin B12 deficiency may occur in androgenetic alopecia patients, associated with pernicious anemia.”
She added that the use biotin supplementation for the treatment of androgenetic alopecia is not supported by available data, and “it is also unclear if selenium plays a role in this disease.”
Dr. Bergfeld reported having no disclosures related to her presentation.
BOSTON – .
This is an important question because patients consider supplements as “natural and healthy,” not as drugs or chemicals, Wilma F. Bergfeld, MD, said at the annual meeting of the American Academy of Dermatology.
Some of these products contain botanicals, which are not always safe, added Dr. Bergfeld, professor of dermatology and pathology at the Cleveland Clinic. “They have many activities, and they are being touted as having some activity in helping the hair or enhancing hair growth,” including having 5-alpha-reductase inhibitors as an ingredient. “Saw palmetto is probably the most common one, but there are a host of natural ingredients that are being put into these supplements, including those that promote androgen induction, as well as antioxidants and anti-inflammatories.”
In the opinion of Dr. Bergfeld, a nutrition-focused physical assessment should include an examination of the scalp and all hairy areas. “It’s also important to see the symmetry and shape of hair growth or hair loss areas, the distribution, hair color, the thickness and texture of the hair fibers,” she added.
Besides asking about what supplements patients are taking, other questions to ask during the visit include: Are you noticing more hair on your brush, pillow, and shoulders, or in the shower? Do you think your hair is thinning? What are your medical problems? Have you experienced rapid weight loss? Have you started any new medications? What medication(s) are you on? What foods do you eat? Do you have a family history of hair loss?
Possible causes of hair loss or changes include environmental factors, stress, hormonal changes, medications, and nutrition.
Common ingredients contained in healthy hair supplements include biotin, folic acid, L-cysteine, L-methionine, MSM (methylsulfonylmethane), vitamin B complex, and vitamins A, C, D, and E. “Vitamin D and A are associated on the hair follicle receptor sites, and they balance each other, so if one is down the other is usually down,” said Dr. Bergfeld, who directs Cleveland Clinic’s hair disorders clinic and its dermatopathology program. Other important ingredients include iron, zinc, manganese, amino acids including L-Lysine, and fatty acids.
Iron deficiency is a known cause of hair loss. “The absorption of iron relies on vitamin C and sometimes lysine,” she said. Red meat has a high iron content and since many patients are restricting red meat intake, “they do need to think about that.” Zinc deficiency is less common in Western countries, she continued, “but when you find it, it’s revolutionary because if they’re shedding hair and their hair character is changing, often some supplementation will do the trick. But remember: Zinc is not only an anti-inflammatory, it’s also an antiandrogen. It has 5-alpha-reductase inhibitor capabilities.”.
Dr. Bergfeld noted that biotin, also known as vitamin B7 and found in many foods, is used in many vitamin supplements marketed for hair loss. The recommended daily allowance (RDA) is 30 mcg/day in adults but the amount in hair supplements can be up to 650% of RDA. “Biotin at high levels is believed to be safe, but can interfere with troponin and other lab testing,” she cautioned. “This can lead to dangerous false laboratory results.”
To date, insufficient data exist to recommend supplementation with zinc, riboflavin, folic acid, or vitamin B12 for hair loss, “but they may help in cases of deficiency,” said Dr. Bergfeld, a past president of the American Hair Research Society. The use of vitamin E and biotin supplementation is not supported in the literature for treating androgenetic alopecia or telogen effluvium. Excessive vitamin A (not beta carotene) and selenium can contribute to hair loss and studies have shown a relationship between androgenetic alopecia and low vitamin D levels. “Vitamin D should be supplemented if serum levels are low, but more studies are needed to determine the effect of iron and zinc supplementation” in patients with androgenetic alopecia, she said.
While there are not enough data to support a recommendation for supplementation of folic or B12 for alopecia, she said, “vitamin B12 deficiency may occur in androgenetic alopecia patients, associated with pernicious anemia.”
She added that the use biotin supplementation for the treatment of androgenetic alopecia is not supported by available data, and “it is also unclear if selenium plays a role in this disease.”
Dr. Bergfeld reported having no disclosures related to her presentation.
AT AAD 22
High antipsychotic switch rates suggest ‘suboptimal’ prescribing for first-episode psychosis
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large-scale, real-world analysis of U.K. prescribing patterns, researchers found more than two-thirds of patients who received antipsychotics for FEP switched medication, and almost half switched drugs three times.
Although this is “one of the largest real-world studies examining antipsychotic treatment strategies,” it reflects findings from previous, smaller studies showing “antipsychotic switching in first episode psychosis is high,” said study investigator Aimee Brinn, Institute of Psychiatry, Psychology & Neuroscience at King’s College London.
This may reflect reports of poor efficacy and suggests that first-line prescribing is “suboptimal,” Ms. Brinn noted. In addition, olanzapine remains the most popular antipsychotic for prescribing despite recent guidelines indicating it is “not ideal ... due to its dangerous metabolic side effects,” she added.
The findings were presented at the Congress of the Schizophrenia International Research Society (SIRS) 2022.
Real-world data
The response to, and tolerability of, antipsychotics differs between patients with FEP; and prescribing patterns “reflect clinician and patient-led decisionmaking,” Ms. Brinn told meeting attendees.
Since randomized controlled trials “do not necessarily reflect prescribing practice in real-world clinical settings,” the researchers gathered data from a large mental health care electronic health record dataset.
The investigators examined records from the South London and Maudsley NHS Foundation Trust (SLaM), which has a catchment area of 1.2 million individuals across four boroughs of London. The group sees approximately 37,500 active patients per week.
The team used the Clinical Interactive Record Search tool to extract data on 2,309 adults with FEP who received care from a SLaM early intervention in psychosis service between April 1, 2008, and March 31, 2019.
They found that 12 different antipsychotics were prescribed as first-line treatment. The most common were olanzapine (43.9%), risperidone (24.7%), and aripiprazole (19.9%).
Results showed that over 81,969.5 person-years of follow-up, at a minimum of 24 months per patient, 68.8% had an antipsychotic switch. The most common first treatment switch, in 17.9% of patients, was from olanzapine to aripiprazole.
Of patients who switched to aripiprazole, 48.4% stayed on the drug, 26% switched back to olanzapine, and 25.6% received other treatment. Overall, 44.7% of patients switched medication at least three times.
Among patients with FEP who did not switch, 42.2% were prescribed olanzapine, 26.2% risperidone, 23.3% aripiprazole, 5.6% quetiapine, and 2.7% amisulpride.
During the post-presentation discussion, Ms. Brinn was asked whether the high rate of first-line olanzapine prescribing could be because patients started treatment as inpatients and were then switched once they were moved to community care.
“We found that a lot of patients would be prescribed olanzapine for around 7 days at the start of their prescription and then switch,” Ms. Brinn said, adding it is “likely” they started as inpatients. The investigators are currently examining the differences between inpatient and outpatient prescriptions to verify whether this is indeed the case, she added.
‘Pulling out the big guns too fast?’
Commenting on the findings, Thomas W. Sedlak, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, said the study raises a “number of questions.”
Both olanzapine and risperidone “tend to have higher treatment effect improvements than aripiprazole, so it’s curious that a switch to aripiprazole was common,” said Dr. Sedlak, who was not involved with the research.
“Are we pulling out the ‘big guns’ too fast, or inappropriately, especially as olanzapine and risperidone carry greater risk of weight gain?” he asked. In addition, “now that olanzapine is available with samidorphan to mitigate weight gain, will that shape future patterns, if it can be paid for?”
Dr. Sedlak noted it was unclear why olanzapine was chosen so often as first-line treatment in the study and agreed it is “possible that hospitalized patients had been prescribed a ‘stronger’ medication like olanzapine compared to never-hospitalized patients.”
He also underlined that it is “not clear if patients in this FEP program are representative of all FEP patients.”
“For instance, if the program is well known to inpatient hospital social workers, then the program might be disproportionately filled with patients who have had more severe symptoms,” Dr. Sedlak said.
The study was supported by Janssen-Cilag. The investigators and Dr. Sedlak have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM SIRS 2022
Preop nivolumab plus chemo ‘a quantum leap’ in NSCLC therapy
NEW ORLEANS – For patients with resectable non–small cell lung cancer (NSCLC), further
The combination resulted in significantly longer event-free survival and a 14-fold greater chance of having a pathological complete response compared with chemotherapy alone.
Adding immunotherapy (IO) to chemotherapy in the neoadjuvant setting represents “a quantum leap in lung cancer therapy,” commented David P. Carbone, MD, PhD, director of the James Thoracic Center at Ohio State University, Columbus.
“Combining IO with surgery I think is a new standard of care and will almost certainly improve overall survival [OS] in early-stage disease, for the first time in decades, in my entire career,” he said while discussing the new data at the annual meeting of the American Association for Cancer Research.
The data come from the phase 3 CheckMate 816 study, an open-label trial involving patients with stage IB-IIIA resectable NSCLC. The study was published in the New England Journal of Medicine to coincide with the presentation.
Results from this trial were the basis of the Food and Drug Administration’s recent approval of neoadjuvant therapy with nivolumab (Opdivo) and platinum-based chemotherapy in this population, which one expert described as “a turning point in how we treat resectable NSCLC.”
“Neoadjuvant IO has multiple theoretical advantages of over adjuvant IO,” commented Dr. Carbone. “CheckMate 816 suggests that practice will prove this theory correct.”
Importance of Neoadjuvant Immunotherapy
New details of the results were presented at the meeting by Nicolas Girard, MD, from Institut Curie in Paris.
Among 358 patients in the trial, the median event-free survival (EFS) was 31.6 months for patients randomly assigned to the combination of the immune checkpoint inhibitor nivolumab and platinum-base chemotherapy, compared with 20.8 months for patients assigned to chemotherapy alone. This translated into a hazard ratio for disease recurrence, progression, or death of 0.63 (P = .005).
In addition, 24% of patients assigned to the nivolumab plus chemotherapy arm had a pathological complete response (pCR) to neoadjuvant therapy, compared with only 2.2% of those assigned to chemotherapy alone (P < .001).
Dr. Girard said the study provided important clues to the importance of neoadjuvant therapy for improving objective responses.
“Event-free survival was improved in patients with a pathological complete response, compared with those without, suggesting pCR is a surrogate endpoint for long-term outcomes in resectable non–small cell lung cancer, and this is the first time [this has been shown] in a randomized, phase 3 study,” he said.
Neoadjuvant slow to catch on
About one -fourth of all patients who are diagnosed with NSCLC have resectable disease, Dr. Girard and colleagues noted. However, 30%-55% of patients who undergo surgery with curative intent ultimately experience recurrence and die from their disease.
Neoadjuvant therapy may improve chances for complete resection and prevent or delay recurrence after surgery, but the absolute difference in 5-year recurrence-free survival and OS with neoadjuvant chemotherapy alone is only about 6%, they noted.
The new results suggest that adding neoadjuvant immunotherapy to chemotherapy will improve upon this, although so far, the OS data from this trial are immature.
In an interim analysis, the median OS rate was 83% at 2 years for patients treated with nivolumab plus chemotherapy, compared with 71% for patients treated with chemotherapy alone. The published results show a significant improvement in the two primary endpoints – EFS and pCR.
In an editorial accompanying the study, Christine M. Lovly, MD, PhD, from the Vanderbilt-Ingram Cancer Center at Vanderbilt University in Nashville, Tenn., commented that the results of the trial are expected to change practice.
“However, several issues remain to be addressed,” she wrote. “First, is a pathological complete response predictive of event-free survival? Can event-free survival be used as a surrogate endpoint for overall survival? Second, although not mandated for this trial, approximately 20% of the patients received postoperative therapy. Is adjuvant therapy necessary? What criteria should be used to select patients to receive adjuvant therapy?”
Dr. Lovly also pointed out that patients with tumors harboring mutations in the genes EGFR or ALK were excluded from the trial.
“Therefore, implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine,” she wrote.
Fears of delaying surgery
In an interview, Upal Basu Roy, PhD, MPH, executive director of research at the LUNGevity Foundation, who was not involved in the study, gave a reason why neoadjuvant therapy is not more widely prescribed for patients with resectable NSCLC.
“Clinicians are always scared, and I think patients are as well, that giving a treatment before surgery would delay surgery,” he said. “When patients are diagnosed with lung cancer and they’re told that surgery offers the potential of cure and then hear that you’re giving them a treatment before surgery and that treatment may potentially delay surgery, that is a huge source of anxiety.”
In addition, clinicians until recently were unsure about which patients were most likely to benefit from neoadjuvant therapy when the only option was chemotherapy, “but that’s changing, obviously, with the recent approval of neoadjuvant nivolumab through CheckMate 816,” he said.
CheckMate 816 details
In the CheckMate 816 study, investigators enrolled patients with newly diagnosed resectable NSCLC (stage IB-IIIA) who had good performance status and no known sensitizing EGFR mutations or ALK alterations.
After stratification by stage, programmed death–1 status, and sex, the team randomly assigned patients to receive either nivolumab 360 mg plus platinum-based chemotherapy every 3 weeks for a total of three cycles or chemotherapy alone.
At the end of neoadjuvant therapy, patients underwent radiologic restaging and surgery within 6 weeks. Patients could also receive optional adjuvant chemotherapy with or without radiotherapy.
Of the 179 patients in each arm, 176 received the assigned treatment. In all, 149 (83%) of those assigned to the combination had definitive surgery, as did 135 (75%) of those assigned to chemotherapy alone.
In addition, 35 patients (20%) of those assigned to nivolumab-chemo and 56 (32%) assigned to chemotherapy alone received adjuvant therapy.
The coprimary endpoints of EFS and pCR favored the combination, both in the overall population and across most subgroups, including patients younger than 65, men and women, Asian patients, those with stage IIIA disease, nonsquamous histology, current smokers and never-smokers, and patients with higher levels of PD–ligand 1 expression.
The rates of grade 3 or 4 treatment-related adverse events were similar between the groups, at 33.5% with the combination and 36.9% with chemotherapy alone.
Rates of adverse events leading to study discontinuation, treatment-related adverse events, and surgery-related adverse events were similar between the groups. There were two treatment-related deaths, both in the chemotherapy-alone arm.
CheckMate 816 was funded by Bristol-Myers Squibb (manufacturer of nivolumab). Girard has consulted for and has received grant support from Bristol-Myers Squibb and other companies. Dr. Carbone has consulted for Bristol-Myers Squibb and other companies. Dr. Lovly has consulted for various companies. Dr. Roy has received grants from Bristol-Myers Squibb to the LUNGevity Foundation.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – For patients with resectable non–small cell lung cancer (NSCLC), further
The combination resulted in significantly longer event-free survival and a 14-fold greater chance of having a pathological complete response compared with chemotherapy alone.
Adding immunotherapy (IO) to chemotherapy in the neoadjuvant setting represents “a quantum leap in lung cancer therapy,” commented David P. Carbone, MD, PhD, director of the James Thoracic Center at Ohio State University, Columbus.
“Combining IO with surgery I think is a new standard of care and will almost certainly improve overall survival [OS] in early-stage disease, for the first time in decades, in my entire career,” he said while discussing the new data at the annual meeting of the American Association for Cancer Research.
The data come from the phase 3 CheckMate 816 study, an open-label trial involving patients with stage IB-IIIA resectable NSCLC. The study was published in the New England Journal of Medicine to coincide with the presentation.
Results from this trial were the basis of the Food and Drug Administration’s recent approval of neoadjuvant therapy with nivolumab (Opdivo) and platinum-based chemotherapy in this population, which one expert described as “a turning point in how we treat resectable NSCLC.”
“Neoadjuvant IO has multiple theoretical advantages of over adjuvant IO,” commented Dr. Carbone. “CheckMate 816 suggests that practice will prove this theory correct.”
Importance of Neoadjuvant Immunotherapy
New details of the results were presented at the meeting by Nicolas Girard, MD, from Institut Curie in Paris.
Among 358 patients in the trial, the median event-free survival (EFS) was 31.6 months for patients randomly assigned to the combination of the immune checkpoint inhibitor nivolumab and platinum-base chemotherapy, compared with 20.8 months for patients assigned to chemotherapy alone. This translated into a hazard ratio for disease recurrence, progression, or death of 0.63 (P = .005).
In addition, 24% of patients assigned to the nivolumab plus chemotherapy arm had a pathological complete response (pCR) to neoadjuvant therapy, compared with only 2.2% of those assigned to chemotherapy alone (P < .001).
Dr. Girard said the study provided important clues to the importance of neoadjuvant therapy for improving objective responses.
“Event-free survival was improved in patients with a pathological complete response, compared with those without, suggesting pCR is a surrogate endpoint for long-term outcomes in resectable non–small cell lung cancer, and this is the first time [this has been shown] in a randomized, phase 3 study,” he said.
Neoadjuvant slow to catch on
About one -fourth of all patients who are diagnosed with NSCLC have resectable disease, Dr. Girard and colleagues noted. However, 30%-55% of patients who undergo surgery with curative intent ultimately experience recurrence and die from their disease.
Neoadjuvant therapy may improve chances for complete resection and prevent or delay recurrence after surgery, but the absolute difference in 5-year recurrence-free survival and OS with neoadjuvant chemotherapy alone is only about 6%, they noted.
The new results suggest that adding neoadjuvant immunotherapy to chemotherapy will improve upon this, although so far, the OS data from this trial are immature.
In an interim analysis, the median OS rate was 83% at 2 years for patients treated with nivolumab plus chemotherapy, compared with 71% for patients treated with chemotherapy alone. The published results show a significant improvement in the two primary endpoints – EFS and pCR.
In an editorial accompanying the study, Christine M. Lovly, MD, PhD, from the Vanderbilt-Ingram Cancer Center at Vanderbilt University in Nashville, Tenn., commented that the results of the trial are expected to change practice.
“However, several issues remain to be addressed,” she wrote. “First, is a pathological complete response predictive of event-free survival? Can event-free survival be used as a surrogate endpoint for overall survival? Second, although not mandated for this trial, approximately 20% of the patients received postoperative therapy. Is adjuvant therapy necessary? What criteria should be used to select patients to receive adjuvant therapy?”
Dr. Lovly also pointed out that patients with tumors harboring mutations in the genes EGFR or ALK were excluded from the trial.
“Therefore, implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine,” she wrote.
Fears of delaying surgery
In an interview, Upal Basu Roy, PhD, MPH, executive director of research at the LUNGevity Foundation, who was not involved in the study, gave a reason why neoadjuvant therapy is not more widely prescribed for patients with resectable NSCLC.
“Clinicians are always scared, and I think patients are as well, that giving a treatment before surgery would delay surgery,” he said. “When patients are diagnosed with lung cancer and they’re told that surgery offers the potential of cure and then hear that you’re giving them a treatment before surgery and that treatment may potentially delay surgery, that is a huge source of anxiety.”
In addition, clinicians until recently were unsure about which patients were most likely to benefit from neoadjuvant therapy when the only option was chemotherapy, “but that’s changing, obviously, with the recent approval of neoadjuvant nivolumab through CheckMate 816,” he said.
CheckMate 816 details
In the CheckMate 816 study, investigators enrolled patients with newly diagnosed resectable NSCLC (stage IB-IIIA) who had good performance status and no known sensitizing EGFR mutations or ALK alterations.
After stratification by stage, programmed death–1 status, and sex, the team randomly assigned patients to receive either nivolumab 360 mg plus platinum-based chemotherapy every 3 weeks for a total of three cycles or chemotherapy alone.
At the end of neoadjuvant therapy, patients underwent radiologic restaging and surgery within 6 weeks. Patients could also receive optional adjuvant chemotherapy with or without radiotherapy.
Of the 179 patients in each arm, 176 received the assigned treatment. In all, 149 (83%) of those assigned to the combination had definitive surgery, as did 135 (75%) of those assigned to chemotherapy alone.
In addition, 35 patients (20%) of those assigned to nivolumab-chemo and 56 (32%) assigned to chemotherapy alone received adjuvant therapy.
The coprimary endpoints of EFS and pCR favored the combination, both in the overall population and across most subgroups, including patients younger than 65, men and women, Asian patients, those with stage IIIA disease, nonsquamous histology, current smokers and never-smokers, and patients with higher levels of PD–ligand 1 expression.
The rates of grade 3 or 4 treatment-related adverse events were similar between the groups, at 33.5% with the combination and 36.9% with chemotherapy alone.
Rates of adverse events leading to study discontinuation, treatment-related adverse events, and surgery-related adverse events were similar between the groups. There were two treatment-related deaths, both in the chemotherapy-alone arm.
CheckMate 816 was funded by Bristol-Myers Squibb (manufacturer of nivolumab). Girard has consulted for and has received grant support from Bristol-Myers Squibb and other companies. Dr. Carbone has consulted for Bristol-Myers Squibb and other companies. Dr. Lovly has consulted for various companies. Dr. Roy has received grants from Bristol-Myers Squibb to the LUNGevity Foundation.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – For patients with resectable non–small cell lung cancer (NSCLC), further
The combination resulted in significantly longer event-free survival and a 14-fold greater chance of having a pathological complete response compared with chemotherapy alone.
Adding immunotherapy (IO) to chemotherapy in the neoadjuvant setting represents “a quantum leap in lung cancer therapy,” commented David P. Carbone, MD, PhD, director of the James Thoracic Center at Ohio State University, Columbus.
“Combining IO with surgery I think is a new standard of care and will almost certainly improve overall survival [OS] in early-stage disease, for the first time in decades, in my entire career,” he said while discussing the new data at the annual meeting of the American Association for Cancer Research.
The data come from the phase 3 CheckMate 816 study, an open-label trial involving patients with stage IB-IIIA resectable NSCLC. The study was published in the New England Journal of Medicine to coincide with the presentation.
Results from this trial were the basis of the Food and Drug Administration’s recent approval of neoadjuvant therapy with nivolumab (Opdivo) and platinum-based chemotherapy in this population, which one expert described as “a turning point in how we treat resectable NSCLC.”
“Neoadjuvant IO has multiple theoretical advantages of over adjuvant IO,” commented Dr. Carbone. “CheckMate 816 suggests that practice will prove this theory correct.”
Importance of Neoadjuvant Immunotherapy
New details of the results were presented at the meeting by Nicolas Girard, MD, from Institut Curie in Paris.
Among 358 patients in the trial, the median event-free survival (EFS) was 31.6 months for patients randomly assigned to the combination of the immune checkpoint inhibitor nivolumab and platinum-base chemotherapy, compared with 20.8 months for patients assigned to chemotherapy alone. This translated into a hazard ratio for disease recurrence, progression, or death of 0.63 (P = .005).
In addition, 24% of patients assigned to the nivolumab plus chemotherapy arm had a pathological complete response (pCR) to neoadjuvant therapy, compared with only 2.2% of those assigned to chemotherapy alone (P < .001).
Dr. Girard said the study provided important clues to the importance of neoadjuvant therapy for improving objective responses.
“Event-free survival was improved in patients with a pathological complete response, compared with those without, suggesting pCR is a surrogate endpoint for long-term outcomes in resectable non–small cell lung cancer, and this is the first time [this has been shown] in a randomized, phase 3 study,” he said.
Neoadjuvant slow to catch on
About one -fourth of all patients who are diagnosed with NSCLC have resectable disease, Dr. Girard and colleagues noted. However, 30%-55% of patients who undergo surgery with curative intent ultimately experience recurrence and die from their disease.
Neoadjuvant therapy may improve chances for complete resection and prevent or delay recurrence after surgery, but the absolute difference in 5-year recurrence-free survival and OS with neoadjuvant chemotherapy alone is only about 6%, they noted.
The new results suggest that adding neoadjuvant immunotherapy to chemotherapy will improve upon this, although so far, the OS data from this trial are immature.
In an interim analysis, the median OS rate was 83% at 2 years for patients treated with nivolumab plus chemotherapy, compared with 71% for patients treated with chemotherapy alone. The published results show a significant improvement in the two primary endpoints – EFS and pCR.
In an editorial accompanying the study, Christine M. Lovly, MD, PhD, from the Vanderbilt-Ingram Cancer Center at Vanderbilt University in Nashville, Tenn., commented that the results of the trial are expected to change practice.
“However, several issues remain to be addressed,” she wrote. “First, is a pathological complete response predictive of event-free survival? Can event-free survival be used as a surrogate endpoint for overall survival? Second, although not mandated for this trial, approximately 20% of the patients received postoperative therapy. Is adjuvant therapy necessary? What criteria should be used to select patients to receive adjuvant therapy?”
Dr. Lovly also pointed out that patients with tumors harboring mutations in the genes EGFR or ALK were excluded from the trial.
“Therefore, implementation of neoadjuvant therapies requires biomarker testing for patients with early-stage disease at the time of diagnosis, a considerable alteration in the routine practice of lung-cancer medicine,” she wrote.
Fears of delaying surgery
In an interview, Upal Basu Roy, PhD, MPH, executive director of research at the LUNGevity Foundation, who was not involved in the study, gave a reason why neoadjuvant therapy is not more widely prescribed for patients with resectable NSCLC.
“Clinicians are always scared, and I think patients are as well, that giving a treatment before surgery would delay surgery,” he said. “When patients are diagnosed with lung cancer and they’re told that surgery offers the potential of cure and then hear that you’re giving them a treatment before surgery and that treatment may potentially delay surgery, that is a huge source of anxiety.”
In addition, clinicians until recently were unsure about which patients were most likely to benefit from neoadjuvant therapy when the only option was chemotherapy, “but that’s changing, obviously, with the recent approval of neoadjuvant nivolumab through CheckMate 816,” he said.
CheckMate 816 details
In the CheckMate 816 study, investigators enrolled patients with newly diagnosed resectable NSCLC (stage IB-IIIA) who had good performance status and no known sensitizing EGFR mutations or ALK alterations.
After stratification by stage, programmed death–1 status, and sex, the team randomly assigned patients to receive either nivolumab 360 mg plus platinum-based chemotherapy every 3 weeks for a total of three cycles or chemotherapy alone.
At the end of neoadjuvant therapy, patients underwent radiologic restaging and surgery within 6 weeks. Patients could also receive optional adjuvant chemotherapy with or without radiotherapy.
Of the 179 patients in each arm, 176 received the assigned treatment. In all, 149 (83%) of those assigned to the combination had definitive surgery, as did 135 (75%) of those assigned to chemotherapy alone.
In addition, 35 patients (20%) of those assigned to nivolumab-chemo and 56 (32%) assigned to chemotherapy alone received adjuvant therapy.
The coprimary endpoints of EFS and pCR favored the combination, both in the overall population and across most subgroups, including patients younger than 65, men and women, Asian patients, those with stage IIIA disease, nonsquamous histology, current smokers and never-smokers, and patients with higher levels of PD–ligand 1 expression.
The rates of grade 3 or 4 treatment-related adverse events were similar between the groups, at 33.5% with the combination and 36.9% with chemotherapy alone.
Rates of adverse events leading to study discontinuation, treatment-related adverse events, and surgery-related adverse events were similar between the groups. There were two treatment-related deaths, both in the chemotherapy-alone arm.
CheckMate 816 was funded by Bristol-Myers Squibb (manufacturer of nivolumab). Girard has consulted for and has received grant support from Bristol-Myers Squibb and other companies. Dr. Carbone has consulted for Bristol-Myers Squibb and other companies. Dr. Lovly has consulted for various companies. Dr. Roy has received grants from Bristol-Myers Squibb to the LUNGevity Foundation.
A version of this article first appeared on Medscape.com.
AT AACR 2022
Made-to-order TILs effective against metastatic melanoma
NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents,
The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.
The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.
“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).
He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.
Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.
However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.
The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.
“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
Patient-derived product
Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.
Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
Details from clinical trial
At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.
These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.
Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.
After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.
Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.
The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.
All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.
The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.
“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.
The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
Remaining questions, next steps
Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.
“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.
Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.
Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.
The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents,
The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.
The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.
“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).
He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.
Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.
However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.
The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.
“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
Patient-derived product
Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.
Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
Details from clinical trial
At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.
These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.
Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.
After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.
Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.
The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.
All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.
The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.
“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.
The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
Remaining questions, next steps
Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.
“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.
Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.
Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.
The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – In just over one-third of patients with metastatic melanoma who had experienced disease progression while receiving multiple prior lines of therapy, including immunotherapy and targeted agents,
The product, called lifileucel, is custom made for each patient and utilizes tumor-infiltrating lymphocytes (TILs) extracted from tumor lesions. This approach differs from other cell-based therapies, such as chimeric antigen receptor (CAR) T cell therapy, which utilizes T cells collected from the patient’s blood.
The new results come from a phase 2 trial conducted in 66 patients with previously treated unresectable or metastatic melanoma who received a single dose of the product. The objective response rate was 36.4%.
“Lifileucel has demonstrated efficacy and durability of response for patients with metastatic melanoma and represents a viable therapeutic option warranting further investigation,” commented Jason Alan Chesney, MD, PhD, from the James Graham Brown Cancer Center, the University of Louisville (Ky.).
He presented the new data at the virtual American Association for Cancer Research (AACR) Annual Meeting 2021.
Customized cell therapy with TILs has been explored for the treatment of melanoma for more than a decade. Some researchers have reported durable response in 25% of patients.
However, “generalizing TIL therapy has been hampered by the complex and really not absolutely defined process for generating cells,” commented Philip Greenberg, MD, professor and head of the program in immunology in the Clinical Research Division of the Fred Hutchinson Cancer Center, Seattle, who was the invited discussant.
The current study demonstrates that cell generation can be performed at a centralized facility that has the required technical expertise. The patient-specific products are then disseminated to multiple centers, he said. The study also demonstrates that TILs can be successfully generated from tumor sites other than skin or lymph nodes.
“Toxicity was, however, significant, although it was generally manageable, and it did occur early, generally within the first 2 weeks,” he noted.
Patient-derived product
Lifileucel is a tailor-made immunotherapy product created from melanoma tumor tissues resected from lesions in skin, lymph nodes, liver, lung, peritoneum, musculoskeletal system, breast, or other visceral organs. The cells are shipped to a central manufacturing facility, whre the TILs are isolated, cultured, expanded, and reinvigorated. The cells are then harvested and cryopreserved. The process takes about 22 days. The cryopreserved product is then shipped back to the treating facility.
Prior to receiving the expanded and rejuvenated TILs, patients undergo myeloablative conditioning with cyclophosphamide followed by fludarabine. The TILs are then delivered in a single infusion, followed by administration of up to six doses of interleukin-2 (IL-2).
Details from clinical trial
At the meeting, Dr. Chesney reported details on the 66 patients in the trial. They had metastatic melanoma that was progressing on treatment. The mean number of prior lines of therapy was 3.3. All of the patients had received prior anti–programmed cell death protein–1 (PD-1) or programmed cell death–ligand-1 (PD-L1) agents; 53 had received a cytotoxic T lymphocyte protein 4 (CTLA-4) inhibitor; and 15 had received a BRAF/MEK inhibitor.
These patients had a mean of six baseline target and nontarget lesions, and 28 patients had liver and/or brain metastases.
Just over a third of patients (24 of 66, 36.4%) had an objective response; three patients had a complete response; and 21 had a partial response. In addition, 29 patients had stable disease, and nine experienced disease progression. Four patients had not undergone the first assessment at the time of data cutoff.
After a median follow-up of 28.1 months, the median duration of response was not reached. It ranged from 2.2 to > 35.2 months.
Since the data cutoff in April 2020, reduction of tumor burden has occurred in 50 of 62 evaluable patients. Reductions in the target lesion sum of diameters has occurred in 11 patients. In one patient, a partial response converted to a complete response 24 months after infusion, Dr. Chesney noted.
The mean number of TILs infused was 27.3 billion (27.3 x 109). Appropriate amounts of TILs were manufactured from tumor samples acquired across all sites, and reductions in target lesion sum of diameter were seen across the range of TIL total cell doses.
All patients experienced at least one adverse event of any grade; all but two experienced grade 3 or 4 adverse events. Two patients died, one as a result of intra-abdominal hemorrhage considered possibly related to TIL therapy, and one from acute respiratory failure deemed not related to TILs.
The most common grade 3 or 4 adverse events were thrombocytopenia, anemia, febrile neutropenia, neutropenia, hypophosphatemia, and lymphopenia.
“The adverse event profile was manageable and was consistent with the underlying and the known profiles of the nonmyeloblative depletion regimen and IL-2,” Dr. Chesney said.
The decreasing frequency of adverse events over time reflects the potential benefit of the one-time infusion, and no new safety risks have been identified during more than 2 years of follow-up, he added.
Remaining questions, next steps
Dr. Greenberg commented that the one of the limitations of the study is that the investigators did not characterize the TIL product.
“Studies have predicted that there’s a particular type of cell, a stemlike T cell, that’s responsible for mediating the efficacy,” he commented. He referred to research from Steven Rosenberg, MD, PhD, and colleagues at the National Cancer Institute, where TILs were first used in 2002.
Dr. Greenberg also raised the question of whether high-dose IL-2 was required post infusion, given that the patients were lymphodepleted before receiving lifileucel.
Future steps for TIL therapy, he said, should include identification of biomarkers for success or failure; strategies to enhance generation and expansion of tumor-reactive T cells; postinfusion strategies, such as using vaccines and/or checkpoint inhibitors to increase therapeutic activity; genetic modifications to enhance the function of TILs in the tumor microenvironment; and research into other tumor types that may be effectively treated with TILs.
The study was supported by Iovance Biotherapeutics. Dr. Chesney has received research funding from Iovance and other companies and has consulted for Amgen and Replimune. Dr. Greenberg has served on scientific advisory boards, has received grant/research support, and owns stock in several companies that do not include Iovance.
A version of this article first appeared on Medscape.com.
AT AACR 2022
‘Major advance’: Sotorasib benefit persists in KRAS+ NSCLC
NEW ORLEANS – with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).
The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.
That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.
“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.
Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.”
In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.
Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.
“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.
He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”
New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”
At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.
“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.
“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
Tarnished triumph
As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.
Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.
Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.
“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
Long follow-up
The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.
The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.
Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.
Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.
Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.
At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.
Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.
Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.
Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.
In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.
The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.
Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).
The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.
That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.
“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.
Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.”
In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.
Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.
“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.
He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”
New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”
At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.
“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.
“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
Tarnished triumph
As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.
Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.
Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.
“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
Long follow-up
The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.
The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.
Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.
Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.
Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.
At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.
Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.
Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.
Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.
In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.
The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.
Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – with the first-in-class KRAS inhibitor sotorasib (Lumakras, Amgen).
The finding comes from an analysis of long-term follow-up data from the CodeBreaK100 trial, which showed a 2-year overall survival (OS) rate of 32.5% in pretreated patients with KRASG12C-mutant disease.
That rate compares favorably with historical data on NSCLC therapies, said Grace K. Dy, MD, from Roswell Park Comprehensive Cancer Center in Buffalo, N.Y.
“We expect about half of that [survival rate] in patients who are treated with docetaxel,” she said in a plenary session at the annual meeting of the American Association for Cancer Research.
Sotorasib was approved by the Food and Drug Administration in May 2021 as the first drug for patients with NSCLC and KRAS mutations and was described as a “historic milestone.”
In this most recent analysis, which combined data from patients enrolled in phases 1 and 2 of the trial, the “objective response rate of 41% of patients was achieved with sotorasib, with a durable [disease] control rate of 84% and a median duration of response of 12.3 months, with no new safety signals emerging,” she said.
Nearly one-fourth of patients saw long-term benefit, as defined by progression-free survival of at least 12 months, and this long-term benefit was seen across variant allele frequencies of KRASG12C, programmed death–ligand 1 (PD-L1) tumor proportion score, and other comutations, she noted.
“KRASG12C inhibitors represent a major advance in the treatment of KRAS-mutant lung cancers and other types as well,” said invited discussant Mark M. Awad, MD, PhD, director of clinical research at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Center, Boston.
He cautioned, however, that “the therapeutic efficacy of these G12C inhibitors is currently limited by several things, including patient factors, intrinsic biology, and the emergence of complex resistance mechanisms.”
New approaches will be needed, he said, “to delay and overcome drug resistance to hopefully keep kicking cancer’s KRAS.”
At a media briefing where Dr. Dy presented the data prior to the oral abstract session, moderator Timothy A. Yap, MBBS, PhD, from the University of Texas MD Anderson Cancer Center, Houston, commented that the development of drug resistance is common in oncology.
“That is exactly why we’re now actively working on multiple different combinatorial approaches in the clinic. There have been pretty compelling data published from Mirati [Therapeutics] and from other companies, from Amgen, that really show the resistance mechanisms that actually come about upon monotherapy with KRASG12C inhibitors, including CDK4/6, including P13K-Akt pathways,” he said.
“The solution there really is, No. 1, we need to identify proactively the resistance mechanisms involved and driving each cancer’s resistance, and No. 2, then apply the combinatorial agent, to bring in a combination that’s a rational approach to match a patient’s molecular profile upon resistance,” he said.
Tarnished triumph
As previously reported, sotorasib was hailed as “a triumph of drug discovery” when early results of the trial were reported at the European Society of Medical Oncology annual meeting in 2020.
Sotorasib is a small-molecule, specific, and irreversible inhibitor of KRAS that interacts with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drug inhibits oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.
But as Dr. Awad reported at the 2021 AACR annual meeting, the efficacy of sotorasib and other KRAS inhibitors in development has been threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.
Dr. Awad reported that among 30 patients with NSCLC or colorectal cancer bearing the KRASG12C mutation who had disease progression while being treated with the investigational inhibitor adagrasib in clinical trials, investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to the drug.
“Diverse mechanisms confer resistance to the KRASG12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” he said.
Long follow-up
The long-term data reported at the 2022 meeting by Dr. Dy and colleagues included data on 48 patients enrolled in phase 1 of the trial, which had a primary endpoint of safety and tolerability, and 126 patients enrolled in phase 2, with a primary endpoint of objective response rate by blinded independent review.
The trial was conducted in centers in the United States, Europe, Australia, Japan, and South Korea.
Nearly all patients were pretreated: 92.5% of patients had received prior platinum-based chemotherapy and 90.2% had received anti–PD-1/PD-L1 immunotherapy.
Patients received oral sotorasib 960 mg once daily and were followed with radiographic scans every 6 weeks for the first year and once every 12 weeks thereafter.
Of the 174 patients enrolled, two were not evaluable for response at 2 years because of a lack of measurable lesions at baseline.
At a median follow-up of 24.9 months, 5 patients (2.9%) had a complete response and 65 (37.8%) had a partial response, for an objective response rate of 40.7%. An additional 74 patients (43%) had stable disease, for a disease control rate of 83.7%. Of the remaining patients, 23 (13.4%) had disease progression, and 5 were either not evaluable or had missing scan data.
Median progression-free survival was 6.3 months. Median time to response was 6 weeks, and median duration of response was 12.3 months. Half of patients who had a response retained that response for at least 12 months.
Median OS was 12.5 months. The 1-year and 2-year OS rates were 50.8% and 32.5%, respectively.
Grade 3 or 4 treatment-related adverse events occurred in 21% of patients, and one patient had new-onset grade 3 hemolytic anemia 1 year after starting therapy. There were no treatment-related deaths and no treatment-related adverse events leading to discontinuation after the first year.
In exploratory analyses, the benefit of the drug was seen across tumors with varying levels of PD-L1 expression and the oncogenic STK11 comutation, and across KRASG12C variant allele frequency.
The investigators also reported that baseline circulating tumor DNA levels correlated with tumor burden, and that patients who had long-term benefits had lower baseline ctDNA. This finding is consistent with the documented role of ctDNA as a marker for poor prognosis regardless of therapy.
Dr. Dy reported receiving consulting fees from AstraZeneca, Eli Lilly, Mirati Therapeutics, and Takeda in the past 2 years. Dr. Yap disclosed receiving consulting fees from multiple companies. Dr. Awad disclosed consulting for multiple companies.
A version of this article first appeared on Medscape.com.
AT AACR 2022
Black, senior patients more likely to get unneeded antibiotics
Black and senior patients are more likely to be overprescribed antibiotics, according to a new study of 7 billion trips to health care centers – findings that doctors say warrant a further look into unequal prescription practices.
Researchers at the University of Texas Health Science Center found that 64% of antibiotic prescriptions to Black patients and 74% of antibiotic prescriptions to patients aged 65 years and older were deemed inappropriate. White patients, meanwhile, received prescriptions that were deemed inappropriate 56% of the time.
Most of those prescriptions were written for conditions like nonbacterial skin problems, viral respiratory tract infections, and bronchitis – none of which can be treated with antibiotics.
The study – which used data from visits to U.S. doctors’ offices, hospitals, and EDs – will be presented at the 2022 European Congress of Clinical Microbiology & Infectious Diseases in Lisbon.
Researchers also found that 58% of antibiotic prescriptions to patients with a Hispanic or Latin American background were also not appropriate for use.
“Our results suggest that Black and [Hispanic/Latino] patients may be not be properly treated and are receiving antibiotic prescriptions even when not indicated,” researcher Eric Young, PharmD, said in a news release.
Doctors typically will prescribe an antibiotic if they fear a patient’s symptoms may lead to an infection, Dr. Young said. This is particularly true if the doctor believes a patient is unlikely to return for a follow-up, which, he says, “more frequently happens in minority populations.”
The Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions are not needed, and up to 50% of antibiotics prescribed are either unnecessary or the wrong type and/or dosage.
Overprescribing of antibiotics has long plagued the medical field. In 2015, the administration of then-President Barack Obama released a National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal to cut unneeded outpatient antibiotic use by at least half by 2020.
When antibiotics are overused, bacteria that infect us evolve to become stronger and defeat the drugs meant to save us.
Though the findings still need more study, at first glance they provide a concerning but unsurprising look at health inequities, said Rachel Villanueva, MD, president of the National Medical Association, the leading organization representing doctors and patients of African descent.
“We do know that these kind of inequities have existed for a long time in our society,” said Dr. Villanueva, a clinical assistant professor at the New York University. “They’re not new and have been well documented for many, many years. But this deserves further research and further evaluation.”
“This is just the first step – we need to do some more evaluation on how different communities are treated in the health care system. Why is this occurring?”
For patients 65 and older, it may be less about bias and more about having a hard time diagnosing certain conditions within that population, said Preeti Malani, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, and director of the National Poll on Healthy Aging.
For example, she said, some older patients may have a harder time describing their symptoms. In some cases, doctors may give these patients a prescription to fill in case the issue does not clear up, because it could be harder for them to get back into the office.
“Sometimes it’s hard to know exactly what’s going on,” Dr. Malani said. “Something I’ve done in my own practice in the past is say, ‘I’m giving you a prescription, but I don’t want you to fill it yet.’”
Dr. Malani said inappropriately prescribing antibiotics can be especially dangerous for people 65 and older because of drug interactions and complications like Achilles tendon rupture and a Clostridioides difficile infection, which can arise after antibiotic use.
“We need more information on what drives this in older adults,” she said.
A version of this article first appeared on Medscape.com.
Black and senior patients are more likely to be overprescribed antibiotics, according to a new study of 7 billion trips to health care centers – findings that doctors say warrant a further look into unequal prescription practices.
Researchers at the University of Texas Health Science Center found that 64% of antibiotic prescriptions to Black patients and 74% of antibiotic prescriptions to patients aged 65 years and older were deemed inappropriate. White patients, meanwhile, received prescriptions that were deemed inappropriate 56% of the time.
Most of those prescriptions were written for conditions like nonbacterial skin problems, viral respiratory tract infections, and bronchitis – none of which can be treated with antibiotics.
The study – which used data from visits to U.S. doctors’ offices, hospitals, and EDs – will be presented at the 2022 European Congress of Clinical Microbiology & Infectious Diseases in Lisbon.
Researchers also found that 58% of antibiotic prescriptions to patients with a Hispanic or Latin American background were also not appropriate for use.
“Our results suggest that Black and [Hispanic/Latino] patients may be not be properly treated and are receiving antibiotic prescriptions even when not indicated,” researcher Eric Young, PharmD, said in a news release.
Doctors typically will prescribe an antibiotic if they fear a patient’s symptoms may lead to an infection, Dr. Young said. This is particularly true if the doctor believes a patient is unlikely to return for a follow-up, which, he says, “more frequently happens in minority populations.”
The Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions are not needed, and up to 50% of antibiotics prescribed are either unnecessary or the wrong type and/or dosage.
Overprescribing of antibiotics has long plagued the medical field. In 2015, the administration of then-President Barack Obama released a National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal to cut unneeded outpatient antibiotic use by at least half by 2020.
When antibiotics are overused, bacteria that infect us evolve to become stronger and defeat the drugs meant to save us.
Though the findings still need more study, at first glance they provide a concerning but unsurprising look at health inequities, said Rachel Villanueva, MD, president of the National Medical Association, the leading organization representing doctors and patients of African descent.
“We do know that these kind of inequities have existed for a long time in our society,” said Dr. Villanueva, a clinical assistant professor at the New York University. “They’re not new and have been well documented for many, many years. But this deserves further research and further evaluation.”
“This is just the first step – we need to do some more evaluation on how different communities are treated in the health care system. Why is this occurring?”
For patients 65 and older, it may be less about bias and more about having a hard time diagnosing certain conditions within that population, said Preeti Malani, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, and director of the National Poll on Healthy Aging.
For example, she said, some older patients may have a harder time describing their symptoms. In some cases, doctors may give these patients a prescription to fill in case the issue does not clear up, because it could be harder for them to get back into the office.
“Sometimes it’s hard to know exactly what’s going on,” Dr. Malani said. “Something I’ve done in my own practice in the past is say, ‘I’m giving you a prescription, but I don’t want you to fill it yet.’”
Dr. Malani said inappropriately prescribing antibiotics can be especially dangerous for people 65 and older because of drug interactions and complications like Achilles tendon rupture and a Clostridioides difficile infection, which can arise after antibiotic use.
“We need more information on what drives this in older adults,” she said.
A version of this article first appeared on Medscape.com.
Black and senior patients are more likely to be overprescribed antibiotics, according to a new study of 7 billion trips to health care centers – findings that doctors say warrant a further look into unequal prescription practices.
Researchers at the University of Texas Health Science Center found that 64% of antibiotic prescriptions to Black patients and 74% of antibiotic prescriptions to patients aged 65 years and older were deemed inappropriate. White patients, meanwhile, received prescriptions that were deemed inappropriate 56% of the time.
Most of those prescriptions were written for conditions like nonbacterial skin problems, viral respiratory tract infections, and bronchitis – none of which can be treated with antibiotics.
The study – which used data from visits to U.S. doctors’ offices, hospitals, and EDs – will be presented at the 2022 European Congress of Clinical Microbiology & Infectious Diseases in Lisbon.
Researchers also found that 58% of antibiotic prescriptions to patients with a Hispanic or Latin American background were also not appropriate for use.
“Our results suggest that Black and [Hispanic/Latino] patients may be not be properly treated and are receiving antibiotic prescriptions even when not indicated,” researcher Eric Young, PharmD, said in a news release.
Doctors typically will prescribe an antibiotic if they fear a patient’s symptoms may lead to an infection, Dr. Young said. This is particularly true if the doctor believes a patient is unlikely to return for a follow-up, which, he says, “more frequently happens in minority populations.”
The Centers for Disease Control and Prevention estimates that at least 30% of outpatient antibiotic prescriptions are not needed, and up to 50% of antibiotics prescribed are either unnecessary or the wrong type and/or dosage.
Overprescribing of antibiotics has long plagued the medical field. In 2015, the administration of then-President Barack Obama released a National Action Plan for Combating Antibiotic-Resistant Bacteria, with a goal to cut unneeded outpatient antibiotic use by at least half by 2020.
When antibiotics are overused, bacteria that infect us evolve to become stronger and defeat the drugs meant to save us.
Though the findings still need more study, at first glance they provide a concerning but unsurprising look at health inequities, said Rachel Villanueva, MD, president of the National Medical Association, the leading organization representing doctors and patients of African descent.
“We do know that these kind of inequities have existed for a long time in our society,” said Dr. Villanueva, a clinical assistant professor at the New York University. “They’re not new and have been well documented for many, many years. But this deserves further research and further evaluation.”
“This is just the first step – we need to do some more evaluation on how different communities are treated in the health care system. Why is this occurring?”
For patients 65 and older, it may be less about bias and more about having a hard time diagnosing certain conditions within that population, said Preeti Malani, MD, a professor of infectious diseases at the University of Michigan, Ann Arbor, and director of the National Poll on Healthy Aging.
For example, she said, some older patients may have a harder time describing their symptoms. In some cases, doctors may give these patients a prescription to fill in case the issue does not clear up, because it could be harder for them to get back into the office.
“Sometimes it’s hard to know exactly what’s going on,” Dr. Malani said. “Something I’ve done in my own practice in the past is say, ‘I’m giving you a prescription, but I don’t want you to fill it yet.’”
Dr. Malani said inappropriately prescribing antibiotics can be especially dangerous for people 65 and older because of drug interactions and complications like Achilles tendon rupture and a Clostridioides difficile infection, which can arise after antibiotic use.
“We need more information on what drives this in older adults,” she said.
A version of this article first appeared on Medscape.com.
Deprived of sleep, many turn to melatonin despite risks
Can’t sleep? When slumber doesn’t come naturally, some are turning to melatonin, an over-the-counter sleep aid that often is mistaken for a supplement. This powerful hormone plays an important role in human biology, and specialists are questioning whether increasing levels could be doing more harm than good.
And while the health advisory checking the evidence is underway, the academy is recommending that melatonin not be used for insomnia in adults or children.
But what is insomnia, and how is it different from a few bad nights of sleep? Insomnia disturbs sleep at least three times a week for more than 3 months, often causing people to feel tired during the day as well.
Production of melatonin (dubbed the “vampire hormone”) begins at night, when it starts getting dark outside. Melatonin release is scheduled by the small but mighty pineal gland at the back of the head. Melatonin signals to the body that it’s time to sleep. And as the sun rises and light shines, melatonin levels decline again to help the body wake.
Sometimes packaged in gummy bear fruit flavors, melatonin can have an alluring appeal to sleep-deprived parents looking for relief for themselves and their children.
Muhammad Adeel Rishi, MD, vice chair of the public safety committee for the American Academy of Sleep Medicine, said he has a doctor colleague who started taking melatonin to help him during the pandemic when he was having trouble falling asleep at night. His doctor friend started giving the hormone to his own children, who were also having sleep issues.
But Dr. Rishi said there are important reasons to not use melatonin for insomnia until more information is available.
Melatonin affects sleep, but this hormone also influences other functions in the body. “It has an impact on body temperature, blood sugar, and even the tone of blood vessels,” Dr. Rishi said.
And because melatonin is available over the counter in the United States, it hasn’t been approved as a medicine under the Food and Drug Administration. A previous study of melatonin products, for instance, flagged problems with inconsistent doses, which make it hard for people to know exactly how much they are getting and prompted calls for more FDA oversight.
Imprecise doses
While melatonin doses typically range from 1 to 5 milligrams, bottles examined have been off target with much more or less hormone in the product than listed on the label.
Researchers from the University of Guelph (Ont.), tested 30 commercially available formulas and found the melatonin content varied from the ingredients labeled on the bottles by more than 10%. In addition to melatonin, the researchers found other substances in the bottles too: In about a quarter of the products, they also identified serotonin.
Impurities
While melatonin plays a role in setting the body’s biological clock and the sleep and wake cycle, serotonin is also at work. Occurring naturally in our bodies, serotonin is involved in mood and helps with deep REM sleep. But adding serotonin in unknown amounts could be unhealthy.
Dr. Rishi said it can be dangerous to use a product as a medication when doses can be so off and there are unknown byproducts in it.
Serotonin can influence the heart, blood vessels, and brain, so it’s not something Dr. Rishi wants to see people taking without paying attention. People taking medication for mood disorders could be especially affected by the serotonin in their sleep aid, he warns.
For anyone taking melatonin, Dr. Rishi recommended they check the bottle to see whether they are using a product with a USP-verified check mark, which indicates that the product meets the standards of the U.S. Pharmacopeia Convention.
The risk of impurities is a good reason for kids to not be given the hormone, but another worry is whether melatonin interferes with puberty in children – which is also a question researchers at the Children’s Hospital of Eastern Ontario in Ottawa are asking.
Disrupting puberty
While short-term melatonin use is considered safe, the researchers reported, concerns that long-term use might delay children’s sexual maturation require more study. One theory is that nightly melatonin use might interrupt the decline of natural hormone levels and interfere with the start of puberty.
Researchers from the Children’s Hospital of Michigan in Detroit also reported an uptick in accidental ingestion of melatonin in children. Kids got their hands on melatonin and swallowed too many capsules more often than other pill-related mishaps during the pandemic.
Dr. Rishi said more research is needed to assess the safe use of melatonin in children. He points out that the hormone can treat circadian rhythm disorders in adults.
While specialists weigh the benefits and risks of melatonin use and where it is safest to try, Dr. Rishi said the hormone does have a role in medicine.
Melatonin will probably need to be regulated by the FDA as a medication – especially for children – Dr. Rishi pointed out. And what place, if any, it will have for managing chronic insomnia is “a big question mark.”
Results of the investigation by the American Academy of Sleep Medicine will be published on its sleepeducation.org website in a few months.
A version of this article first appeared on WebMD.com.
Can’t sleep? When slumber doesn’t come naturally, some are turning to melatonin, an over-the-counter sleep aid that often is mistaken for a supplement. This powerful hormone plays an important role in human biology, and specialists are questioning whether increasing levels could be doing more harm than good.
And while the health advisory checking the evidence is underway, the academy is recommending that melatonin not be used for insomnia in adults or children.
But what is insomnia, and how is it different from a few bad nights of sleep? Insomnia disturbs sleep at least three times a week for more than 3 months, often causing people to feel tired during the day as well.
Production of melatonin (dubbed the “vampire hormone”) begins at night, when it starts getting dark outside. Melatonin release is scheduled by the small but mighty pineal gland at the back of the head. Melatonin signals to the body that it’s time to sleep. And as the sun rises and light shines, melatonin levels decline again to help the body wake.
Sometimes packaged in gummy bear fruit flavors, melatonin can have an alluring appeal to sleep-deprived parents looking for relief for themselves and their children.
Muhammad Adeel Rishi, MD, vice chair of the public safety committee for the American Academy of Sleep Medicine, said he has a doctor colleague who started taking melatonin to help him during the pandemic when he was having trouble falling asleep at night. His doctor friend started giving the hormone to his own children, who were also having sleep issues.
But Dr. Rishi said there are important reasons to not use melatonin for insomnia until more information is available.
Melatonin affects sleep, but this hormone also influences other functions in the body. “It has an impact on body temperature, blood sugar, and even the tone of blood vessels,” Dr. Rishi said.
And because melatonin is available over the counter in the United States, it hasn’t been approved as a medicine under the Food and Drug Administration. A previous study of melatonin products, for instance, flagged problems with inconsistent doses, which make it hard for people to know exactly how much they are getting and prompted calls for more FDA oversight.
Imprecise doses
While melatonin doses typically range from 1 to 5 milligrams, bottles examined have been off target with much more or less hormone in the product than listed on the label.
Researchers from the University of Guelph (Ont.), tested 30 commercially available formulas and found the melatonin content varied from the ingredients labeled on the bottles by more than 10%. In addition to melatonin, the researchers found other substances in the bottles too: In about a quarter of the products, they also identified serotonin.
Impurities
While melatonin plays a role in setting the body’s biological clock and the sleep and wake cycle, serotonin is also at work. Occurring naturally in our bodies, serotonin is involved in mood and helps with deep REM sleep. But adding serotonin in unknown amounts could be unhealthy.
Dr. Rishi said it can be dangerous to use a product as a medication when doses can be so off and there are unknown byproducts in it.
Serotonin can influence the heart, blood vessels, and brain, so it’s not something Dr. Rishi wants to see people taking without paying attention. People taking medication for mood disorders could be especially affected by the serotonin in their sleep aid, he warns.
For anyone taking melatonin, Dr. Rishi recommended they check the bottle to see whether they are using a product with a USP-verified check mark, which indicates that the product meets the standards of the U.S. Pharmacopeia Convention.
The risk of impurities is a good reason for kids to not be given the hormone, but another worry is whether melatonin interferes with puberty in children – which is also a question researchers at the Children’s Hospital of Eastern Ontario in Ottawa are asking.
Disrupting puberty
While short-term melatonin use is considered safe, the researchers reported, concerns that long-term use might delay children’s sexual maturation require more study. One theory is that nightly melatonin use might interrupt the decline of natural hormone levels and interfere with the start of puberty.
Researchers from the Children’s Hospital of Michigan in Detroit also reported an uptick in accidental ingestion of melatonin in children. Kids got their hands on melatonin and swallowed too many capsules more often than other pill-related mishaps during the pandemic.
Dr. Rishi said more research is needed to assess the safe use of melatonin in children. He points out that the hormone can treat circadian rhythm disorders in adults.
While specialists weigh the benefits and risks of melatonin use and where it is safest to try, Dr. Rishi said the hormone does have a role in medicine.
Melatonin will probably need to be regulated by the FDA as a medication – especially for children – Dr. Rishi pointed out. And what place, if any, it will have for managing chronic insomnia is “a big question mark.”
Results of the investigation by the American Academy of Sleep Medicine will be published on its sleepeducation.org website in a few months.
A version of this article first appeared on WebMD.com.
Can’t sleep? When slumber doesn’t come naturally, some are turning to melatonin, an over-the-counter sleep aid that often is mistaken for a supplement. This powerful hormone plays an important role in human biology, and specialists are questioning whether increasing levels could be doing more harm than good.
And while the health advisory checking the evidence is underway, the academy is recommending that melatonin not be used for insomnia in adults or children.
But what is insomnia, and how is it different from a few bad nights of sleep? Insomnia disturbs sleep at least three times a week for more than 3 months, often causing people to feel tired during the day as well.
Production of melatonin (dubbed the “vampire hormone”) begins at night, when it starts getting dark outside. Melatonin release is scheduled by the small but mighty pineal gland at the back of the head. Melatonin signals to the body that it’s time to sleep. And as the sun rises and light shines, melatonin levels decline again to help the body wake.
Sometimes packaged in gummy bear fruit flavors, melatonin can have an alluring appeal to sleep-deprived parents looking for relief for themselves and their children.
Muhammad Adeel Rishi, MD, vice chair of the public safety committee for the American Academy of Sleep Medicine, said he has a doctor colleague who started taking melatonin to help him during the pandemic when he was having trouble falling asleep at night. His doctor friend started giving the hormone to his own children, who were also having sleep issues.
But Dr. Rishi said there are important reasons to not use melatonin for insomnia until more information is available.
Melatonin affects sleep, but this hormone also influences other functions in the body. “It has an impact on body temperature, blood sugar, and even the tone of blood vessels,” Dr. Rishi said.
And because melatonin is available over the counter in the United States, it hasn’t been approved as a medicine under the Food and Drug Administration. A previous study of melatonin products, for instance, flagged problems with inconsistent doses, which make it hard for people to know exactly how much they are getting and prompted calls for more FDA oversight.
Imprecise doses
While melatonin doses typically range from 1 to 5 milligrams, bottles examined have been off target with much more or less hormone in the product than listed on the label.
Researchers from the University of Guelph (Ont.), tested 30 commercially available formulas and found the melatonin content varied from the ingredients labeled on the bottles by more than 10%. In addition to melatonin, the researchers found other substances in the bottles too: In about a quarter of the products, they also identified serotonin.
Impurities
While melatonin plays a role in setting the body’s biological clock and the sleep and wake cycle, serotonin is also at work. Occurring naturally in our bodies, serotonin is involved in mood and helps with deep REM sleep. But adding serotonin in unknown amounts could be unhealthy.
Dr. Rishi said it can be dangerous to use a product as a medication when doses can be so off and there are unknown byproducts in it.
Serotonin can influence the heart, blood vessels, and brain, so it’s not something Dr. Rishi wants to see people taking without paying attention. People taking medication for mood disorders could be especially affected by the serotonin in their sleep aid, he warns.
For anyone taking melatonin, Dr. Rishi recommended they check the bottle to see whether they are using a product with a USP-verified check mark, which indicates that the product meets the standards of the U.S. Pharmacopeia Convention.
The risk of impurities is a good reason for kids to not be given the hormone, but another worry is whether melatonin interferes with puberty in children – which is also a question researchers at the Children’s Hospital of Eastern Ontario in Ottawa are asking.
Disrupting puberty
While short-term melatonin use is considered safe, the researchers reported, concerns that long-term use might delay children’s sexual maturation require more study. One theory is that nightly melatonin use might interrupt the decline of natural hormone levels and interfere with the start of puberty.
Researchers from the Children’s Hospital of Michigan in Detroit also reported an uptick in accidental ingestion of melatonin in children. Kids got their hands on melatonin and swallowed too many capsules more often than other pill-related mishaps during the pandemic.
Dr. Rishi said more research is needed to assess the safe use of melatonin in children. He points out that the hormone can treat circadian rhythm disorders in adults.
While specialists weigh the benefits and risks of melatonin use and where it is safest to try, Dr. Rishi said the hormone does have a role in medicine.
Melatonin will probably need to be regulated by the FDA as a medication – especially for children – Dr. Rishi pointed out. And what place, if any, it will have for managing chronic insomnia is “a big question mark.”
Results of the investigation by the American Academy of Sleep Medicine will be published on its sleepeducation.org website in a few months.
A version of this article first appeared on WebMD.com.
Can pickle juice help ease cirrhotic cramps?
In the trial, patients with cirrhotic cramps who sipped pickle brine at the onset of a muscle cramp saw a significant decrease in cramp severity relative to peers who sipped tap water when the cramp hit.
“The acid (vinegar) in the brine triggers a nerve reflex to stop the cramp when it hits the throat. This is why only a sip is needed,” lead investigator Elliot Tapper, MD, division of gastroenterology and hepatology, University of Michigan, Ann Arbor, told this news organization. The study was published online April 13 in American Journal of Gastroenterology.
Common and bothersome
Cramps are common in adults with cirrhosis, irrespective of disease severity. They can sometimes last for hours, and treatment options are limited.
In a prior study, 1 tablespoon of pickle juice rapidly stopped experimentally induced cramps.
“This is something that athletes use, and kidney doctors often recommend to their patients, so it is nothing unique to cirrhosis,” Dr. Tapper said.
The PICCLES trial involved 74 adults (mean age, 56.6 years) with at least 4 muscle cramps in the prior month. In the cohort, 54% were men, and 41% had ascites.
The median cramp frequency was 11-12 per month, with an average cramp severity of more than 4 out of 10 on the Visual Analog Scale (VAS) for cramps.
Some patients were receiving medications for their cramps at baseline, such as magnesium, potassium, baclofen, vitamin E, taurine, and gabapentin/pregabalin.
Thirty-eight patients were randomly allocated to sip pickle juice and 36 to sip tap water at the onset of a muscle cramp.
The proportion of cramps treated was similar in the pickle juice and tap water groups (77% and 72%). More patients in the pickle juice group said their cramps were aborted by the intervention (69% vs. 40%).
The primary outcome was the change in cramp severity at 28-days VAS for cramps. Cramps were assessed 10 times over 28 days using interactive text messages.
Pickle juice was associated with a larger average reduction in cramp severity than tap water (–2.25 points vs. –0.36 on the VAS-cramps), a difference that was statistically significant (P = .03).
There were no significant changes in the proportion of days with cramp severity of more than 5 on the VAS, or on sleep quality or health-related quality of life.
Because pickle juice contains sodium, the researchers also assessed weight change as a safety outcome. They found no significant differences in weight change between the two groups overall or in the subset with ascites.
Pickle juice is a “safe option that can stop painful cramps,” Dr. Tapper said in an interview, but was “disheartened” that it did not improve quality of life.
Dr. Tapper encourages patients with cramps to ask their doctor about pickle juice and doctors to ask their patients about muscle cramps.
“Awareness of a patient’s cramps is often lacking. Asking about cramps is not routine but could be the most important advance relating to this study,” he said.
While sips of pickle juice are “unlikely to cause harm,” Dr. Tapper said, he is “a little nervous about advising patients to address their complex needs alone. [Doctors] are there to think through the root causes and help make adjustments that could prevent the cramps in the first place,” he said.
Outside experts weigh in
This news organization reached out to several outside experts for their perspective on the study.
Nancy Reau, MD, professor of internal medicine, associate director of solid organ transplantation, and section chief of hepatology. Rush University Medical Center, Chicago, noted that interventions to manage and prevent muscle cramps are “important, as cramping is common in cirrhosis and strongly affects quality of life.”
Dr. Reau cautioned that while pickle juice “sounds benign, it does have a lot of salt. Despite the salt content, this study didn’t show any difference between patients with and without ascites.
“However, cramping is more common in our patients with sarcopenia and those on diuretics for fluid management and it would be easy to see how this might impact fluid management,” Dr. Reau noted.
“Given that it is the acid (not the salt) in the pickle juice, there might be low salt alternatives,” Dr. Reau said.
Echoing Dr. Reau, Ankur Shah, MD, division of kidney disease and hypertension, Brown University, Providence, R.I., noted that “overuse of pickle juice could place patients at risk of developing high blood pressure and fluid overload, and pickle juice should be included in the sodium restriction guidance given to patients with high blood pressure and heart failure.”
In this study, however, the individual dose consumed was low, Dr. Shah noted.
He said the study “elegantly provides evidence to support the practice of sipping pickle juice for cramping.”
The authors should be “applauded for studying a simple solution with the most rigorous of methodologies, a randomized controlled trial,” Dr. Shah added.
“This simple treatment may be helpful to patients far beyond those with just cirrhosis, and expect future studies to explore this treatment in other populations,” Dr. Shah said in an interview.
Paul Martin, MD, chief of the division of digestive health and liver diseases and Mandel Chair in Gastroenterology, University of Miami, noted that, while muscle cramps can have a major impact on quality of life, “in terms of some of the other complications of cirrhosis that health care providers are dealing with, they may seem relatively innocuous, but obviously patients have a slightly different interpretation because of the effect cramps can have on sleep and so on.
“There have been a variety of home remedies to treat muscle cramps, but this study is intriguing as it suggests that pickle juice, which is freely available, helps mitigate the severity of the cramps. However, it’s unclear whether it prevents cramps,” Dr. Martin said in an interview.
Given that the study is getting traction on Twitter, Dr. Martin encouraged health care providers to be aware of the study and prepared to answer questions from patients.
The study had no specific funding. Dr. Tapper has served as a consultant to Novartis, Axcella, and Allergan, has served on advisory boards for Mallinckrodt, Bausch Health, Kaleido, and Novo Nordisk, and has received unrestricted research grants from Gilead and Valeant. Dr. Reau, Dr. Shah, and Dr. Martin have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In the trial, patients with cirrhotic cramps who sipped pickle brine at the onset of a muscle cramp saw a significant decrease in cramp severity relative to peers who sipped tap water when the cramp hit.
“The acid (vinegar) in the brine triggers a nerve reflex to stop the cramp when it hits the throat. This is why only a sip is needed,” lead investigator Elliot Tapper, MD, division of gastroenterology and hepatology, University of Michigan, Ann Arbor, told this news organization. The study was published online April 13 in American Journal of Gastroenterology.
Common and bothersome
Cramps are common in adults with cirrhosis, irrespective of disease severity. They can sometimes last for hours, and treatment options are limited.
In a prior study, 1 tablespoon of pickle juice rapidly stopped experimentally induced cramps.
“This is something that athletes use, and kidney doctors often recommend to their patients, so it is nothing unique to cirrhosis,” Dr. Tapper said.
The PICCLES trial involved 74 adults (mean age, 56.6 years) with at least 4 muscle cramps in the prior month. In the cohort, 54% were men, and 41% had ascites.
The median cramp frequency was 11-12 per month, with an average cramp severity of more than 4 out of 10 on the Visual Analog Scale (VAS) for cramps.
Some patients were receiving medications for their cramps at baseline, such as magnesium, potassium, baclofen, vitamin E, taurine, and gabapentin/pregabalin.
Thirty-eight patients were randomly allocated to sip pickle juice and 36 to sip tap water at the onset of a muscle cramp.
The proportion of cramps treated was similar in the pickle juice and tap water groups (77% and 72%). More patients in the pickle juice group said their cramps were aborted by the intervention (69% vs. 40%).
The primary outcome was the change in cramp severity at 28-days VAS for cramps. Cramps were assessed 10 times over 28 days using interactive text messages.
Pickle juice was associated with a larger average reduction in cramp severity than tap water (–2.25 points vs. –0.36 on the VAS-cramps), a difference that was statistically significant (P = .03).
There were no significant changes in the proportion of days with cramp severity of more than 5 on the VAS, or on sleep quality or health-related quality of life.
Because pickle juice contains sodium, the researchers also assessed weight change as a safety outcome. They found no significant differences in weight change between the two groups overall or in the subset with ascites.
Pickle juice is a “safe option that can stop painful cramps,” Dr. Tapper said in an interview, but was “disheartened” that it did not improve quality of life.
Dr. Tapper encourages patients with cramps to ask their doctor about pickle juice and doctors to ask their patients about muscle cramps.
“Awareness of a patient’s cramps is often lacking. Asking about cramps is not routine but could be the most important advance relating to this study,” he said.
While sips of pickle juice are “unlikely to cause harm,” Dr. Tapper said, he is “a little nervous about advising patients to address their complex needs alone. [Doctors] are there to think through the root causes and help make adjustments that could prevent the cramps in the first place,” he said.
Outside experts weigh in
This news organization reached out to several outside experts for their perspective on the study.
Nancy Reau, MD, professor of internal medicine, associate director of solid organ transplantation, and section chief of hepatology. Rush University Medical Center, Chicago, noted that interventions to manage and prevent muscle cramps are “important, as cramping is common in cirrhosis and strongly affects quality of life.”
Dr. Reau cautioned that while pickle juice “sounds benign, it does have a lot of salt. Despite the salt content, this study didn’t show any difference between patients with and without ascites.
“However, cramping is more common in our patients with sarcopenia and those on diuretics for fluid management and it would be easy to see how this might impact fluid management,” Dr. Reau noted.
“Given that it is the acid (not the salt) in the pickle juice, there might be low salt alternatives,” Dr. Reau said.
Echoing Dr. Reau, Ankur Shah, MD, division of kidney disease and hypertension, Brown University, Providence, R.I., noted that “overuse of pickle juice could place patients at risk of developing high blood pressure and fluid overload, and pickle juice should be included in the sodium restriction guidance given to patients with high blood pressure and heart failure.”
In this study, however, the individual dose consumed was low, Dr. Shah noted.
He said the study “elegantly provides evidence to support the practice of sipping pickle juice for cramping.”
The authors should be “applauded for studying a simple solution with the most rigorous of methodologies, a randomized controlled trial,” Dr. Shah added.
“This simple treatment may be helpful to patients far beyond those with just cirrhosis, and expect future studies to explore this treatment in other populations,” Dr. Shah said in an interview.
Paul Martin, MD, chief of the division of digestive health and liver diseases and Mandel Chair in Gastroenterology, University of Miami, noted that, while muscle cramps can have a major impact on quality of life, “in terms of some of the other complications of cirrhosis that health care providers are dealing with, they may seem relatively innocuous, but obviously patients have a slightly different interpretation because of the effect cramps can have on sleep and so on.
“There have been a variety of home remedies to treat muscle cramps, but this study is intriguing as it suggests that pickle juice, which is freely available, helps mitigate the severity of the cramps. However, it’s unclear whether it prevents cramps,” Dr. Martin said in an interview.
Given that the study is getting traction on Twitter, Dr. Martin encouraged health care providers to be aware of the study and prepared to answer questions from patients.
The study had no specific funding. Dr. Tapper has served as a consultant to Novartis, Axcella, and Allergan, has served on advisory boards for Mallinckrodt, Bausch Health, Kaleido, and Novo Nordisk, and has received unrestricted research grants from Gilead and Valeant. Dr. Reau, Dr. Shah, and Dr. Martin have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In the trial, patients with cirrhotic cramps who sipped pickle brine at the onset of a muscle cramp saw a significant decrease in cramp severity relative to peers who sipped tap water when the cramp hit.
“The acid (vinegar) in the brine triggers a nerve reflex to stop the cramp when it hits the throat. This is why only a sip is needed,” lead investigator Elliot Tapper, MD, division of gastroenterology and hepatology, University of Michigan, Ann Arbor, told this news organization. The study was published online April 13 in American Journal of Gastroenterology.
Common and bothersome
Cramps are common in adults with cirrhosis, irrespective of disease severity. They can sometimes last for hours, and treatment options are limited.
In a prior study, 1 tablespoon of pickle juice rapidly stopped experimentally induced cramps.
“This is something that athletes use, and kidney doctors often recommend to their patients, so it is nothing unique to cirrhosis,” Dr. Tapper said.
The PICCLES trial involved 74 adults (mean age, 56.6 years) with at least 4 muscle cramps in the prior month. In the cohort, 54% were men, and 41% had ascites.
The median cramp frequency was 11-12 per month, with an average cramp severity of more than 4 out of 10 on the Visual Analog Scale (VAS) for cramps.
Some patients were receiving medications for their cramps at baseline, such as magnesium, potassium, baclofen, vitamin E, taurine, and gabapentin/pregabalin.
Thirty-eight patients were randomly allocated to sip pickle juice and 36 to sip tap water at the onset of a muscle cramp.
The proportion of cramps treated was similar in the pickle juice and tap water groups (77% and 72%). More patients in the pickle juice group said their cramps were aborted by the intervention (69% vs. 40%).
The primary outcome was the change in cramp severity at 28-days VAS for cramps. Cramps were assessed 10 times over 28 days using interactive text messages.
Pickle juice was associated with a larger average reduction in cramp severity than tap water (–2.25 points vs. –0.36 on the VAS-cramps), a difference that was statistically significant (P = .03).
There were no significant changes in the proportion of days with cramp severity of more than 5 on the VAS, or on sleep quality or health-related quality of life.
Because pickle juice contains sodium, the researchers also assessed weight change as a safety outcome. They found no significant differences in weight change between the two groups overall or in the subset with ascites.
Pickle juice is a “safe option that can stop painful cramps,” Dr. Tapper said in an interview, but was “disheartened” that it did not improve quality of life.
Dr. Tapper encourages patients with cramps to ask their doctor about pickle juice and doctors to ask their patients about muscle cramps.
“Awareness of a patient’s cramps is often lacking. Asking about cramps is not routine but could be the most important advance relating to this study,” he said.
While sips of pickle juice are “unlikely to cause harm,” Dr. Tapper said, he is “a little nervous about advising patients to address their complex needs alone. [Doctors] are there to think through the root causes and help make adjustments that could prevent the cramps in the first place,” he said.
Outside experts weigh in
This news organization reached out to several outside experts for their perspective on the study.
Nancy Reau, MD, professor of internal medicine, associate director of solid organ transplantation, and section chief of hepatology. Rush University Medical Center, Chicago, noted that interventions to manage and prevent muscle cramps are “important, as cramping is common in cirrhosis and strongly affects quality of life.”
Dr. Reau cautioned that while pickle juice “sounds benign, it does have a lot of salt. Despite the salt content, this study didn’t show any difference between patients with and without ascites.
“However, cramping is more common in our patients with sarcopenia and those on diuretics for fluid management and it would be easy to see how this might impact fluid management,” Dr. Reau noted.
“Given that it is the acid (not the salt) in the pickle juice, there might be low salt alternatives,” Dr. Reau said.
Echoing Dr. Reau, Ankur Shah, MD, division of kidney disease and hypertension, Brown University, Providence, R.I., noted that “overuse of pickle juice could place patients at risk of developing high blood pressure and fluid overload, and pickle juice should be included in the sodium restriction guidance given to patients with high blood pressure and heart failure.”
In this study, however, the individual dose consumed was low, Dr. Shah noted.
He said the study “elegantly provides evidence to support the practice of sipping pickle juice for cramping.”
The authors should be “applauded for studying a simple solution with the most rigorous of methodologies, a randomized controlled trial,” Dr. Shah added.
“This simple treatment may be helpful to patients far beyond those with just cirrhosis, and expect future studies to explore this treatment in other populations,” Dr. Shah said in an interview.
Paul Martin, MD, chief of the division of digestive health and liver diseases and Mandel Chair in Gastroenterology, University of Miami, noted that, while muscle cramps can have a major impact on quality of life, “in terms of some of the other complications of cirrhosis that health care providers are dealing with, they may seem relatively innocuous, but obviously patients have a slightly different interpretation because of the effect cramps can have on sleep and so on.
“There have been a variety of home remedies to treat muscle cramps, but this study is intriguing as it suggests that pickle juice, which is freely available, helps mitigate the severity of the cramps. However, it’s unclear whether it prevents cramps,” Dr. Martin said in an interview.
Given that the study is getting traction on Twitter, Dr. Martin encouraged health care providers to be aware of the study and prepared to answer questions from patients.
The study had no specific funding. Dr. Tapper has served as a consultant to Novartis, Axcella, and Allergan, has served on advisory boards for Mallinckrodt, Bausch Health, Kaleido, and Novo Nordisk, and has received unrestricted research grants from Gilead and Valeant. Dr. Reau, Dr. Shah, and Dr. Martin have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.