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First guidelines for keto diets in adults with epilepsy released
Just as in children with epilepsy, ketogenic diet therapies can be safe and effective in adults with epilepsy but should only be undertaken with the support of medical professionals trained in their use, the group said.
“Motivation is the key to successful ketogenic diet therapy adherence,” first author Mackenzie Cervenka, MD, director of the Adult Epilepsy Diet Center and associate professor of neurology at Johns Hopkins University, Baltimore, said in an interview.
“Patients who are autonomous require self-motivation and having a strong support structure is important as well. For those patients who are dependents, their caregivers need to be motivated to manage their diet,” said Dr. Cervenka.
The guidelines were published online Oct. 30 in Neurology Clinical Practice.
Novel in adult neurology
Ketogenic diet therapies are high-fat, low-carbohydrate, and adequate-protein diets that induce fat metabolism and ketone production. Despite its use as an effective antiseizure therapy since the 1920s, ketogenic diet therapies remain novel in adult neurology.
Furthermore, while there are established guidelines for ketogenic diet therapies to reduce seizures in children, there were no formal recommendations for adults, until now.
Drawing on the experience of experts at 20 centers using ketogenic diet therapies in more than 2,100 adults with epilepsy in 10 countries, Dr. Cervenka and an international team developed recommendations on use of ketogenic diet therapies in adults.
The panel noted, “with a relatively mild side effect profile and the potential to reduce seizures in nearly 60% of adults with drug-resistant epilepsy, ketogenic diet therapies should be part of the repertoire of available options.”
Ketogenic diet therapies are appropriate to offer to adults with seizure types and epilepsy syndromes for which these treatments are known to be effective in children, they said. These include tuberous sclerosis complex, Rett syndrome, Lennox-Gastaut syndrome, glucose transporter type 1 deficiency syndrome, genetic generalized epilepsies, and focal epilepsies caused by underlying migrational disorders and resistant to antiseizure medication.
However, adults with drug-resistant focal epilepsy should be offered surgical evaluation first, given the higher anticipated rate of seizure freedom via this route, the panel said.
A focus on compliance
Experts at nearly all of the centers report using two or more ketogenic diet therapies. Ninety percent use the modified Atkins diet, 84% use the classic ketogenic diet, and 63% use the modified ketogenic diet and/or low glycemic index treatment. More than half of the centers (58%) use medium-chain triglyceride oil in combination with another ketogenic diet therapy to boost ketone body production.
The most important factors influencing the choice of ketogenic diet therapy are ease of diet application for the patient (100%) and patient and/or caregiver preference, home setting, and mode of feeding (90% each).
The panel recommended that ketogenic diet therapies be tailored to fit the needs of the individual, taking into account his or her physical and mental characteristics, underlying medical conditions, food preferences, type and amount of support from family and others, level of self-sufficiency, feeding habits, and ease of following the diet.
“Most of the differences between the child and adult recommendations have to do with compliance. Often, it’s more of a challenge for adults than for children,” said Dr. Cervenka.
The panel recommended providing adult patients with recipe ideas, individualized training on the ketogenic diet lifestyle from a dietitian or nutritionist, and guidance for meal planning and preparation before starting the diet. This will provide the greatest likelihood of success, as patients often report difficulties coping with carbohydrate restriction.
“In pediatric practice, positive responders typically remain on a ketogenic diet therapy for 2 years before considering weaning. Ketogenic diet therapy in adults is not time-limited. However, a minimum of 3 months of ketogenic diet therapy is recommended before any judgment of response is made,” the panel advised.
The panel pointed out the absolute metabolic contraindications and cautions related to feeding difficulties, gastrointestinal dysfunction, and digestion remain the same for both children and adults. However, they added that a range of common adult conditions such as hyperlipidemia, heart disease, diabetes, low bone density, and pregnancy “bring additional consideration, caution, and monitoring to ketogenic diet therapy use.”
Beyond epilepsy
The guidelines also call for pre–ketogenic diet therapy biochemical studies to screen adults for preexisting abnormalities and establish a reference for comparing follow-up results after 3, 6, and 12 months, and then annually or as needed.
They also noted that metabolic studies such as urine organic acid and serum amino acid levels are generally not needed in adults unless there is a strong clinical suspicion for an underlying metabolic disorder.
Updated genetic evaluation may also be considered in adults with intellectual disability and epilepsy of unknown etiology. Serial bone mineral density scans may be obtained every 5 years.
The guidelines also call for ketone monitoring (blood beta-hydroxybutyrate or urine amino acids) during the early months of ketogenic diet therapy as an objective indication of compliance and biochemical response.
Dietary adjustments should focus on optimizing the treatment response, minimizing side effects, and maximizing sustainability.
Adults on a ketogenic diet therapy should also be advised to take multivitamin and mineral supplements and drink plenty of fluids.
The panel said emerging evidence also supports the use of ketogenic diet therapies in other adult neurologic disorders such as migraine, Parkinson’s disease, dementia, and multiple sclerosis.
However, the panel said further evidence is needed to guide recommendations on use of ketogenic diet therapies in other neurologic conditions.
The research had no targeted funding. Dr. Cervenka has reported receiving grants from Nutricia, Vitaflo, BrightFocus Foundation, and Army Research Laboratory; honoraria from the American Epilepsy Society, the Neurology Center, Epigenix, LivaNova, and Nutricia; royalties from Demos; and consulting for Nutricia, Glut1 Deficiency Foundation, and Sage Therapeutics. Disclosures for the other authors are listed in the article.
A version of this article originally appeared on Medscape.com.
Just as in children with epilepsy, ketogenic diet therapies can be safe and effective in adults with epilepsy but should only be undertaken with the support of medical professionals trained in their use, the group said.
“Motivation is the key to successful ketogenic diet therapy adherence,” first author Mackenzie Cervenka, MD, director of the Adult Epilepsy Diet Center and associate professor of neurology at Johns Hopkins University, Baltimore, said in an interview.
“Patients who are autonomous require self-motivation and having a strong support structure is important as well. For those patients who are dependents, their caregivers need to be motivated to manage their diet,” said Dr. Cervenka.
The guidelines were published online Oct. 30 in Neurology Clinical Practice.
Novel in adult neurology
Ketogenic diet therapies are high-fat, low-carbohydrate, and adequate-protein diets that induce fat metabolism and ketone production. Despite its use as an effective antiseizure therapy since the 1920s, ketogenic diet therapies remain novel in adult neurology.
Furthermore, while there are established guidelines for ketogenic diet therapies to reduce seizures in children, there were no formal recommendations for adults, until now.
Drawing on the experience of experts at 20 centers using ketogenic diet therapies in more than 2,100 adults with epilepsy in 10 countries, Dr. Cervenka and an international team developed recommendations on use of ketogenic diet therapies in adults.
The panel noted, “with a relatively mild side effect profile and the potential to reduce seizures in nearly 60% of adults with drug-resistant epilepsy, ketogenic diet therapies should be part of the repertoire of available options.”
Ketogenic diet therapies are appropriate to offer to adults with seizure types and epilepsy syndromes for which these treatments are known to be effective in children, they said. These include tuberous sclerosis complex, Rett syndrome, Lennox-Gastaut syndrome, glucose transporter type 1 deficiency syndrome, genetic generalized epilepsies, and focal epilepsies caused by underlying migrational disorders and resistant to antiseizure medication.
However, adults with drug-resistant focal epilepsy should be offered surgical evaluation first, given the higher anticipated rate of seizure freedom via this route, the panel said.
A focus on compliance
Experts at nearly all of the centers report using two or more ketogenic diet therapies. Ninety percent use the modified Atkins diet, 84% use the classic ketogenic diet, and 63% use the modified ketogenic diet and/or low glycemic index treatment. More than half of the centers (58%) use medium-chain triglyceride oil in combination with another ketogenic diet therapy to boost ketone body production.
The most important factors influencing the choice of ketogenic diet therapy are ease of diet application for the patient (100%) and patient and/or caregiver preference, home setting, and mode of feeding (90% each).
The panel recommended that ketogenic diet therapies be tailored to fit the needs of the individual, taking into account his or her physical and mental characteristics, underlying medical conditions, food preferences, type and amount of support from family and others, level of self-sufficiency, feeding habits, and ease of following the diet.
“Most of the differences between the child and adult recommendations have to do with compliance. Often, it’s more of a challenge for adults than for children,” said Dr. Cervenka.
The panel recommended providing adult patients with recipe ideas, individualized training on the ketogenic diet lifestyle from a dietitian or nutritionist, and guidance for meal planning and preparation before starting the diet. This will provide the greatest likelihood of success, as patients often report difficulties coping with carbohydrate restriction.
“In pediatric practice, positive responders typically remain on a ketogenic diet therapy for 2 years before considering weaning. Ketogenic diet therapy in adults is not time-limited. However, a minimum of 3 months of ketogenic diet therapy is recommended before any judgment of response is made,” the panel advised.
The panel pointed out the absolute metabolic contraindications and cautions related to feeding difficulties, gastrointestinal dysfunction, and digestion remain the same for both children and adults. However, they added that a range of common adult conditions such as hyperlipidemia, heart disease, diabetes, low bone density, and pregnancy “bring additional consideration, caution, and monitoring to ketogenic diet therapy use.”
Beyond epilepsy
The guidelines also call for pre–ketogenic diet therapy biochemical studies to screen adults for preexisting abnormalities and establish a reference for comparing follow-up results after 3, 6, and 12 months, and then annually or as needed.
They also noted that metabolic studies such as urine organic acid and serum amino acid levels are generally not needed in adults unless there is a strong clinical suspicion for an underlying metabolic disorder.
Updated genetic evaluation may also be considered in adults with intellectual disability and epilepsy of unknown etiology. Serial bone mineral density scans may be obtained every 5 years.
The guidelines also call for ketone monitoring (blood beta-hydroxybutyrate or urine amino acids) during the early months of ketogenic diet therapy as an objective indication of compliance and biochemical response.
Dietary adjustments should focus on optimizing the treatment response, minimizing side effects, and maximizing sustainability.
Adults on a ketogenic diet therapy should also be advised to take multivitamin and mineral supplements and drink plenty of fluids.
The panel said emerging evidence also supports the use of ketogenic diet therapies in other adult neurologic disorders such as migraine, Parkinson’s disease, dementia, and multiple sclerosis.
However, the panel said further evidence is needed to guide recommendations on use of ketogenic diet therapies in other neurologic conditions.
The research had no targeted funding. Dr. Cervenka has reported receiving grants from Nutricia, Vitaflo, BrightFocus Foundation, and Army Research Laboratory; honoraria from the American Epilepsy Society, the Neurology Center, Epigenix, LivaNova, and Nutricia; royalties from Demos; and consulting for Nutricia, Glut1 Deficiency Foundation, and Sage Therapeutics. Disclosures for the other authors are listed in the article.
A version of this article originally appeared on Medscape.com.
Just as in children with epilepsy, ketogenic diet therapies can be safe and effective in adults with epilepsy but should only be undertaken with the support of medical professionals trained in their use, the group said.
“Motivation is the key to successful ketogenic diet therapy adherence,” first author Mackenzie Cervenka, MD, director of the Adult Epilepsy Diet Center and associate professor of neurology at Johns Hopkins University, Baltimore, said in an interview.
“Patients who are autonomous require self-motivation and having a strong support structure is important as well. For those patients who are dependents, their caregivers need to be motivated to manage their diet,” said Dr. Cervenka.
The guidelines were published online Oct. 30 in Neurology Clinical Practice.
Novel in adult neurology
Ketogenic diet therapies are high-fat, low-carbohydrate, and adequate-protein diets that induce fat metabolism and ketone production. Despite its use as an effective antiseizure therapy since the 1920s, ketogenic diet therapies remain novel in adult neurology.
Furthermore, while there are established guidelines for ketogenic diet therapies to reduce seizures in children, there were no formal recommendations for adults, until now.
Drawing on the experience of experts at 20 centers using ketogenic diet therapies in more than 2,100 adults with epilepsy in 10 countries, Dr. Cervenka and an international team developed recommendations on use of ketogenic diet therapies in adults.
The panel noted, “with a relatively mild side effect profile and the potential to reduce seizures in nearly 60% of adults with drug-resistant epilepsy, ketogenic diet therapies should be part of the repertoire of available options.”
Ketogenic diet therapies are appropriate to offer to adults with seizure types and epilepsy syndromes for which these treatments are known to be effective in children, they said. These include tuberous sclerosis complex, Rett syndrome, Lennox-Gastaut syndrome, glucose transporter type 1 deficiency syndrome, genetic generalized epilepsies, and focal epilepsies caused by underlying migrational disorders and resistant to antiseizure medication.
However, adults with drug-resistant focal epilepsy should be offered surgical evaluation first, given the higher anticipated rate of seizure freedom via this route, the panel said.
A focus on compliance
Experts at nearly all of the centers report using two or more ketogenic diet therapies. Ninety percent use the modified Atkins diet, 84% use the classic ketogenic diet, and 63% use the modified ketogenic diet and/or low glycemic index treatment. More than half of the centers (58%) use medium-chain triglyceride oil in combination with another ketogenic diet therapy to boost ketone body production.
The most important factors influencing the choice of ketogenic diet therapy are ease of diet application for the patient (100%) and patient and/or caregiver preference, home setting, and mode of feeding (90% each).
The panel recommended that ketogenic diet therapies be tailored to fit the needs of the individual, taking into account his or her physical and mental characteristics, underlying medical conditions, food preferences, type and amount of support from family and others, level of self-sufficiency, feeding habits, and ease of following the diet.
“Most of the differences between the child and adult recommendations have to do with compliance. Often, it’s more of a challenge for adults than for children,” said Dr. Cervenka.
The panel recommended providing adult patients with recipe ideas, individualized training on the ketogenic diet lifestyle from a dietitian or nutritionist, and guidance for meal planning and preparation before starting the diet. This will provide the greatest likelihood of success, as patients often report difficulties coping with carbohydrate restriction.
“In pediatric practice, positive responders typically remain on a ketogenic diet therapy for 2 years before considering weaning. Ketogenic diet therapy in adults is not time-limited. However, a minimum of 3 months of ketogenic diet therapy is recommended before any judgment of response is made,” the panel advised.
The panel pointed out the absolute metabolic contraindications and cautions related to feeding difficulties, gastrointestinal dysfunction, and digestion remain the same for both children and adults. However, they added that a range of common adult conditions such as hyperlipidemia, heart disease, diabetes, low bone density, and pregnancy “bring additional consideration, caution, and monitoring to ketogenic diet therapy use.”
Beyond epilepsy
The guidelines also call for pre–ketogenic diet therapy biochemical studies to screen adults for preexisting abnormalities and establish a reference for comparing follow-up results after 3, 6, and 12 months, and then annually or as needed.
They also noted that metabolic studies such as urine organic acid and serum amino acid levels are generally not needed in adults unless there is a strong clinical suspicion for an underlying metabolic disorder.
Updated genetic evaluation may also be considered in adults with intellectual disability and epilepsy of unknown etiology. Serial bone mineral density scans may be obtained every 5 years.
The guidelines also call for ketone monitoring (blood beta-hydroxybutyrate or urine amino acids) during the early months of ketogenic diet therapy as an objective indication of compliance and biochemical response.
Dietary adjustments should focus on optimizing the treatment response, minimizing side effects, and maximizing sustainability.
Adults on a ketogenic diet therapy should also be advised to take multivitamin and mineral supplements and drink plenty of fluids.
The panel said emerging evidence also supports the use of ketogenic diet therapies in other adult neurologic disorders such as migraine, Parkinson’s disease, dementia, and multiple sclerosis.
However, the panel said further evidence is needed to guide recommendations on use of ketogenic diet therapies in other neurologic conditions.
The research had no targeted funding. Dr. Cervenka has reported receiving grants from Nutricia, Vitaflo, BrightFocus Foundation, and Army Research Laboratory; honoraria from the American Epilepsy Society, the Neurology Center, Epigenix, LivaNova, and Nutricia; royalties from Demos; and consulting for Nutricia, Glut1 Deficiency Foundation, and Sage Therapeutics. Disclosures for the other authors are listed in the article.
A version of this article originally appeared on Medscape.com.
Statins beneficial in elderly, guidelines should be strengthened
Contrary to historical evidence, two new studies show.
“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.
“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.
“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).
The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.
“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.
“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
No RCTs have included patients older than 70
For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.
However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.
Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.
As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
Primary prevention: CV events increase with elevated LDL cholesterol in older age
Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.
Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.
Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.
In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).
Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.
Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).
The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.
“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.
With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.
With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.
“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”
“These robust findings are novel,” he and his colleagues stressed.
Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.
The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
Unequivocal reductions in events in elderly, comparable with younger patients
In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.
The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.
The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.
The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).
Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).
“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.
“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.
“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”
The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”
The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.
A version of this article originally appeared on Medscape.com.
Contrary to historical evidence, two new studies show.
“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.
“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.
“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).
The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.
“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.
“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
No RCTs have included patients older than 70
For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.
However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.
Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.
As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
Primary prevention: CV events increase with elevated LDL cholesterol in older age
Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.
Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.
Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.
In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).
Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.
Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).
The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.
“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.
With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.
With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.
“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”
“These robust findings are novel,” he and his colleagues stressed.
Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.
The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
Unequivocal reductions in events in elderly, comparable with younger patients
In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.
The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.
The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.
The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).
Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).
“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.
“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.
“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”
The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”
The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.
A version of this article originally appeared on Medscape.com.
Contrary to historical evidence, two new studies show.
“By contrast with previous historical studies, our data show that LDL cholesterol is an important risk factor for myocardial infarction and atherosclerotic cardiovascular disease in a contemporary primary prevention cohort of individuals aged 70 to 100 years,” Borge Nordestgaard, MD, of the University of Copenhagen, and colleagues noted in the first of the two studies, published this week in the Lancet.
“By lowering LDL cholesterol in healthy individuals aged 70-100 years, the potential for preventing myocardial infarctions and atherosclerotic cardiovascular disease is huge, and at a substantially lower number needed to treat when compared with those aged 20-69 years,” they added.
“These findings support the concept of the cumulative burden of LDL cholesterol over one’s lifetime and the progressive increase in risk for atherosclerotic cardiovascular disease, including myocardial infarction, with age,” added Frederick J. Raal, PhD, and Farzahna Mohamed, MB BCh, of the University of the Witwatersrand, Johannesburg, South Africa, in an editorial published with both new studies in the Lancet (2020 Nov 10. doi: 10.1016/S0140-6736[20]32333-3).
The studies underscore the need for clinicians to consider continued risks associated with elevated LDL cholesterol in older age, they stressed, adding that statins are also beneficial for younger persons at risk to prevent conditions from worsening.
“The average age of patients in all the trials analyzed was older than 60 years, an age when atherosclerotic cardiovascular disease is already well established,” the editorialists wrote.
“Lipid-lowering therapy should be initiated at a younger age, preferably before age 40 years, in those at risk to delay the onset of atherosclerosis, rather than try to manage the condition once fully established or advanced,” they stressed.
No RCTs have included patients older than 70
For persons aged 40-75 years, elevated LDL cholesterol levels are a known risk factor for MI and atherosclerotic cardiovascular disease, and there is consensus in guidelines regarding treatment with statins.
However, the risk for people older than 70 is controversial. Some studies show little or no association between elevated LDL cholesterol levels and an increased risk for MI.
Contributing to the uncertainty is that few of the randomized, controlled trials that have investigated the question have included patients aged older than 70 years.
As a consequence, many practice guidelines have noted that the level of evidence in older patients is low, and some organizations have lowered the strength of recommendations regarding the treatment for older patients in comparison with younger patients.
Primary prevention: CV events increase with elevated LDL cholesterol in older age
Dr. Nordestgaard and colleagues studied data on 91,131 people living in Copenhagen who did not have atherosclerotic cardiovascular disease or diabetes at baseline and were not taking statins.
Of the participants, 10,592 were aged 70-79 years, and 3,188 participants were aged 80-100 years.
Over an average follow-up period of 7.7 years, 1,515 participants had a first MI, and 3,389 developed atherosclerotic cardiovascular disease.
In the primary-prevention cohort, after multivariate adjustment, the risk of having a heart attack per 1.0 mmol/L increase in LDL cholesterol was increased in the group overall (hazard ratio, 1.34). The increased risk was observed for all age groups, including those aged 80-100 years (HR, 1.28), 70-79 (HR, 1.25), 60-69 (HR, 1.29), 50-59 (HR, 1.28), and 20-49 (HR, 1.68).
Risk for atherosclerotic cardiovascular disease was also raised per 1.0 mmol/L increase in LDL cholesterol overall (HR, 1.16) and in all age groups, particularly those aged 70-100 years.
Greater elevations in LDL cholesterol (5.0 mmol/L or higher, indicative of possible familial hypercholesterolemia) were associated with a notably higher risk for heart attack after multivariate adjustment in people aged 80-100 (HR, 2.99). Risk was also higher among those aged 70-79 (HR, 1.82).
The highest incidence was in those older than 70. The rate was 8.5 heart attacks per 1,000 people per year among those aged 80-100 and 5.2 heart attacks per 1,000 in those aged 70-79. The rates were 2.5 per 1,000 among those 60-69, 1.8 for those aged 50-59, and 0.8 for those aged 20-49.
“The absolute risk [of cardiovascular events] is of course much higher in the elderly than those under the age of 75, but what was a surprise was how clear our results were on a relative risk scale, that the risk associated with elevated LDL [cholesterol] was as high in people aged 80-100 as the younger patients,” Dr. Nordestgaard said in an interview.
With regard to the benefits of cholesterol-lowering drugs, the study showed that the number needed to prevent one heart attack over 5 years was 80 among those aged 80-100; the number was 439 for people aged 50-59.
With regard to stronger statins, when moderate-intensity statins were used, the number needed to treat to prevent one cardiovascular disease event of any type dropped to 42 for patients aged 80-100. It was 88 for those aged 70-79, 164 for those aged 60-69, 345 for those aged 50-59, and 769 for those aged 20-49.
“The clinical significance of this is that it appears those in older age groups indeed benefit from cholesterol-lowering therapy,” Dr. Nordestgaard said. “I think many people have this idea that LDL [cholesterol] is not important over the age of about 70-75, but that’s not the case.”
“These robust findings are novel,” he and his colleagues stressed.
Despite these observational findings, the South African editorialists noted that “whether lipid-lowering therapy should be initiated for primary prevention in people aged 75 years or older is unclear,” owing to the host of risks and benefits that need to be balanced.
The findings of an ongoing randomized, placebo-controlled trial (STAREE) may answer this question, they wrote. It is investigating primary prevention in 18,000 older patients (≥70 years) who are being randomly assigned to receive atorvastatin 40 mg/d or placebo. The study is seeking to determine whether statin treatment extends the length of a disability-free life, which will be assessed on the basis of survival outside permanent residential care. Results are expected in 2022-2023.
Unequivocal reductions in events in elderly, comparable with younger patients
In the second study (Lancet. 2020 Nov 10. doi: 10.1016/S0140-6736[20]32332-1), Baris Gencer, MD, of Brigham and Women’s Hospital, Boston, =and colleagues evaluated the effects of statins and other cholesterol-lowering drugs, including ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors, in older versus younger patients.
The systematic review and meta-analysis of 29 randomized controlled trials, also published in the Lancet, were presented virtually as a poster as part of the 2020 American Heart Association scientific session. It included data on 244,090 patients, including 21,492 aged 75 years and older.
The meta-analysis included studies of cardiovascular outcomes of a guideline-recommended LDL cholesterol–lowering drug, with a median follow-up of at least 2 years and inclusion of data on patients aged 75 years and older.
The results showed that over a median follow-up of 2.2 to 6 years, statin use by older patients was associated with a relative risk reduction of major vascular events of 26% per 1 mmol/L reduction in LDL cholesterol (P = .0019), which was comparable with a risk reduction of 15% per 1 mmol/L reduction in LDL cholesterol for patients younger than 75 years (P = .37, compared with older patients).
Treatment of older patients with LDL cholesterol–lowering drugs was also associated with significantly improved outcomes in cardiovascular death (risk ratio, 0.85), MI (RR, 0.80), stroke (RR, 0.73), and coronary revascularization (RR, 0.80).
“We found an unequivocal reduction in the risk of major vascular events with both statin and nonstatin LDL cholesterol-lowering treatments, which was similar to that seen in younger patients,” the authors wrote.
“Cholesterol-lowering medications are affordable drugs that have reduced risk of heart disease for millions of people worldwide, but until now, their benefits for older people have remained less certain,” said lead author Marc Sabatine, MD, also of Brigham and Women’s Hospital, in a Lancet press release.
“Our analysis indicates that these therapies are as effective in reducing cardiovascular events and deaths in people aged 75 years and over as they are in younger people. We found no offsetting safety concerns, and together, these results should strengthen guideline recommendations for the use of cholesterol-lowering medications, including statin and nonstatin therapy, in elderly people.”
The editorialists agreed: “More than 80% of fatal cardiovascular events occur in individuals older than 65 years, and the incidence of cardiovascular events is increasing in those older than 80 years; therefore, the findings of Gencer and colleagues’ study should encourage the use of lipid-lowering therapy in older patients.”
The authors of the two studies have disclosed no relevant financial relationships. Dr. Raal has received research grants, honoraria, or consulting fees for advisory board membership, professional input, and lectures on lipid-lowering drug therapy from Amgen, Regeneron, Sanofi, Novartis, and the Medicines Company.
A version of this article originally appeared on Medscape.com.
Concussion linked to risk for dementia, Parkinson’s disease, and ADHD
new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.
The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.
The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.
The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
Almost 190,000 participants
Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.
An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.
In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.
Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.
Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).
The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
Dose effect?
Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).
After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.
Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).
A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.
Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.
“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
Association versus causation
Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.
“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.
Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.
“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.
The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.
The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.
The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.
The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
Almost 190,000 participants
Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.
An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.
In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.
Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.
Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).
The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
Dose effect?
Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).
After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.
Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).
A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.
Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.
“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
Association versus causation
Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.
“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.
Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.
“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.
The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
new research suggests. Results from a retrospective, population-based cohort study showed that controlling for socioeconomic status and overall health did not significantly affect this association.
The link between concussion and risk for ADHD and for mood and anxiety disorder was stronger in the women than in the men. In addition, having a history of multiple concussions strengthened the association between concussion and subsequent mood and anxiety disorder, dementia, and Parkinson’s disease compared with experiencing just one concussion.
The findings are similar to those of previous studies, noted lead author Marc P. Morissette, PhD, research assistant at the Pan Am Clinic Foundation in Winnipeg, Manitoba, Canada. “The main methodological differences separating our study from previous studies in this area is a focus on concussion-specific injuries identified from medical records and the potential for study participants to have up to 25 years of follow-up data,” said Dr. Morissette.
The findings were published online July 27 in Family Medicine and Community Health, a BMJ journal.
Almost 190,000 participants
Several studies have shown associations between head injury and increased risk for ADHD, depression, anxiety, Alzheimer’s disease, and Parkinson’s disease. However, many of these studies relied on self-reported medical history, included all forms of traumatic brain injury, and failed to adjust for preexisting health conditions.
An improved understanding of concussion and the risks associated with it could help physicians manage their patients’ long-term needs, the investigators noted.
In the current study, the researchers examined anonymized administrative health data collected between the periods of 1990–1991 and 2014–2015 in the Manitoba Population Research Data Repository at the Manitoba Center for Health Policy.
Eligible patients had been diagnosed with concussion in accordance with standard criteria. Participants were excluded if they had been diagnosed with dementia or Parkinson’s disease before the incident concussion during the study period. The investigators matched three control participants to each included patient on the basis of age, sex, and location.
Study outcome was time from index date (date of first concussion) to diagnosis of ADHD, mood and anxiety disorder, dementia, or Parkinson’s disease. The researchers controlled for socioeconomic status using the Socioeconomic Factor Index, version 2 (SEFI2), and for preexisting medical conditions using the Charlson Comorbidity Index (CCI).
The study included 28,021 men (mean age, 25 years) and 19,462 women (mean age, 30 years) in the concussion group and 81,871 men (mean age, 25 years) and 57,159 women (mean age, 30 years) in the control group. Mean SEFI2 score was approximately −0.05, and mean CCI score was approximately 0.2.
Dose effect?
Results showed that concussion was associated with an increased risk for ADHD (hazard ratio [HR], 1.39), mood and anxiety disorder (HR, 1.72), dementia (HR, 1.72), and Parkinson’s disease (HR, 1.57).
After a concussion, the risk of developing ADHD was 28% higher and the risk of developing mood and anxiety disorder was 7% higher among women than among men. Gender was not associated with risk for dementia or Parkinson’s disease after concussion.
Sustaining a second concussion increased the strength of the association with risk for dementia compared with sustaining a single concussion (HR, 1.62). Similarly, sustaining more than three concussions increased the strength of the association with the risk for mood and anxiety disorders (HR for more than three vs one concussion, 1.22) and Parkinson›s disease (HR, 3.27).
A sensitivity analysis found similar associations between concussion and risk for mood and anxiety disorder among all age groups. Younger participants were at greater risk for ADHD, however, and older participants were at greater risk for dementia and Parkinson’s disease.
Increased awareness of concussion and the outcomes of interest, along with improved diagnostic tools, may have influenced the study’s findings, Dr. Morissette noted. “The sex-based differences may be due to either pathophysiological differences in response to concussive injuries or potentially a difference in willingness to seek medical care or share symptoms, concussion-related or otherwise, with a medical professional,” he said.
“We are hopeful that our findings will encourage practitioners to be cognizant of various conditions that may present in individuals who have previously experienced a concussion,” Dr. Morissette added. “If physicians are aware of the various associations identified following a concussion, it may lead to more thorough clinical examination at initial presentation, along with more dedicated care throughout the patient’s life.”
Association versus causation
Commenting on the research, Steven Erickson, MD, sports medicine specialist at Banner–University Medicine Neuroscience Institute, Phoenix, Ariz., noted that although the study showed an association between concussion and subsequent diagnosis of ADHD, anxiety, and Parkinson’s disease, “this association should not be misconstrued as causation.” He added that the study’s conclusions “are just as likely to be due to labeling theory” or a self-fulfilling prophecy.
“Patients diagnosed with ADHD, anxiety, or Parkinson’s disease may recall concussion and associate the two diagnoses; but patients who have not previously been diagnosed with a concussion cannot draw that conclusion,” said Dr. Erickson, who was not involved with the research.
Citing the apparent gender difference in the strength of the association between concussion and the outcomes of interest, Dr. Erickson noted that women are more likely to report symptoms in general “and therefore are more likely to be diagnosed with ADHD and anxiety disorders” because of differences in reporting rather than incidence of disease.
“Further research needs to be done to definitively determine a causal relationship between concussion and any psychiatric or neurologic diagnosis,” Dr. Erickson concluded.
The study was funded by the Pan Am Clinic Foundation. Dr. Morissette and Dr. Erickson have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
From Family Medicine and Community Health
Pigment traits, sun sensitivity associated with risk of non-Hodgkin lymphomas and chronic lymphocytic leukemia
Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.
The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.
Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
Common etiology?
Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.
The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.
Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.
These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.
“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.
The study was sponsored by the French government. The authors stated that they had no conflicts of interest.
SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.
Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.
The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.
Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
Common etiology?
Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.
The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.
Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.
These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.
“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.
The study was sponsored by the French government. The authors stated that they had no conflicts of interest.
SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.
Risk factors for keratinocyte carcinomas, primarily pigment traits and sun sensitivity, were associated with the risk of developing non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL) in an analysis of 92,097 women in France.
The presence of “many or very many nevi [moles]” was particularly associated with the risk of CLL among individuals in the E3N cohort, according to a report published online in Cancer Medicine. E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Researchers collected cancer data at baseline and every 2-3 years.
Hazard ratios and 95% confidence intervals for associations between patients pigmentary traits and sun exposure and their risk for CLL/NHL were estimated using Cox models, according to study author Louis-Marie Garcin, MD, of the Université Paris-Saclay, Villejuif, and colleagues.
Common etiology?
Among the 92,097 women included in the study, 622 incident cases of CLL/NHL were observed over a median of 24-years’ follow-up.
The presence of nevi was associated with CLL/NHL risk. The HR for “many or very many nevi” relative to “no nevi” was 1.56. The association with number of nevi was strongest for the risk of CLL, with an HR for “many or very many nevi” of 3.00 vs. 1.32 for NHL. In addition, the researchers found that women whose skin was highly sensitive to sunburn also had a higher risk of CLL (HR, 1.96), while no increased risk of NHL was observed. All HR values were within their respective 95% confidence intervals.
Relevant characteristics that were found to not be associated with added CLL/NHL risk were skin or hair color, number of freckles, and average daily UV dose during spring and summer in the location of residence at birth or at inclusion.
These observations suggest that CLL in particular may share some constitutional risk factors with keratinocyte cancers, according to the researchers.
“We report an association between nevi frequency and CLL/NHL risk, suggesting a partly common genetic etiology of these tumors. Future research should investigate common pathophysiological pathways that could promote the development of both skin carcinoma and CLL/NHL,” the researchers concluded.
The study was sponsored by the French government. The authors stated that they had no conflicts of interest.
SOURCE: Garcin L-M et al. Cancer Med. 2020. doi: 10.1002/cam4.3586.
FROM CANCER MEDICINE
Late-onset epilepsy tied to a threefold increased dementia risk
Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy.
“This is an exciting area, as we are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other cohort studies are finding similar results, including the Veterans’ Health Study and the Framingham Study,” she added.
The study was published online Oct. 23 in Neurology
Bidirectional relationship?
Previous research has established that dementia is a risk factor for epilepsy, but recent studies also suggest an increased risk of incident dementia among patients with adult-onset epilepsy. Several risk factors for late-onset epilepsy, including diabetes and hypertension, also are risk factors for dementia. However, the effect of late-onset epilepsy on dementia risk in patients with these comorbidities has not been clarified.
To investigate, the researchers examined data from the Atherosclerosis Risk in Communities (ARIC) study. Participants include Black and White men and women from four U.S. communities. Baseline visits in this longitudinal cohort study began between 1987 and 1989, and follow-up included seven additional visits and regular phone calls.
The investigators identified participants with late-onset epilepsy by searching for Medicare claims related to seizures or epilepsy filed between 1991 and 2015. Those with two or more such claims and age of onset of 67 years or greater were considered to have late-onset epilepsy. Participants with preexisting conditions such as brain tumors or multiple sclerosis were excluded.
ARIC participants who presented in person for visits 2, 4, 5, and 6 underwent cognitive testing with the Delayed Word Recall Test, the Digit Symbol Substitution Test, and the Word Fluency Test.
Testing at visits 5 and 6 also included other tests, such as the Mini-Mental State Examination, the Boston Naming test, and the Wechsler Memory Scale-III. Dr. Johnson and colleagues excluded data for visit 7 from the analysis because dementia adjudication was not yet complete.
The researchers identified participants with dementia using data from visits 5 and 6 and ascertained time of dementia onset through participant and informant interviews, phone calls, and hospital discharge data. Participants also were screened for mild cognitive impairment (MCI) at visits 5 and 6.
Data were analyzed using a Cox proportional hazards model and multinomial logistic regression. In subsequent analyses, researchers adjusted the data for age, sex, race, smoking status, alcohol use, hypertension, diabetes, body mass index (BMI), APOE4 status, and prevalent stroke.
The researchers found that of 9,033 study participants, 671 had late-onset epilepsy. The late-onset epilepsy group was older at baseline (56.5 vs. 55.1 years) and more likely to have hypertension (38.9% vs. 33.3%), diabetes (16.1% vs. 9.6%), and two alleles of APOE4 genotype (3.9% vs. 2.5%), compared with those without the disorder.
In all, 1,687 participants developed dementia during follow-up. The rate of incident dementia was 41.6% in participants with late-onset epilepsy and 16.8% in participants without late-onset epilepsy. The adjusted hazard ratio of subsequent dementia in participants with late-onset epilepsy versus those without the disorder was 3.05 (95% confidence interval, 2.65-3.51).
The median time to dementia ascertainment after late-onset epilepsy was 3.66 years.
Counterintuitive finding
The relationship between late-onset epilepsy and subsequent dementia was stronger in patients without stroke. The investigators offered a possible explanation for this counterintuitive finding. “We observed an interaction between [late-onset epilepsy] and stroke, with a lower (but still substantial) association between [late-onset epilepsy] and dementia in those with a history of stroke. This may be due to the known strong association between stroke and dementia, which may wash out the contributions of [late-onset epilepsy] to cognitive impairment,” the researchers wrote.
“There may also be under-capturing of dementia diagnoses among participants with stroke in the ascertainment from [Centers for Medicare & Medicaid Services] codes, as physicians may be reluctant to make a separate code for ‘dementia’ in those with cognitive impairment after stroke,” they added.
When the researchers restricted the analysis only to participants who attended visits 5 and 6 and had late-onset epilepsy ascertainment available, they found that the relative risk ratio for dementia at visit 6 was 2.90 (95% CI, 1.22-6.92; P = .009). The RRR for MCI was 0.97 (95% CI, 0.39-2.38; P = .803). The greater functional impairment in patients with late-onset epilepsy may explain the lack of a relationship between late-onset epilepsy and MCI.
“It will be important for neurologists to be aware of the possibility of cognitive impairment following late-onset epilepsy and to check in with patients and family members to see if there are concerns,” said Dr. Johnson.
“We should also be talking about the importance of lowering other risk factors for dementia by making sure cardiovascular risk factors are controlled and encouraging physical and cognitive activity,” she added.
The results require confirmation in a clinical population, the investigators noted. In addition, future research is necessary to clarify whether seizures directly increase the risk of dementia or whether shared neuropathology between epilepsy and dementia explains the risk.
“In the near future, I plan to enroll participants with late-onset epilepsy in an observational study to better understand factors that may contribute to cognitive change. Collaborations will be key as we seek to further understand what causes these changes and what could be done to prevent them,” Dr. Johnson added.
Strengths and weaknesses
In an accompanying editorial, W. Allen Hauser, MD, professor emeritus of neurology and epidemiology at Columbia University in New York, and colleagues noted that the findings support a bidirectional relationship between dementia and epilepsy, adding that accumulation of amyloid beta peptide is a plausible underlying pathophysiology that may explain this relationship.
Future research should clarify the effect of factors such as seizure type, seizure frequency, and age of onset on the risk of dementia among patients with epilepsy, the editorialists wrote. Such investigations could help elucidate the underlying mechanisms of these conditions and help to improve treatment, they added.
Commenting on the findings, Ilo Leppik, MD, professor of neurology and pharmacy at the University of Minnesota in Minneapolis described the research as “a very well-done study by qualified researchers in the field. … For the last century, medicine has unfortunately become compartmentalized by specialty and then subspecialty. The brain and disorders of the brain do not recognize these silos. … It is not a stretch of the known science to begin to understand that epilepsy and dementia have common anatomical and physiological underpinnings.”
The long period of prospectively gathering data and the measurement of cognitive function through various modalities are among the study’s great strengths, said Dr. Leppik. However, the study’s weakness is its reliance on Medicare claims data, which mainly would reflect convulsive seizures.
“What is missing is how many persons had subtle focal-unaware seizures that may not be identified unless a careful history is taken,” said Dr. Leppik. “Thus, this study likely underestimates the frequency of epilepsy.”
Neurologists who evaluate a person with early dementia should be on the lookout for a history of subtle seizures, said Dr. Leppik. Animal studies suggest treatment with levetiracetam or brivaracetam may slow the course of dementia, and a clinical study in participants with early dementia is underway.
“Treatment with an antiseizure drug may prove to be beneficial, especially if evidence for the presence of subtle epilepsy can be found,” Dr. Leppik added.
Greater collaboration between epileptologists and dementia specialists and larger studies of antiseizure drugs are necessary, he noted. “These studies can incorporate sophisticated structural and biochemical [analyses] to better identify the relationships between brain mechanisms that likely underlie both seizures and dementia. The ultimate promise is that early treatment of seizures may alter the course of dementia,” Dr. Leppik said.
The study by Dr. Johnson and colleagues was supported by a contract from the National Institute on Aging; ARIC from the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the Department of Health & Human Services. The authors and Dr. Leppik have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy.
“This is an exciting area, as we are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other cohort studies are finding similar results, including the Veterans’ Health Study and the Framingham Study,” she added.
The study was published online Oct. 23 in Neurology
Bidirectional relationship?
Previous research has established that dementia is a risk factor for epilepsy, but recent studies also suggest an increased risk of incident dementia among patients with adult-onset epilepsy. Several risk factors for late-onset epilepsy, including diabetes and hypertension, also are risk factors for dementia. However, the effect of late-onset epilepsy on dementia risk in patients with these comorbidities has not been clarified.
To investigate, the researchers examined data from the Atherosclerosis Risk in Communities (ARIC) study. Participants include Black and White men and women from four U.S. communities. Baseline visits in this longitudinal cohort study began between 1987 and 1989, and follow-up included seven additional visits and regular phone calls.
The investigators identified participants with late-onset epilepsy by searching for Medicare claims related to seizures or epilepsy filed between 1991 and 2015. Those with two or more such claims and age of onset of 67 years or greater were considered to have late-onset epilepsy. Participants with preexisting conditions such as brain tumors or multiple sclerosis were excluded.
ARIC participants who presented in person for visits 2, 4, 5, and 6 underwent cognitive testing with the Delayed Word Recall Test, the Digit Symbol Substitution Test, and the Word Fluency Test.
Testing at visits 5 and 6 also included other tests, such as the Mini-Mental State Examination, the Boston Naming test, and the Wechsler Memory Scale-III. Dr. Johnson and colleagues excluded data for visit 7 from the analysis because dementia adjudication was not yet complete.
The researchers identified participants with dementia using data from visits 5 and 6 and ascertained time of dementia onset through participant and informant interviews, phone calls, and hospital discharge data. Participants also were screened for mild cognitive impairment (MCI) at visits 5 and 6.
Data were analyzed using a Cox proportional hazards model and multinomial logistic regression. In subsequent analyses, researchers adjusted the data for age, sex, race, smoking status, alcohol use, hypertension, diabetes, body mass index (BMI), APOE4 status, and prevalent stroke.
The researchers found that of 9,033 study participants, 671 had late-onset epilepsy. The late-onset epilepsy group was older at baseline (56.5 vs. 55.1 years) and more likely to have hypertension (38.9% vs. 33.3%), diabetes (16.1% vs. 9.6%), and two alleles of APOE4 genotype (3.9% vs. 2.5%), compared with those without the disorder.
In all, 1,687 participants developed dementia during follow-up. The rate of incident dementia was 41.6% in participants with late-onset epilepsy and 16.8% in participants without late-onset epilepsy. The adjusted hazard ratio of subsequent dementia in participants with late-onset epilepsy versus those without the disorder was 3.05 (95% confidence interval, 2.65-3.51).
The median time to dementia ascertainment after late-onset epilepsy was 3.66 years.
Counterintuitive finding
The relationship between late-onset epilepsy and subsequent dementia was stronger in patients without stroke. The investigators offered a possible explanation for this counterintuitive finding. “We observed an interaction between [late-onset epilepsy] and stroke, with a lower (but still substantial) association between [late-onset epilepsy] and dementia in those with a history of stroke. This may be due to the known strong association between stroke and dementia, which may wash out the contributions of [late-onset epilepsy] to cognitive impairment,” the researchers wrote.
“There may also be under-capturing of dementia diagnoses among participants with stroke in the ascertainment from [Centers for Medicare & Medicaid Services] codes, as physicians may be reluctant to make a separate code for ‘dementia’ in those with cognitive impairment after stroke,” they added.
When the researchers restricted the analysis only to participants who attended visits 5 and 6 and had late-onset epilepsy ascertainment available, they found that the relative risk ratio for dementia at visit 6 was 2.90 (95% CI, 1.22-6.92; P = .009). The RRR for MCI was 0.97 (95% CI, 0.39-2.38; P = .803). The greater functional impairment in patients with late-onset epilepsy may explain the lack of a relationship between late-onset epilepsy and MCI.
“It will be important for neurologists to be aware of the possibility of cognitive impairment following late-onset epilepsy and to check in with patients and family members to see if there are concerns,” said Dr. Johnson.
“We should also be talking about the importance of lowering other risk factors for dementia by making sure cardiovascular risk factors are controlled and encouraging physical and cognitive activity,” she added.
The results require confirmation in a clinical population, the investigators noted. In addition, future research is necessary to clarify whether seizures directly increase the risk of dementia or whether shared neuropathology between epilepsy and dementia explains the risk.
“In the near future, I plan to enroll participants with late-onset epilepsy in an observational study to better understand factors that may contribute to cognitive change. Collaborations will be key as we seek to further understand what causes these changes and what could be done to prevent them,” Dr. Johnson added.
Strengths and weaknesses
In an accompanying editorial, W. Allen Hauser, MD, professor emeritus of neurology and epidemiology at Columbia University in New York, and colleagues noted that the findings support a bidirectional relationship between dementia and epilepsy, adding that accumulation of amyloid beta peptide is a plausible underlying pathophysiology that may explain this relationship.
Future research should clarify the effect of factors such as seizure type, seizure frequency, and age of onset on the risk of dementia among patients with epilepsy, the editorialists wrote. Such investigations could help elucidate the underlying mechanisms of these conditions and help to improve treatment, they added.
Commenting on the findings, Ilo Leppik, MD, professor of neurology and pharmacy at the University of Minnesota in Minneapolis described the research as “a very well-done study by qualified researchers in the field. … For the last century, medicine has unfortunately become compartmentalized by specialty and then subspecialty. The brain and disorders of the brain do not recognize these silos. … It is not a stretch of the known science to begin to understand that epilepsy and dementia have common anatomical and physiological underpinnings.”
The long period of prospectively gathering data and the measurement of cognitive function through various modalities are among the study’s great strengths, said Dr. Leppik. However, the study’s weakness is its reliance on Medicare claims data, which mainly would reflect convulsive seizures.
“What is missing is how many persons had subtle focal-unaware seizures that may not be identified unless a careful history is taken,” said Dr. Leppik. “Thus, this study likely underestimates the frequency of epilepsy.”
Neurologists who evaluate a person with early dementia should be on the lookout for a history of subtle seizures, said Dr. Leppik. Animal studies suggest treatment with levetiracetam or brivaracetam may slow the course of dementia, and a clinical study in participants with early dementia is underway.
“Treatment with an antiseizure drug may prove to be beneficial, especially if evidence for the presence of subtle epilepsy can be found,” Dr. Leppik added.
Greater collaboration between epileptologists and dementia specialists and larger studies of antiseizure drugs are necessary, he noted. “These studies can incorporate sophisticated structural and biochemical [analyses] to better identify the relationships between brain mechanisms that likely underlie both seizures and dementia. The ultimate promise is that early treatment of seizures may alter the course of dementia,” Dr. Leppik said.
The study by Dr. Johnson and colleagues was supported by a contract from the National Institute on Aging; ARIC from the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the Department of Health & Human Services. The authors and Dr. Leppik have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Results of a retrospective analysis show that patients who develop epilepsy at age 67 or older have a threefold increased risk of subsequent dementia versus their counterparts without epilepsy.
“This is an exciting area, as we are finding that just as the risk of seizures is increased in neurodegenerative diseases, the risk of dementia is increased after late-onset epilepsy and seizures,” study investigator Emily L. Johnson, MD, assistant professor of neurology at Johns Hopkins University, Baltimore, said in an interview. “Several other cohort studies are finding similar results, including the Veterans’ Health Study and the Framingham Study,” she added.
The study was published online Oct. 23 in Neurology
Bidirectional relationship?
Previous research has established that dementia is a risk factor for epilepsy, but recent studies also suggest an increased risk of incident dementia among patients with adult-onset epilepsy. Several risk factors for late-onset epilepsy, including diabetes and hypertension, also are risk factors for dementia. However, the effect of late-onset epilepsy on dementia risk in patients with these comorbidities has not been clarified.
To investigate, the researchers examined data from the Atherosclerosis Risk in Communities (ARIC) study. Participants include Black and White men and women from four U.S. communities. Baseline visits in this longitudinal cohort study began between 1987 and 1989, and follow-up included seven additional visits and regular phone calls.
The investigators identified participants with late-onset epilepsy by searching for Medicare claims related to seizures or epilepsy filed between 1991 and 2015. Those with two or more such claims and age of onset of 67 years or greater were considered to have late-onset epilepsy. Participants with preexisting conditions such as brain tumors or multiple sclerosis were excluded.
ARIC participants who presented in person for visits 2, 4, 5, and 6 underwent cognitive testing with the Delayed Word Recall Test, the Digit Symbol Substitution Test, and the Word Fluency Test.
Testing at visits 5 and 6 also included other tests, such as the Mini-Mental State Examination, the Boston Naming test, and the Wechsler Memory Scale-III. Dr. Johnson and colleagues excluded data for visit 7 from the analysis because dementia adjudication was not yet complete.
The researchers identified participants with dementia using data from visits 5 and 6 and ascertained time of dementia onset through participant and informant interviews, phone calls, and hospital discharge data. Participants also were screened for mild cognitive impairment (MCI) at visits 5 and 6.
Data were analyzed using a Cox proportional hazards model and multinomial logistic regression. In subsequent analyses, researchers adjusted the data for age, sex, race, smoking status, alcohol use, hypertension, diabetes, body mass index (BMI), APOE4 status, and prevalent stroke.
The researchers found that of 9,033 study participants, 671 had late-onset epilepsy. The late-onset epilepsy group was older at baseline (56.5 vs. 55.1 years) and more likely to have hypertension (38.9% vs. 33.3%), diabetes (16.1% vs. 9.6%), and two alleles of APOE4 genotype (3.9% vs. 2.5%), compared with those without the disorder.
In all, 1,687 participants developed dementia during follow-up. The rate of incident dementia was 41.6% in participants with late-onset epilepsy and 16.8% in participants without late-onset epilepsy. The adjusted hazard ratio of subsequent dementia in participants with late-onset epilepsy versus those without the disorder was 3.05 (95% confidence interval, 2.65-3.51).
The median time to dementia ascertainment after late-onset epilepsy was 3.66 years.
Counterintuitive finding
The relationship between late-onset epilepsy and subsequent dementia was stronger in patients without stroke. The investigators offered a possible explanation for this counterintuitive finding. “We observed an interaction between [late-onset epilepsy] and stroke, with a lower (but still substantial) association between [late-onset epilepsy] and dementia in those with a history of stroke. This may be due to the known strong association between stroke and dementia, which may wash out the contributions of [late-onset epilepsy] to cognitive impairment,” the researchers wrote.
“There may also be under-capturing of dementia diagnoses among participants with stroke in the ascertainment from [Centers for Medicare & Medicaid Services] codes, as physicians may be reluctant to make a separate code for ‘dementia’ in those with cognitive impairment after stroke,” they added.
When the researchers restricted the analysis only to participants who attended visits 5 and 6 and had late-onset epilepsy ascertainment available, they found that the relative risk ratio for dementia at visit 6 was 2.90 (95% CI, 1.22-6.92; P = .009). The RRR for MCI was 0.97 (95% CI, 0.39-2.38; P = .803). The greater functional impairment in patients with late-onset epilepsy may explain the lack of a relationship between late-onset epilepsy and MCI.
“It will be important for neurologists to be aware of the possibility of cognitive impairment following late-onset epilepsy and to check in with patients and family members to see if there are concerns,” said Dr. Johnson.
“We should also be talking about the importance of lowering other risk factors for dementia by making sure cardiovascular risk factors are controlled and encouraging physical and cognitive activity,” she added.
The results require confirmation in a clinical population, the investigators noted. In addition, future research is necessary to clarify whether seizures directly increase the risk of dementia or whether shared neuropathology between epilepsy and dementia explains the risk.
“In the near future, I plan to enroll participants with late-onset epilepsy in an observational study to better understand factors that may contribute to cognitive change. Collaborations will be key as we seek to further understand what causes these changes and what could be done to prevent them,” Dr. Johnson added.
Strengths and weaknesses
In an accompanying editorial, W. Allen Hauser, MD, professor emeritus of neurology and epidemiology at Columbia University in New York, and colleagues noted that the findings support a bidirectional relationship between dementia and epilepsy, adding that accumulation of amyloid beta peptide is a plausible underlying pathophysiology that may explain this relationship.
Future research should clarify the effect of factors such as seizure type, seizure frequency, and age of onset on the risk of dementia among patients with epilepsy, the editorialists wrote. Such investigations could help elucidate the underlying mechanisms of these conditions and help to improve treatment, they added.
Commenting on the findings, Ilo Leppik, MD, professor of neurology and pharmacy at the University of Minnesota in Minneapolis described the research as “a very well-done study by qualified researchers in the field. … For the last century, medicine has unfortunately become compartmentalized by specialty and then subspecialty. The brain and disorders of the brain do not recognize these silos. … It is not a stretch of the known science to begin to understand that epilepsy and dementia have common anatomical and physiological underpinnings.”
The long period of prospectively gathering data and the measurement of cognitive function through various modalities are among the study’s great strengths, said Dr. Leppik. However, the study’s weakness is its reliance on Medicare claims data, which mainly would reflect convulsive seizures.
“What is missing is how many persons had subtle focal-unaware seizures that may not be identified unless a careful history is taken,” said Dr. Leppik. “Thus, this study likely underestimates the frequency of epilepsy.”
Neurologists who evaluate a person with early dementia should be on the lookout for a history of subtle seizures, said Dr. Leppik. Animal studies suggest treatment with levetiracetam or brivaracetam may slow the course of dementia, and a clinical study in participants with early dementia is underway.
“Treatment with an antiseizure drug may prove to be beneficial, especially if evidence for the presence of subtle epilepsy can be found,” Dr. Leppik added.
Greater collaboration between epileptologists and dementia specialists and larger studies of antiseizure drugs are necessary, he noted. “These studies can incorporate sophisticated structural and biochemical [analyses] to better identify the relationships between brain mechanisms that likely underlie both seizures and dementia. The ultimate promise is that early treatment of seizures may alter the course of dementia,” Dr. Leppik said.
The study by Dr. Johnson and colleagues was supported by a contract from the National Institute on Aging; ARIC from the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the Department of Health & Human Services. The authors and Dr. Leppik have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM NEUROLOGY
Ibrutinib associated with decreased circulating malignant cells and restored T-cell function in CLL patients
Ibrutinib showed significant impact on circulating malignant and nonmalignant immune cells and was found to restore healthy T-cell function in patients with chronic lymphocytic leukemia (CLL), according to the results of a comparative study of CLL patients and healthy controls.
Researchers compared circulating counts of 21 immune blood cell subsets throughout the first year of treatment in 55 patients with relapsed/refractory (R/R) CLL from the RESONATE trial and 50 previously untreated CLL patients from the RESONATE-2 trial with 20 untreated age-matched healthy donors, according to a report published online in Leukemia Research.
In addition, T-cell function was assessed in response to T-cell–receptor stimulation in 21 patients with R/R CLL, compared with 18 age-matched healthy donors, according to Isabelle G. Solman, MS, an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. and colleagues.
Positive indicators
Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes, according to the researchers.
Ibrutinib also significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets that were examined, they added.
“These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function,” the researchers indicated.
“Ibrutinib has a significant, progressively positive impact on both malignant and nonmalignant immune cells in CLL. These positive effects on circulating nonmalignant immune cells may contribute to long-term CLL disease control, overall health status, and decreased susceptibility to infection,” they concluded.
The study was funded by Pharmacyclics, an AbbVie Company. Ms. Solman is an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. as were several other authors.
SOURCE: Solman IG et al. Leuk Res. 2020;97. doi: 10.1016/j.leukres.2020.106432.
Ibrutinib showed significant impact on circulating malignant and nonmalignant immune cells and was found to restore healthy T-cell function in patients with chronic lymphocytic leukemia (CLL), according to the results of a comparative study of CLL patients and healthy controls.
Researchers compared circulating counts of 21 immune blood cell subsets throughout the first year of treatment in 55 patients with relapsed/refractory (R/R) CLL from the RESONATE trial and 50 previously untreated CLL patients from the RESONATE-2 trial with 20 untreated age-matched healthy donors, according to a report published online in Leukemia Research.
In addition, T-cell function was assessed in response to T-cell–receptor stimulation in 21 patients with R/R CLL, compared with 18 age-matched healthy donors, according to Isabelle G. Solman, MS, an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. and colleagues.
Positive indicators
Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes, according to the researchers.
Ibrutinib also significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets that were examined, they added.
“These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function,” the researchers indicated.
“Ibrutinib has a significant, progressively positive impact on both malignant and nonmalignant immune cells in CLL. These positive effects on circulating nonmalignant immune cells may contribute to long-term CLL disease control, overall health status, and decreased susceptibility to infection,” they concluded.
The study was funded by Pharmacyclics, an AbbVie Company. Ms. Solman is an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. as were several other authors.
SOURCE: Solman IG et al. Leuk Res. 2020;97. doi: 10.1016/j.leukres.2020.106432.
Ibrutinib showed significant impact on circulating malignant and nonmalignant immune cells and was found to restore healthy T-cell function in patients with chronic lymphocytic leukemia (CLL), according to the results of a comparative study of CLL patients and healthy controls.
Researchers compared circulating counts of 21 immune blood cell subsets throughout the first year of treatment in 55 patients with relapsed/refractory (R/R) CLL from the RESONATE trial and 50 previously untreated CLL patients from the RESONATE-2 trial with 20 untreated age-matched healthy donors, according to a report published online in Leukemia Research.
In addition, T-cell function was assessed in response to T-cell–receptor stimulation in 21 patients with R/R CLL, compared with 18 age-matched healthy donors, according to Isabelle G. Solman, MS, an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. and colleagues.
Positive indicators
Ibrutinib significantly decreased pathologically high circulating B cells, regulatory T cells, effector/memory CD4+ and CD8+ T cells (including exhausted and chronically activated T cells), natural killer (NK) T cells, and myeloid-derived suppressor cells; preserved naive T cells and NK cells; and increased circulating classical monocytes, according to the researchers.
Ibrutinib also significantly restored T-cell proliferative ability, degranulation, and cytokine secretion. Over the same period, ofatumumab or chlorambucil did not confer the same spectrum of normalization as ibrutinib in multiple immune subsets that were examined, they added.
“These results establish that ibrutinib has a significant and likely positive impact on circulating malignant and nonmalignant immune cells and restores healthy T-cell function,” the researchers indicated.
“Ibrutinib has a significant, progressively positive impact on both malignant and nonmalignant immune cells in CLL. These positive effects on circulating nonmalignant immune cells may contribute to long-term CLL disease control, overall health status, and decreased susceptibility to infection,” they concluded.
The study was funded by Pharmacyclics, an AbbVie Company. Ms. Solman is an employee of Translational Medicine, Pharmacyclics, Sunnyvale, Calif. as were several other authors.
SOURCE: Solman IG et al. Leuk Res. 2020;97. doi: 10.1016/j.leukres.2020.106432.
FROM LEUKEMIA RESEARCH
Genomic analysis reveals insights into pathogenesis of neuroblastoma
Insights into the genetic drivers of the disease were identified based on data from whole-genome, whole-exome, and/or transcriptome sequencing of tumor samples.
“The comprehensive genome-wide analysis performed here allowed us to discover age-associated alterations in MYCN, TERT, PTPRD, and Ras pathway alterations, which, together with ATRX, represent the majority of common driver gene alterations in neuroblastoma,” wrote study author Samuel W. Brady, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues.
The group’s findings were published in Nature Communications.
The researchers integrated and analyzed data from 702 neuroblastomas encompassing all age and risk categories, with the goal of identifying rare driver events and age-related molecular aberrations. Among the samples, 23 were from patients who had relapsed.
The researchers found that 40% of samples had somatic alterations in known driver genes, with the most common alterations being MYCN (19%; primarily amplification), TERT (17%; structural variations [SVs]), SHANK2 (13%; SVs), PTPRD (11%; SVs and focal deletions), ALK (10%; single nucleotide variants [SNVs] and SVs), and ATRX (8%; multiple mutation types).
MYCN and TERT alterations were more common in younger children (median age of 2.3 years and 3.8 years, respectively), while ATRX alterations were more frequently seen in older patients (median age of 5.6 years).
“These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models,” the researchers wrote.
Furthermore, they found evidence to suggest the COSMIC mutational signature 18 is the most common cause of driver SNVs in neuroblastoma, including most Ras-activating and ALK variants.
Signature 18 was enriched in neuroblastomas with increased expression of mitochondrial ribosome and electron transport–associated genes, 17q gain, and MYCN amplification.
“[T]his mutagenic process, which is caused by ROS [reactive oxygen species] in other settings (though not proven in neuroblastoma), may promote evolution and heterogeneity, as many driver SNVs, such as ALK mutations, are later events in neuroblastoma,” the researchers explained.
Based on these findings, the authors concluded that neuroblastomas with 17q gain may be amenable to precision medicines, possibly through targeting altered mitochondrial function.
“[Our] findings will identify patients who might be eligible for targeted therapy and those that may be at higher risk based on a combination of genetic alterations detected by these genome-wide sequencing methods,” commented study author Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital.
The study was supported by grants from the National Cancer Institute and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. One author disclosed financial affiliations with Y-mabs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon.
SOURCE: Brady SW et al. Nat Commun. 2020 Oct 14. doi: 10.1038/s41467-020-18987-4.
Insights into the genetic drivers of the disease were identified based on data from whole-genome, whole-exome, and/or transcriptome sequencing of tumor samples.
“The comprehensive genome-wide analysis performed here allowed us to discover age-associated alterations in MYCN, TERT, PTPRD, and Ras pathway alterations, which, together with ATRX, represent the majority of common driver gene alterations in neuroblastoma,” wrote study author Samuel W. Brady, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues.
The group’s findings were published in Nature Communications.
The researchers integrated and analyzed data from 702 neuroblastomas encompassing all age and risk categories, with the goal of identifying rare driver events and age-related molecular aberrations. Among the samples, 23 were from patients who had relapsed.
The researchers found that 40% of samples had somatic alterations in known driver genes, with the most common alterations being MYCN (19%; primarily amplification), TERT (17%; structural variations [SVs]), SHANK2 (13%; SVs), PTPRD (11%; SVs and focal deletions), ALK (10%; single nucleotide variants [SNVs] and SVs), and ATRX (8%; multiple mutation types).
MYCN and TERT alterations were more common in younger children (median age of 2.3 years and 3.8 years, respectively), while ATRX alterations were more frequently seen in older patients (median age of 5.6 years).
“These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models,” the researchers wrote.
Furthermore, they found evidence to suggest the COSMIC mutational signature 18 is the most common cause of driver SNVs in neuroblastoma, including most Ras-activating and ALK variants.
Signature 18 was enriched in neuroblastomas with increased expression of mitochondrial ribosome and electron transport–associated genes, 17q gain, and MYCN amplification.
“[T]his mutagenic process, which is caused by ROS [reactive oxygen species] in other settings (though not proven in neuroblastoma), may promote evolution and heterogeneity, as many driver SNVs, such as ALK mutations, are later events in neuroblastoma,” the researchers explained.
Based on these findings, the authors concluded that neuroblastomas with 17q gain may be amenable to precision medicines, possibly through targeting altered mitochondrial function.
“[Our] findings will identify patients who might be eligible for targeted therapy and those that may be at higher risk based on a combination of genetic alterations detected by these genome-wide sequencing methods,” commented study author Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital.
The study was supported by grants from the National Cancer Institute and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. One author disclosed financial affiliations with Y-mabs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon.
SOURCE: Brady SW et al. Nat Commun. 2020 Oct 14. doi: 10.1038/s41467-020-18987-4.
Insights into the genetic drivers of the disease were identified based on data from whole-genome, whole-exome, and/or transcriptome sequencing of tumor samples.
“The comprehensive genome-wide analysis performed here allowed us to discover age-associated alterations in MYCN, TERT, PTPRD, and Ras pathway alterations, which, together with ATRX, represent the majority of common driver gene alterations in neuroblastoma,” wrote study author Samuel W. Brady, PhD, of St. Jude Children’s Research Hospital in Memphis, Tenn., and colleagues.
The group’s findings were published in Nature Communications.
The researchers integrated and analyzed data from 702 neuroblastomas encompassing all age and risk categories, with the goal of identifying rare driver events and age-related molecular aberrations. Among the samples, 23 were from patients who had relapsed.
The researchers found that 40% of samples had somatic alterations in known driver genes, with the most common alterations being MYCN (19%; primarily amplification), TERT (17%; structural variations [SVs]), SHANK2 (13%; SVs), PTPRD (11%; SVs and focal deletions), ALK (10%; single nucleotide variants [SNVs] and SVs), and ATRX (8%; multiple mutation types).
MYCN and TERT alterations were more common in younger children (median age of 2.3 years and 3.8 years, respectively), while ATRX alterations were more frequently seen in older patients (median age of 5.6 years).
“These findings suggest that the sympathetic nervous system, the tissue from which neuroblastoma arises, is susceptible to different oncogenic insults at different times during development, which could be explored in future investigations using animal models,” the researchers wrote.
Furthermore, they found evidence to suggest the COSMIC mutational signature 18 is the most common cause of driver SNVs in neuroblastoma, including most Ras-activating and ALK variants.
Signature 18 was enriched in neuroblastomas with increased expression of mitochondrial ribosome and electron transport–associated genes, 17q gain, and MYCN amplification.
“[T]his mutagenic process, which is caused by ROS [reactive oxygen species] in other settings (though not proven in neuroblastoma), may promote evolution and heterogeneity, as many driver SNVs, such as ALK mutations, are later events in neuroblastoma,” the researchers explained.
Based on these findings, the authors concluded that neuroblastomas with 17q gain may be amenable to precision medicines, possibly through targeting altered mitochondrial function.
“[Our] findings will identify patients who might be eligible for targeted therapy and those that may be at higher risk based on a combination of genetic alterations detected by these genome-wide sequencing methods,” commented study author Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital.
The study was supported by grants from the National Cancer Institute and by the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital. One author disclosed financial affiliations with Y-mabs Therapeutics, Abpro-Labs, Eureka Therapeutics, and Biotec Pharmacon.
SOURCE: Brady SW et al. Nat Commun. 2020 Oct 14. doi: 10.1038/s41467-020-18987-4.
FROM NATURE COMMUNICATIONS
Guideline Concordance with Durvalumab in Unresectable Stage III Non-Small Cell Lung Cancer: A Single Center Veterans Hospital Experience
The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).1 After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.4 Adherence to guidelines have been shown to improve patient survival across several cancer types.5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.8,9
Stage III NSCLC is associated with poor survival rates.10 Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.4 Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.11 Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.11
A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.11
Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.
Methods
The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.
The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.
This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.
Results
A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.
The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.
CRT Patients
The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.
Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.
Durvalumab Treatment
After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.
Discussion
NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.3
Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.4 Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.2 Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.
Clinical Trials vs Real World
The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.12 In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.13
Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.14
A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.1 These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.
Limitations
Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.15 Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.19 Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.
Conlcusions
This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.
Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.12 It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.
1. US Food and Drug Administration. FDA approves durvalumab after chemoradiation for unresectable stage II. Published February 20, 2018. Accessed October 9, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-after-chemoradiation-unresectable-stage-iii-nsclc
2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937
3. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697
4. Ettinger DS, Wood DE, Aisner DL et al. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. Version8.2020. Updated September 15, 2020. Accessed October 9, 2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
5. Bristow RE, Chang J, Ziogas A, Campos B, Chavez LR, Anton-Culver H. Impact of National Cancer Institute Comprehensive Cancer Centers on ovarian cancer treatment and survival. J Am Coll Surg. 2015;220(5):940-950. doi:10.1016/j.jamcollsurg.2015.01.056
6. Boland GM, Chang GJ, Haynes AB, et al. Association between adherence to National Comprehensive Cancer Network treatment guidelines and improved survival in patients with colon cancer. Cancer. 2013;119(8):1593-1601. doi:10.1002/cncr.27935
7. Schwentner L, Wöckel A, König J, et al. Adherence to treatment guidelines and survival in triple-negative breast cancer: a retrospective multi-center cohort study with 9,156 patients. BMC Cancer. 2013;13:487. Published 2013 Oct 21. doi:10.1186/1471-2407-13-487
8. Jazieh A, Alkaiyat MO, Ali Y, Hashim MA, Abdelhafiz N, Al Olayan A. Improving adherence to lung cancer guidelines: a quality improvement project that uses chart review, audit and feedback approach. BMJ Open Qual. 2019;8(3):e000436. Published 2019 Aug 26. doi:10.1136/bmjoq-2018-000436
9. Shaverdian N, Offin MD, Rimner A, et al. Utilization and factors precluding the initiation of consolidative durvalumab in unresectable stage III non-small cell lung cancer. Radiother Oncol. 2020;144:101-104. doi:10.1016/j.radonc.2019.11.015
10. National Cancer Institute. SEER cancer statistics review, 1975-2015, Table 15.1 cancer of the lung and bronchus. Accessed October 19, 2020 https://seer.cancer.gov/archive/csr/1975_2015/results_merged/sect_15_lung_bronchus.pdf. Updated September 10, 2018
11. Passaro A, Spitaleri G, Gyawali B, de Marinis F. Immunotherapy in non-small-cell lung cancer patients with performance status 2: clinical decision making with scant evidence. J Clin Oncol. 2019;37(22):1863-1867. doi:10.1200/JCO.18.02118
12. Driessen EJM, Janssen-Heijnen MLG, Maas HA, Dingemans AC, van Loon JGM. Study protocol of the NVALT25-ELDAPT trial: selecting the optimal treatment for older patients with stage III non-small-cell lung cancer. Clin Lung Cancer. 2018;19(6):e849-e852. doi:10.1016/j.cllc.2018.07.003
13. Schulkes KJ, Nguyen C, van den Bos F, van Elden LJ, Hamaker ME. Selection of Patients in Ongoing Clinical Trials on Lung Cancer. Lung. 2016;194(6):967-974. doi:10.1007/s00408-016-9943-7
14. Blonde L, Khunti K, Harris SB, Meizinger C, Skolnik NS. Interpretation and impact of real-world clinical data for the practicing clinician. Adv Ther. 2018;35(11):1763-1774. doi:10.1007/s12325-018-0805-y
15. Garrison LP Jr, Neumann PJ, Erickson P, Marshall D, Mullins CD. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value Health. 2007;10(5):326-335. doi:10.1111/j.1524-4733.2007.00186.x
16. Assari S. Veterans and risk of heart disease in the United States: a cohort with 20 years of follow up. Int J Prev Med. 2014;5(6):703-709.
17. Shahoumian TA, Phillips BR, Backus LI. Cigarette smoking, reduction and quit attempts: prevalence among veterans with coronary heart disease. Prev Chronic Dis. 2016;13:E41. Published 2016 Mar 24. doi:10.5888/pcd13.150282
18. Murphy DE, Chaudhry Z, Almoosa KF, Panos RJ. High prevalence of chronic obstructive pulmonary disease among veterans in the urban midwest. Mil Med. 2011;176(5):552-560. doi:10.7205/milmed-d-10-00377
19. Kozel FA, Didehbani N, DeLaRosa B, et al. Factors impacting functional status in veterans of recent conflicts with PTSD. J Neuropsychiatry Clin Neurosci. 2016;28(2):112-117. doi:10.1176/appi.neuropsych.15070183
The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).1 After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.4 Adherence to guidelines have been shown to improve patient survival across several cancer types.5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.8,9
Stage III NSCLC is associated with poor survival rates.10 Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.4 Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.11 Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.11
A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.11
Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.
Methods
The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.
The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.
This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.
Results
A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.
The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.
CRT Patients
The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.
Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.
Durvalumab Treatment
After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.
Discussion
NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.3
Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.4 Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.2 Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.
Clinical Trials vs Real World
The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.12 In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.13
Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.14
A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.1 These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.
Limitations
Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.15 Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.19 Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.
Conlcusions
This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.
Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.12 It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.
The US Food and Drug Administration (FDA) approved the use of durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy (CRT).1 After 2 randomized phase 3 studies in 2017 and 2018 showed significant progression-free and overall survival respectively,2,3 durvalumab became a category 1 recommendation for the above indication per National Comprehensive Cancer Network (NCCN) guidelines.4 Adherence to guidelines have been shown to improve patient survival across several cancer types.5-7 However, guideline adherence rates have been variable across health institutions. Therefore, further study is warranted to evaluate nonadherent practices with the goal of improving the quality of cancer care delivery.8,9
Stage III NSCLC is associated with poor survival rates.10 Concurrent CRT remains the standard of care in patients with good performance status based on clinical trial populations.4 Lung cancer remains a disease of the elderly, with a median age at diagnosis of 70 years.11 Discrepancies in the treatment of lung cancer in older adults can vary widely due to a lack of evidence surrounding the treatment in those who have comorbidities and poor performance status, widening the gap between clinical trial and real-world populations.11
A recent review by Passaro and colleagues revealed that at least 11 pivotal randomized controlled trials have shown the activity of immune checkpoint inhibitors (ICI) in locally advanced and metastatic lung cancer. However, these studies have mostly excluded patients with a performance status of the Eastern Cooperative Oncology Group (ECOG) level ≥ 2.11
Durvalumab is one of many new therapies to enter clinical practice to demonstrate survival benefit, but its use among veterans with stage III NSCLC in adherence with National Comprehensive Cancer Network (NCCN) guidelines was not robust at the Birmingham Veterans Affairs Medical Center (VAMC) in Alabama. Therefore, we decided to study the level of adherence and to identify barriers to conformity to the category 1 NCCN recommendations.
Methods
The Birmingham VAMC Outpatient Oncology Clinic billing data identified all individuals diagnosed with lung cancer treated between October 2017 and August 2019. Patients who did not have NSCLC that was stage III and unresectable were excluded from our study. Patients who did not receive a majority of their treatment at US Department of Veterans Affairs (VA) facilities were excluded as well. Each patient’s demographic, functional level, and tumor characteristics during the treatment planning phase and follow-up visits were obtained. Two investigators who evaluated health care provider documentation using the VA Computerized Patient Record System (CPRS) conducted chart reviews.
The primary outcomes were the proportion of patients who received concurrent CRT and the proportion who received durvalumab consolidation. Our chart review also categorized reasons for nonreceipt of concurrent CRT and subsequent durvalumab. Documented reasons for guideline discordancy were generated empirically and broadly. We noted if documentation was unclear and included reasons for why a veteran was not a candidate for CRT, the presence of toxicities associated with CRT, and a patient’s refusal for therapy despite medical advice. Descriptive data were analyzed for all clinical or demographic characteristics and outcomes.
This was considered an internal quality improvement initiative. As such, Birmingham VAMC did not require institutional review board approval for the study. The facility is accredited by the American College of Surgeons Commission on Cancer.
Results
A total of 41 veterans with stage III NSCLC were identified to have established care in the Birmingham VAMC Oncology Clinic between October 2017 and August 2019. Of these, 7 received the majority of their treatment from community-based non-VA facilities and 14 were not candidates for CRT and were excluded from this study.
The mean (SD) age of study participants was 70.0 (8.4) years (range, 57 to 92 years). Most of the study veterans (33; 97.1%) were male and 20 (58.8%) were African American (Table). Eighteen (53%) of study participants had clinical stage IIIa NSCLC; 19 (56%) showed a squamous subtype of NSCLC. A majority (53%) of the veterans studied were evaluated to be functionally fit with an ECOG status of 0 to 1, although documentation of ECOG status was lacking in 5 (14.7%) patients in the initial treatment planning visit records. It was unclear if performance status had been reevaluated and changes noted over the course of concurrent CRT.
CRT Patients
The relative distribution of veterans who underwent CRT for stage III NSCLC plus the reasons they did not receive guideline-based treatment with durvalumab is shown in the Figure. Fourteen patients (41%) were inappropriate candidates for CRT; the most common reason for this was their poor performance status upon initial evaluation and 3 patients (8.8%) in the study had extensive disease or were upstaged upon follow-up clinic visit.
Twenty (59%) veterans in the study initiated CRT. However, only 16 (47.1%) completed CRT. Those who dropped out of CRT did so because of toxicities that included various cytopenia, gastrointestinal toxicities due to radiation and/or chemotherapy, or failure to thrive.
Durvalumab Treatment
After initiation of CRT, 9 (26.5%) patients did not go on to receive durvalumab. Three patients (8.8%) suffered toxicities during CRT. One study patient was found to have a severe respiratory infection requiring intensive care unit admission. Another study patient was found to have a new sternal lesion on follow-up positron emission tomography. One declined because of a history of severe antineutrophil cytoplasmic antibodies vasculitis, which made durvalumab use unsafe. Three patients (8.8%) declined treatment with CRT or durvalumab because of personal preference. Documentation was unclear as to why durvalumab was prescribed to one patient who had completed CRT.
Discussion
NCCN guidelines on the use of durvalumab in NSCLC are based on the phase 3 PACIFIC placebo-controlled randomized clinical trial. This trial, which included only patients with documented performance status of ECOG 0 or 1, reported that grade 3 or 4 events occurred in 30.5% of patients randomized to consolidative durvalumab. Treatment was discontinued in 15.4% of patients due to adverse events.3
Our study examined consolidation therapy with durvalumab in patients with unresectable stage III NSCLC with an ECOG performance status of 0 to 1 who had not progressed after 2 or more cycles of definitive concurrent CRT.4 Patients with previous exposure to immunotherapy, a history of immunodeficiency, active infection, unresolved toxicity from CRT, autoimmune disease, and patients who received sequential CRT were excluded.2 Surprisingly, the adherence rate to guidelines was close to 100% with appropriate documentation and justification of CRT initiation and durvalumab use. Five (14.7%) of veterans with unresectable stage III NSCLC did not have clear documentation of ECOG status on initial visit and only 1 veteran who completed CRT did not have clear documentation as to why durvalumab was not provided. Unfortunately, 23 (68.6%) veterans in the study were unable to receive durvalumab, a potentially disease-modifying drug; nearly one-third (10) of veterans were deemed poor candidates for concurrent CRT despite the fact that 52.9% (18) of veterans in the study had a documented ECOG of 0 or 1 on initial evaluation.
Clinical Trials vs Real World
The heterogeneity between anticipated study populations, those who were able to receive durvalumab in the PACIFIC trial, compared with our observed real-world veteran population, likely stems from the lack of information about how comorbidity and fitness can affect the choice of therapeutic intervention in patients with lung cancer.12 In addition, older adults who participated in randomized controlled trials (RCTs) are not representative of the average older adult who presents to medical oncology clinics, making the application of guideline concordant care difficult.13
Similar real-world observations parallel to our analyses have confirmed, complemented and/or refuted findings of RCTs, and have helped impact the treatment of multiple acute and chronic conditions including influenza, cardiovascular disease, and diabetes.14
A component of socioeconomic barriers and access to supportive care played roles in the decisions of certain patients who chose not to undergo concurrent CRT despite medical advice. These 2 obstacles also affected the decision making for some in the study when considering the use of durvalumab (administered by a 60-minute IV infusion every 2 weeks for 1 year) per recommended guidelines.1 These hurdles need further study in the context of their effect on quality of life and the difficulties generated by various social determinants of health.
Limitations
Study limitations included the biased and confounding factors previously described about retrospective and nonrandomized observational studies that are controlled for during RCTs.15 Electronic health record data may have been incorrectly collected resulting in missing or wrong data points that affect the validity of our conclusion. Recall bias with regard to documentation by health care providers describing reasons why CRT or durvalumab were not initiated or the patient’s ability to recall previous treatments and report ECOG status or toxicities also may have impacted our findings. Comorbidities and poor performance status, frequently occurring among veterans, negatively impact cancer treatment decisions and may result in a detection bias. For example, tobacco use, cardiovascular disease, including heart failure, and chronic obstructive pulmonary disease, are notoriously higher in the US veteran population when compared with civilian cohorts.16-18 Also, veterans with poorly controlled depression and posttraumatic stress disorder resulting in functional impairment are a factor.19 Steps were taken to address some of these biases by performing repeat checks of tabulated data and employing 2 independent reviewers to evaluate all relevant clinical documentation, compare results, and reach a consensus.
Conlcusions
This retrospective analysis of adherence to category 1 NCCN guidelines for durvalumab use among patients at the Birmingham VAMC Oncology Clinic reinforced our practice and identified minor deficiencies in documentation that would impact future clinical visits. More importantly, it depicted the massive disparity in treatment candidacy among Birmingham veterans compared with clinical trial populations. Efforts will be made to address factors impacting a veteran’s candidacy for CRT and explore other variables such as socioeconomic barriers to treatment. Multiple complementary tools to assess patients’ frailty, such as the Charlson Comorbidity Index (CCI), are now being used for a variety of disorders including cancers. More robust data and standardization are needed to validate the use of these assessments in predicting response to immune checkpoint inhibitors.
Immune checkpoint inhibitors are currently being evaluated in stage III NSCLC studies and may be implemented as routine practice in the future.12 It is important to distinguish fit from frail veterans with lung cancer for treatment selection. We would like to see the expansion of the eligibility criteria for clinical trials to include patients with a performance status of ECOG 2 in order for results to be truly generalizable to the real-world population. Our hope is that such work will improve not only the quality of lung cancer care, but also the quality of care across multiple tumor types.
1. US Food and Drug Administration. FDA approves durvalumab after chemoradiation for unresectable stage II. Published February 20, 2018. Accessed October 9, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-after-chemoradiation-unresectable-stage-iii-nsclc
2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937
3. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697
4. Ettinger DS, Wood DE, Aisner DL et al. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. Version8.2020. Updated September 15, 2020. Accessed October 9, 2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
5. Bristow RE, Chang J, Ziogas A, Campos B, Chavez LR, Anton-Culver H. Impact of National Cancer Institute Comprehensive Cancer Centers on ovarian cancer treatment and survival. J Am Coll Surg. 2015;220(5):940-950. doi:10.1016/j.jamcollsurg.2015.01.056
6. Boland GM, Chang GJ, Haynes AB, et al. Association between adherence to National Comprehensive Cancer Network treatment guidelines and improved survival in patients with colon cancer. Cancer. 2013;119(8):1593-1601. doi:10.1002/cncr.27935
7. Schwentner L, Wöckel A, König J, et al. Adherence to treatment guidelines and survival in triple-negative breast cancer: a retrospective multi-center cohort study with 9,156 patients. BMC Cancer. 2013;13:487. Published 2013 Oct 21. doi:10.1186/1471-2407-13-487
8. Jazieh A, Alkaiyat MO, Ali Y, Hashim MA, Abdelhafiz N, Al Olayan A. Improving adherence to lung cancer guidelines: a quality improvement project that uses chart review, audit and feedback approach. BMJ Open Qual. 2019;8(3):e000436. Published 2019 Aug 26. doi:10.1136/bmjoq-2018-000436
9. Shaverdian N, Offin MD, Rimner A, et al. Utilization and factors precluding the initiation of consolidative durvalumab in unresectable stage III non-small cell lung cancer. Radiother Oncol. 2020;144:101-104. doi:10.1016/j.radonc.2019.11.015
10. National Cancer Institute. SEER cancer statistics review, 1975-2015, Table 15.1 cancer of the lung and bronchus. Accessed October 19, 2020 https://seer.cancer.gov/archive/csr/1975_2015/results_merged/sect_15_lung_bronchus.pdf. Updated September 10, 2018
11. Passaro A, Spitaleri G, Gyawali B, de Marinis F. Immunotherapy in non-small-cell lung cancer patients with performance status 2: clinical decision making with scant evidence. J Clin Oncol. 2019;37(22):1863-1867. doi:10.1200/JCO.18.02118
12. Driessen EJM, Janssen-Heijnen MLG, Maas HA, Dingemans AC, van Loon JGM. Study protocol of the NVALT25-ELDAPT trial: selecting the optimal treatment for older patients with stage III non-small-cell lung cancer. Clin Lung Cancer. 2018;19(6):e849-e852. doi:10.1016/j.cllc.2018.07.003
13. Schulkes KJ, Nguyen C, van den Bos F, van Elden LJ, Hamaker ME. Selection of Patients in Ongoing Clinical Trials on Lung Cancer. Lung. 2016;194(6):967-974. doi:10.1007/s00408-016-9943-7
14. Blonde L, Khunti K, Harris SB, Meizinger C, Skolnik NS. Interpretation and impact of real-world clinical data for the practicing clinician. Adv Ther. 2018;35(11):1763-1774. doi:10.1007/s12325-018-0805-y
15. Garrison LP Jr, Neumann PJ, Erickson P, Marshall D, Mullins CD. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value Health. 2007;10(5):326-335. doi:10.1111/j.1524-4733.2007.00186.x
16. Assari S. Veterans and risk of heart disease in the United States: a cohort with 20 years of follow up. Int J Prev Med. 2014;5(6):703-709.
17. Shahoumian TA, Phillips BR, Backus LI. Cigarette smoking, reduction and quit attempts: prevalence among veterans with coronary heart disease. Prev Chronic Dis. 2016;13:E41. Published 2016 Mar 24. doi:10.5888/pcd13.150282
18. Murphy DE, Chaudhry Z, Almoosa KF, Panos RJ. High prevalence of chronic obstructive pulmonary disease among veterans in the urban midwest. Mil Med. 2011;176(5):552-560. doi:10.7205/milmed-d-10-00377
19. Kozel FA, Didehbani N, DeLaRosa B, et al. Factors impacting functional status in veterans of recent conflicts with PTSD. J Neuropsychiatry Clin Neurosci. 2016;28(2):112-117. doi:10.1176/appi.neuropsych.15070183
1. US Food and Drug Administration. FDA approves durvalumab after chemoradiation for unresectable stage II. Published February 20, 2018. Accessed October 9, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-after-chemoradiation-unresectable-stage-iii-nsclc
2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937
3. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697
4. Ettinger DS, Wood DE, Aisner DL et al. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. Version8.2020. Updated September 15, 2020. Accessed October 9, 2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
5. Bristow RE, Chang J, Ziogas A, Campos B, Chavez LR, Anton-Culver H. Impact of National Cancer Institute Comprehensive Cancer Centers on ovarian cancer treatment and survival. J Am Coll Surg. 2015;220(5):940-950. doi:10.1016/j.jamcollsurg.2015.01.056
6. Boland GM, Chang GJ, Haynes AB, et al. Association between adherence to National Comprehensive Cancer Network treatment guidelines and improved survival in patients with colon cancer. Cancer. 2013;119(8):1593-1601. doi:10.1002/cncr.27935
7. Schwentner L, Wöckel A, König J, et al. Adherence to treatment guidelines and survival in triple-negative breast cancer: a retrospective multi-center cohort study with 9,156 patients. BMC Cancer. 2013;13:487. Published 2013 Oct 21. doi:10.1186/1471-2407-13-487
8. Jazieh A, Alkaiyat MO, Ali Y, Hashim MA, Abdelhafiz N, Al Olayan A. Improving adherence to lung cancer guidelines: a quality improvement project that uses chart review, audit and feedback approach. BMJ Open Qual. 2019;8(3):e000436. Published 2019 Aug 26. doi:10.1136/bmjoq-2018-000436
9. Shaverdian N, Offin MD, Rimner A, et al. Utilization and factors precluding the initiation of consolidative durvalumab in unresectable stage III non-small cell lung cancer. Radiother Oncol. 2020;144:101-104. doi:10.1016/j.radonc.2019.11.015
10. National Cancer Institute. SEER cancer statistics review, 1975-2015, Table 15.1 cancer of the lung and bronchus. Accessed October 19, 2020 https://seer.cancer.gov/archive/csr/1975_2015/results_merged/sect_15_lung_bronchus.pdf. Updated September 10, 2018
11. Passaro A, Spitaleri G, Gyawali B, de Marinis F. Immunotherapy in non-small-cell lung cancer patients with performance status 2: clinical decision making with scant evidence. J Clin Oncol. 2019;37(22):1863-1867. doi:10.1200/JCO.18.02118
12. Driessen EJM, Janssen-Heijnen MLG, Maas HA, Dingemans AC, van Loon JGM. Study protocol of the NVALT25-ELDAPT trial: selecting the optimal treatment for older patients with stage III non-small-cell lung cancer. Clin Lung Cancer. 2018;19(6):e849-e852. doi:10.1016/j.cllc.2018.07.003
13. Schulkes KJ, Nguyen C, van den Bos F, van Elden LJ, Hamaker ME. Selection of Patients in Ongoing Clinical Trials on Lung Cancer. Lung. 2016;194(6):967-974. doi:10.1007/s00408-016-9943-7
14. Blonde L, Khunti K, Harris SB, Meizinger C, Skolnik NS. Interpretation and impact of real-world clinical data for the practicing clinician. Adv Ther. 2018;35(11):1763-1774. doi:10.1007/s12325-018-0805-y
15. Garrison LP Jr, Neumann PJ, Erickson P, Marshall D, Mullins CD. Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report. Value Health. 2007;10(5):326-335. doi:10.1111/j.1524-4733.2007.00186.x
16. Assari S. Veterans and risk of heart disease in the United States: a cohort with 20 years of follow up. Int J Prev Med. 2014;5(6):703-709.
17. Shahoumian TA, Phillips BR, Backus LI. Cigarette smoking, reduction and quit attempts: prevalence among veterans with coronary heart disease. Prev Chronic Dis. 2016;13:E41. Published 2016 Mar 24. doi:10.5888/pcd13.150282
18. Murphy DE, Chaudhry Z, Almoosa KF, Panos RJ. High prevalence of chronic obstructive pulmonary disease among veterans in the urban midwest. Mil Med. 2011;176(5):552-560. doi:10.7205/milmed-d-10-00377
19. Kozel FA, Didehbani N, DeLaRosa B, et al. Factors impacting functional status in veterans of recent conflicts with PTSD. J Neuropsychiatry Clin Neurosci. 2016;28(2):112-117. doi:10.1176/appi.neuropsych.15070183
A skin test for Parkinson’s disease diagnosis?
a new study suggests. For the study, researchers used a chemical assay to detect clumping of the protein alpha-synuclein, a hallmark of Parkinson’s disease, in autopsy skin samples taken from patients who had Parkinson’s disease confirmed by brain pathology and from controls without the disease. The test showed a high degree of sensitivity and specificity for the diagnosis of Parkinson’s disease.
The study was published online in Movement Disorders.
“This test has a lot of promise,” said senior author Anumantha Kanthasamy, PhD, professor of biomedical sciences at Iowa State University in Ames. “At present there are no peripheral biomarkers for Parkinson’s disease. The current diagnosis is just based on symptoms, and the symptoms can be similar to many other neurological diseases,” he added. “It can take many years to establish a correct diagnosis and the accuracy is low even with experienced neurologists.”
If the current results can be replicated in samples from live patients and in those with very early stages of Parkinson’s disease, a skin test could allow early diagnosis and the possibility of starting preventive treatments to slow disease progression before symptoms develop too severely, the researchers suggest.
Sensitive and specific test
The blinded study used a seeding assay – used previously to detect misfolded proteins in prion diseases – to analyze 50 skin samples provided by the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program based at Banner Sun Health Research Institute in Sun City.
Half of the skin samples came from patients with Parkinson’s disease and half came from people without neurologic disease. The protein assay correctly diagnosed 24 out of 25 patients with Parkinson’s disease and only one of the 25 controls had the protein clumping.
“At present, the only way to definitely diagnose Parkinson’s disease is on autopsy – by the detection of alpha-synuclein clumps [Lewy bodies] in the brain,” commented Charles Adler, MD, professor of neurology at Mayo Clinic Arizona in Scottsdale and a coinvestigator of the study. “In our research, we have also seen clumping of alpha-synuclein in many other organs including submandibular gland, colon, skin, heart, and stomach, but in terms of access, the skin is probably the easiest source.”
In this study, “we found this seeding assay for alpha-synuclein clumps to be extremely sensitive and specific in the diagnosis of Parkinson’s disease,” he added. “This is very valuable data as we have samples from patients with autopsy-validated Parkinson’s disease.”
A reliable biomarker?
The researchers are now starting a study in living patients with funding from the National Institutes of Health in which they will repeat the process comparing skin samples from patients with clinically diagnosed Parkinson’s disease and controls.
“We need to know whether analyzing alpha-synuclein clumping in skin biopsies from live patients with Parkinson’s disease would serve as a reliable biomarker for disease progression. Will clumping of this protein in skin samples increase over time and does it correspond with disease progression?” Dr. Adler said.
In future they are also hoping to test individuals who have not yet developed Parkinson’s disease but may have some prodromal type symptoms and to test whether this assay could measure a treatment effect of drug therapy.
Dr. Adler noted that they are currently conducting an autopsy study of skin samples from individuals who did not have clinical Parkinson’s disease when alive but in whom Lewy bodies have been found postmortem.
“This suggests that the disease pathology starts before Parkinson’s symptoms develop, and in the future, if we can diagnose Parkinson’s disease earlier then we may be able to stop progression,” he said.
“There is a long list of compounds that have been studied to try and slow progression but haven’t shown benefits, but by the time patients develop symptoms they already have significant disease and [have] lost most of their dopamine neurons,” he added. “If we could backtrack by 10 years, then these drugs may well make a difference.”
Dr. Adler also noted that currently more advanced patients may undergo invasive procedures such as deep brain stimulation or surgery. “It is of utmost importance that they have an accurate diagnosis before being subjected to such procedures.”
In addition, he pointed out that an accurate test would help the drug development process. “It is vitally important to enroll patients with an accurate diagnosis in clinical trials of new drugs. At present, a large percentage of patients in these trials may not actually have Parkinson’s disease, which makes it very difficult to show a treatment effect.”
Important step, but preliminary
Commenting on the research, James Beck, PhD, chief scientific officer of the Parkinson’s Foundation, said the study “is an important step toward the creation of a new way to potentially diagnose Parkinson’s disease.”
But he cautioned that this is a preliminary study. “To really confirm the possibility of using this approach for diagnosing Parkinson’s disease, a larger study will be necessary. And it will be important to test this in a population with early disease – the most difficult group to accurately diagnose.”
Also commenting on the findings, Beate Ritz, MD, PhD, an epidemiologist at UCLA Fielding School of Public Health in Los Angeles, who is part of a team also working on ways to measure abnormal alpha-synuclein to diagnose Parkinson’s disease, described the current study of skin samples as “pretty nifty.”
“Their research shows clearly that they can distinguish between patients with Parkinson’s disease and controls in this way,” she said. “The big advantage of this study is that they have brain pathology, so they know exactly which individuals had Parkinson’s disease.”
Dr. Ritz is working with Gal Bitan, PhD, from the UCLA Brain Research Institute on a potential blood test to measure abnormal alpha-synuclein.
Dr. Ritz explained that it is not possible to measure alpha-synuclein pathology in regular blood samples as it is expressed normally in red blood cells, but they are measuring the protein and its more toxic phosphorylated form from exosomes, which contain the waste discarded by cells using technology that determines the origin of these exosomes.
“Alpha-synuclein itself is not a problem. It is the way it misfolds that causes toxicity and disrupts the workings of the cell,” Dr. Ritz added. “In Parkinson’s disease, it is particularly toxic to dopaminergic neurons, and in multiple system atrophy, it is toxic to glial cells, so if we can identify the source of the protein then that could be helpful.”
The study was funded by the National Institutes of Health and the US Army Medical Research Materiel Command. The study authors, Dr. Beck, and Dr. Ritz have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new study suggests. For the study, researchers used a chemical assay to detect clumping of the protein alpha-synuclein, a hallmark of Parkinson’s disease, in autopsy skin samples taken from patients who had Parkinson’s disease confirmed by brain pathology and from controls without the disease. The test showed a high degree of sensitivity and specificity for the diagnosis of Parkinson’s disease.
The study was published online in Movement Disorders.
“This test has a lot of promise,” said senior author Anumantha Kanthasamy, PhD, professor of biomedical sciences at Iowa State University in Ames. “At present there are no peripheral biomarkers for Parkinson’s disease. The current diagnosis is just based on symptoms, and the symptoms can be similar to many other neurological diseases,” he added. “It can take many years to establish a correct diagnosis and the accuracy is low even with experienced neurologists.”
If the current results can be replicated in samples from live patients and in those with very early stages of Parkinson’s disease, a skin test could allow early diagnosis and the possibility of starting preventive treatments to slow disease progression before symptoms develop too severely, the researchers suggest.
Sensitive and specific test
The blinded study used a seeding assay – used previously to detect misfolded proteins in prion diseases – to analyze 50 skin samples provided by the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program based at Banner Sun Health Research Institute in Sun City.
Half of the skin samples came from patients with Parkinson’s disease and half came from people without neurologic disease. The protein assay correctly diagnosed 24 out of 25 patients with Parkinson’s disease and only one of the 25 controls had the protein clumping.
“At present, the only way to definitely diagnose Parkinson’s disease is on autopsy – by the detection of alpha-synuclein clumps [Lewy bodies] in the brain,” commented Charles Adler, MD, professor of neurology at Mayo Clinic Arizona in Scottsdale and a coinvestigator of the study. “In our research, we have also seen clumping of alpha-synuclein in many other organs including submandibular gland, colon, skin, heart, and stomach, but in terms of access, the skin is probably the easiest source.”
In this study, “we found this seeding assay for alpha-synuclein clumps to be extremely sensitive and specific in the diagnosis of Parkinson’s disease,” he added. “This is very valuable data as we have samples from patients with autopsy-validated Parkinson’s disease.”
A reliable biomarker?
The researchers are now starting a study in living patients with funding from the National Institutes of Health in which they will repeat the process comparing skin samples from patients with clinically diagnosed Parkinson’s disease and controls.
“We need to know whether analyzing alpha-synuclein clumping in skin biopsies from live patients with Parkinson’s disease would serve as a reliable biomarker for disease progression. Will clumping of this protein in skin samples increase over time and does it correspond with disease progression?” Dr. Adler said.
In future they are also hoping to test individuals who have not yet developed Parkinson’s disease but may have some prodromal type symptoms and to test whether this assay could measure a treatment effect of drug therapy.
Dr. Adler noted that they are currently conducting an autopsy study of skin samples from individuals who did not have clinical Parkinson’s disease when alive but in whom Lewy bodies have been found postmortem.
“This suggests that the disease pathology starts before Parkinson’s symptoms develop, and in the future, if we can diagnose Parkinson’s disease earlier then we may be able to stop progression,” he said.
“There is a long list of compounds that have been studied to try and slow progression but haven’t shown benefits, but by the time patients develop symptoms they already have significant disease and [have] lost most of their dopamine neurons,” he added. “If we could backtrack by 10 years, then these drugs may well make a difference.”
Dr. Adler also noted that currently more advanced patients may undergo invasive procedures such as deep brain stimulation or surgery. “It is of utmost importance that they have an accurate diagnosis before being subjected to such procedures.”
In addition, he pointed out that an accurate test would help the drug development process. “It is vitally important to enroll patients with an accurate diagnosis in clinical trials of new drugs. At present, a large percentage of patients in these trials may not actually have Parkinson’s disease, which makes it very difficult to show a treatment effect.”
Important step, but preliminary
Commenting on the research, James Beck, PhD, chief scientific officer of the Parkinson’s Foundation, said the study “is an important step toward the creation of a new way to potentially diagnose Parkinson’s disease.”
But he cautioned that this is a preliminary study. “To really confirm the possibility of using this approach for diagnosing Parkinson’s disease, a larger study will be necessary. And it will be important to test this in a population with early disease – the most difficult group to accurately diagnose.”
Also commenting on the findings, Beate Ritz, MD, PhD, an epidemiologist at UCLA Fielding School of Public Health in Los Angeles, who is part of a team also working on ways to measure abnormal alpha-synuclein to diagnose Parkinson’s disease, described the current study of skin samples as “pretty nifty.”
“Their research shows clearly that they can distinguish between patients with Parkinson’s disease and controls in this way,” she said. “The big advantage of this study is that they have brain pathology, so they know exactly which individuals had Parkinson’s disease.”
Dr. Ritz is working with Gal Bitan, PhD, from the UCLA Brain Research Institute on a potential blood test to measure abnormal alpha-synuclein.
Dr. Ritz explained that it is not possible to measure alpha-synuclein pathology in regular blood samples as it is expressed normally in red blood cells, but they are measuring the protein and its more toxic phosphorylated form from exosomes, which contain the waste discarded by cells using technology that determines the origin of these exosomes.
“Alpha-synuclein itself is not a problem. It is the way it misfolds that causes toxicity and disrupts the workings of the cell,” Dr. Ritz added. “In Parkinson’s disease, it is particularly toxic to dopaminergic neurons, and in multiple system atrophy, it is toxic to glial cells, so if we can identify the source of the protein then that could be helpful.”
The study was funded by the National Institutes of Health and the US Army Medical Research Materiel Command. The study authors, Dr. Beck, and Dr. Ritz have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new study suggests. For the study, researchers used a chemical assay to detect clumping of the protein alpha-synuclein, a hallmark of Parkinson’s disease, in autopsy skin samples taken from patients who had Parkinson’s disease confirmed by brain pathology and from controls without the disease. The test showed a high degree of sensitivity and specificity for the diagnosis of Parkinson’s disease.
The study was published online in Movement Disorders.
“This test has a lot of promise,” said senior author Anumantha Kanthasamy, PhD, professor of biomedical sciences at Iowa State University in Ames. “At present there are no peripheral biomarkers for Parkinson’s disease. The current diagnosis is just based on symptoms, and the symptoms can be similar to many other neurological diseases,” he added. “It can take many years to establish a correct diagnosis and the accuracy is low even with experienced neurologists.”
If the current results can be replicated in samples from live patients and in those with very early stages of Parkinson’s disease, a skin test could allow early diagnosis and the possibility of starting preventive treatments to slow disease progression before symptoms develop too severely, the researchers suggest.
Sensitive and specific test
The blinded study used a seeding assay – used previously to detect misfolded proteins in prion diseases – to analyze 50 skin samples provided by the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program based at Banner Sun Health Research Institute in Sun City.
Half of the skin samples came from patients with Parkinson’s disease and half came from people without neurologic disease. The protein assay correctly diagnosed 24 out of 25 patients with Parkinson’s disease and only one of the 25 controls had the protein clumping.
“At present, the only way to definitely diagnose Parkinson’s disease is on autopsy – by the detection of alpha-synuclein clumps [Lewy bodies] in the brain,” commented Charles Adler, MD, professor of neurology at Mayo Clinic Arizona in Scottsdale and a coinvestigator of the study. “In our research, we have also seen clumping of alpha-synuclein in many other organs including submandibular gland, colon, skin, heart, and stomach, but in terms of access, the skin is probably the easiest source.”
In this study, “we found this seeding assay for alpha-synuclein clumps to be extremely sensitive and specific in the diagnosis of Parkinson’s disease,” he added. “This is very valuable data as we have samples from patients with autopsy-validated Parkinson’s disease.”
A reliable biomarker?
The researchers are now starting a study in living patients with funding from the National Institutes of Health in which they will repeat the process comparing skin samples from patients with clinically diagnosed Parkinson’s disease and controls.
“We need to know whether analyzing alpha-synuclein clumping in skin biopsies from live patients with Parkinson’s disease would serve as a reliable biomarker for disease progression. Will clumping of this protein in skin samples increase over time and does it correspond with disease progression?” Dr. Adler said.
In future they are also hoping to test individuals who have not yet developed Parkinson’s disease but may have some prodromal type symptoms and to test whether this assay could measure a treatment effect of drug therapy.
Dr. Adler noted that they are currently conducting an autopsy study of skin samples from individuals who did not have clinical Parkinson’s disease when alive but in whom Lewy bodies have been found postmortem.
“This suggests that the disease pathology starts before Parkinson’s symptoms develop, and in the future, if we can diagnose Parkinson’s disease earlier then we may be able to stop progression,” he said.
“There is a long list of compounds that have been studied to try and slow progression but haven’t shown benefits, but by the time patients develop symptoms they already have significant disease and [have] lost most of their dopamine neurons,” he added. “If we could backtrack by 10 years, then these drugs may well make a difference.”
Dr. Adler also noted that currently more advanced patients may undergo invasive procedures such as deep brain stimulation or surgery. “It is of utmost importance that they have an accurate diagnosis before being subjected to such procedures.”
In addition, he pointed out that an accurate test would help the drug development process. “It is vitally important to enroll patients with an accurate diagnosis in clinical trials of new drugs. At present, a large percentage of patients in these trials may not actually have Parkinson’s disease, which makes it very difficult to show a treatment effect.”
Important step, but preliminary
Commenting on the research, James Beck, PhD, chief scientific officer of the Parkinson’s Foundation, said the study “is an important step toward the creation of a new way to potentially diagnose Parkinson’s disease.”
But he cautioned that this is a preliminary study. “To really confirm the possibility of using this approach for diagnosing Parkinson’s disease, a larger study will be necessary. And it will be important to test this in a population with early disease – the most difficult group to accurately diagnose.”
Also commenting on the findings, Beate Ritz, MD, PhD, an epidemiologist at UCLA Fielding School of Public Health in Los Angeles, who is part of a team also working on ways to measure abnormal alpha-synuclein to diagnose Parkinson’s disease, described the current study of skin samples as “pretty nifty.”
“Their research shows clearly that they can distinguish between patients with Parkinson’s disease and controls in this way,” she said. “The big advantage of this study is that they have brain pathology, so they know exactly which individuals had Parkinson’s disease.”
Dr. Ritz is working with Gal Bitan, PhD, from the UCLA Brain Research Institute on a potential blood test to measure abnormal alpha-synuclein.
Dr. Ritz explained that it is not possible to measure alpha-synuclein pathology in regular blood samples as it is expressed normally in red blood cells, but they are measuring the protein and its more toxic phosphorylated form from exosomes, which contain the waste discarded by cells using technology that determines the origin of these exosomes.
“Alpha-synuclein itself is not a problem. It is the way it misfolds that causes toxicity and disrupts the workings of the cell,” Dr. Ritz added. “In Parkinson’s disease, it is particularly toxic to dopaminergic neurons, and in multiple system atrophy, it is toxic to glial cells, so if we can identify the source of the protein then that could be helpful.”
The study was funded by the National Institutes of Health and the US Army Medical Research Materiel Command. The study authors, Dr. Beck, and Dr. Ritz have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM MOVEMENT DISORDERS
CAR T for all R/R DLBCL patients: The jury is still out
Is it time to consider chimeric antigen receptor (CAR) T-cell therapy for all relapsed/refractory diffuse large B-cell lymphoma patients? Maybe not, according to Andrew Zelenetz, MD, PhD.
CAR T-cell therapy has demonstrated activity in relapsed/refractory non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), transformed indolent NHL, and mantle cell lymphoma, and can provide durable complete responses in a portion of patients with chemorefractory disease, Dr. Zelenetz, chair of the National Comprehensive Cancer Network Lymphoma Guidelines Panel and a specialist in lymphoma at Memorial Sloan Kettering Cancer Center in New York, said at the NCCN Hematologic Malignancies Annual Congress.
In chemosensitive patients, however, its role requires further examination, especially given findings from a recent analysis of patients from the Center for International Blood & Marrow Transplant Research (CIBMTR) registry showing comparable outcomes with high-dose chemotherapy and autologous stem cell rescue for patients with a positron emission testing–positive partial response (PR) after second-line chemotherapy, he said.
Of 249 patients who underwent a first autologous transplant for DLBCL between 2003 and 2018, received front-line rituximab chemotherapy, and had PET– or computed tomography–positive disease prior to transplant, 182 had early chemotherapy failure (within 12 months) and 67 had late chemotherapy failure (at 12 months or later) after therapy, according to findings from the study as reported at ASCO 2020.
The adjusted nonrelapse mortality rates in the early- and late-failure patients, respectively, were not significantly different at 7% and 3% at 1 year, and at 10% and 8% at 5 years. The corresponding progression/relapse rates were 41% and 35% at 1 year and 48% and 57% at 5 years; these were also not significantly different.
The adjusted progression-free survival (PFS) and overall survival (OS) in the groups at 5 years also did not differ significantly (PFS of 41% in both the early- and late-failure groups, and OS of 51% and 63%, respectively).
These outcomes are comparable to those seen with CAR T-cell therapy in refractory DLBCL patients in trials of CAR T-cell products, including the ZUMA-1 study of axicabtagene cyloleucel (Yescarta), which, in a 2019 update, showed survival plateaus of about 40% vs. the 5%-10% expected rate based on pre-CAR-T outcomes data; the JULIET trial of tisagenlecleucel (Kymriah), which showed survival plateaus in the range of 30%-35%; and the recently published TRANSCEND study of the investigational modified CAR-T product, lisocabtagene maraleucel, which also showed survival plateaus “in the range of 40%.”
“So all three agents are showing that CAR T cells represent a new treatment for diffuse large B-cell lymphoma in the relapsed/refractory setting,” Dr. Zelenetz said. “And as a result, [CAR T-cell therapy has] been included in the NCCN guidelines for transformed follicular lymphoma, for transformed marginal zone lymphoma, and for diffuse large B-cell lymphoma, as well as for refractory large B-cell lymphoma.
“But are CAR T cells absolutely required? Generally what we consider these days is that if you’re not in a PET-negative CR prior to high-dose therapy stem cell rescue, you should go on to CAR T cells,” Dr. Zelenetz said.
The analysis based on the CIBMTR registry data, however, suggests there may be other alternatives.
“The bottom line is that nonrelapse mortality was very low. Progression occurred in about half of the patients, but if we look at the overall and progression-free survival curves, there’s a plateau at around 45%,” Dr. Zelenetz said, explaining that the results are “very similar to the results that we’re getting in third-line treatment with CAR T cells, and this is a very similar population [of] PET-positive patients after second-line chemotherapy.”
CAR T-cell therapy can provide a durable CR in a portion of chemorefractory patients, and although there is room for improvement, “this represents a major step forward for these patients,” he said.
However, it’s not clear that CAR T cells are clearly superior to high-dose therapy and stem cell rescue for chemosensitive patients, he added, noting that “additional randomized trials are needed to answer this question, and they are ongoing as we speak.”
Dr. Zelenetz reported clinical research support or data safety monitoring board activity for BeiGene, Genentech, Juno Therapeutics, and MEI Pharma, and scientific advisory board, consulting, or expert witness activity for Celgene Corporation, Curries, Genentech, Gilead Sciences, Janssen Pharmaceutical Products, and several other pharmaceutical and biotechnology companies.
Is it time to consider chimeric antigen receptor (CAR) T-cell therapy for all relapsed/refractory diffuse large B-cell lymphoma patients? Maybe not, according to Andrew Zelenetz, MD, PhD.
CAR T-cell therapy has demonstrated activity in relapsed/refractory non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), transformed indolent NHL, and mantle cell lymphoma, and can provide durable complete responses in a portion of patients with chemorefractory disease, Dr. Zelenetz, chair of the National Comprehensive Cancer Network Lymphoma Guidelines Panel and a specialist in lymphoma at Memorial Sloan Kettering Cancer Center in New York, said at the NCCN Hematologic Malignancies Annual Congress.
In chemosensitive patients, however, its role requires further examination, especially given findings from a recent analysis of patients from the Center for International Blood & Marrow Transplant Research (CIBMTR) registry showing comparable outcomes with high-dose chemotherapy and autologous stem cell rescue for patients with a positron emission testing–positive partial response (PR) after second-line chemotherapy, he said.
Of 249 patients who underwent a first autologous transplant for DLBCL between 2003 and 2018, received front-line rituximab chemotherapy, and had PET– or computed tomography–positive disease prior to transplant, 182 had early chemotherapy failure (within 12 months) and 67 had late chemotherapy failure (at 12 months or later) after therapy, according to findings from the study as reported at ASCO 2020.
The adjusted nonrelapse mortality rates in the early- and late-failure patients, respectively, were not significantly different at 7% and 3% at 1 year, and at 10% and 8% at 5 years. The corresponding progression/relapse rates were 41% and 35% at 1 year and 48% and 57% at 5 years; these were also not significantly different.
The adjusted progression-free survival (PFS) and overall survival (OS) in the groups at 5 years also did not differ significantly (PFS of 41% in both the early- and late-failure groups, and OS of 51% and 63%, respectively).
These outcomes are comparable to those seen with CAR T-cell therapy in refractory DLBCL patients in trials of CAR T-cell products, including the ZUMA-1 study of axicabtagene cyloleucel (Yescarta), which, in a 2019 update, showed survival plateaus of about 40% vs. the 5%-10% expected rate based on pre-CAR-T outcomes data; the JULIET trial of tisagenlecleucel (Kymriah), which showed survival plateaus in the range of 30%-35%; and the recently published TRANSCEND study of the investigational modified CAR-T product, lisocabtagene maraleucel, which also showed survival plateaus “in the range of 40%.”
“So all three agents are showing that CAR T cells represent a new treatment for diffuse large B-cell lymphoma in the relapsed/refractory setting,” Dr. Zelenetz said. “And as a result, [CAR T-cell therapy has] been included in the NCCN guidelines for transformed follicular lymphoma, for transformed marginal zone lymphoma, and for diffuse large B-cell lymphoma, as well as for refractory large B-cell lymphoma.
“But are CAR T cells absolutely required? Generally what we consider these days is that if you’re not in a PET-negative CR prior to high-dose therapy stem cell rescue, you should go on to CAR T cells,” Dr. Zelenetz said.
The analysis based on the CIBMTR registry data, however, suggests there may be other alternatives.
“The bottom line is that nonrelapse mortality was very low. Progression occurred in about half of the patients, but if we look at the overall and progression-free survival curves, there’s a plateau at around 45%,” Dr. Zelenetz said, explaining that the results are “very similar to the results that we’re getting in third-line treatment with CAR T cells, and this is a very similar population [of] PET-positive patients after second-line chemotherapy.”
CAR T-cell therapy can provide a durable CR in a portion of chemorefractory patients, and although there is room for improvement, “this represents a major step forward for these patients,” he said.
However, it’s not clear that CAR T cells are clearly superior to high-dose therapy and stem cell rescue for chemosensitive patients, he added, noting that “additional randomized trials are needed to answer this question, and they are ongoing as we speak.”
Dr. Zelenetz reported clinical research support or data safety monitoring board activity for BeiGene, Genentech, Juno Therapeutics, and MEI Pharma, and scientific advisory board, consulting, or expert witness activity for Celgene Corporation, Curries, Genentech, Gilead Sciences, Janssen Pharmaceutical Products, and several other pharmaceutical and biotechnology companies.
Is it time to consider chimeric antigen receptor (CAR) T-cell therapy for all relapsed/refractory diffuse large B-cell lymphoma patients? Maybe not, according to Andrew Zelenetz, MD, PhD.
CAR T-cell therapy has demonstrated activity in relapsed/refractory non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), transformed indolent NHL, and mantle cell lymphoma, and can provide durable complete responses in a portion of patients with chemorefractory disease, Dr. Zelenetz, chair of the National Comprehensive Cancer Network Lymphoma Guidelines Panel and a specialist in lymphoma at Memorial Sloan Kettering Cancer Center in New York, said at the NCCN Hematologic Malignancies Annual Congress.
In chemosensitive patients, however, its role requires further examination, especially given findings from a recent analysis of patients from the Center for International Blood & Marrow Transplant Research (CIBMTR) registry showing comparable outcomes with high-dose chemotherapy and autologous stem cell rescue for patients with a positron emission testing–positive partial response (PR) after second-line chemotherapy, he said.
Of 249 patients who underwent a first autologous transplant for DLBCL between 2003 and 2018, received front-line rituximab chemotherapy, and had PET– or computed tomography–positive disease prior to transplant, 182 had early chemotherapy failure (within 12 months) and 67 had late chemotherapy failure (at 12 months or later) after therapy, according to findings from the study as reported at ASCO 2020.
The adjusted nonrelapse mortality rates in the early- and late-failure patients, respectively, were not significantly different at 7% and 3% at 1 year, and at 10% and 8% at 5 years. The corresponding progression/relapse rates were 41% and 35% at 1 year and 48% and 57% at 5 years; these were also not significantly different.
The adjusted progression-free survival (PFS) and overall survival (OS) in the groups at 5 years also did not differ significantly (PFS of 41% in both the early- and late-failure groups, and OS of 51% and 63%, respectively).
These outcomes are comparable to those seen with CAR T-cell therapy in refractory DLBCL patients in trials of CAR T-cell products, including the ZUMA-1 study of axicabtagene cyloleucel (Yescarta), which, in a 2019 update, showed survival plateaus of about 40% vs. the 5%-10% expected rate based on pre-CAR-T outcomes data; the JULIET trial of tisagenlecleucel (Kymriah), which showed survival plateaus in the range of 30%-35%; and the recently published TRANSCEND study of the investigational modified CAR-T product, lisocabtagene maraleucel, which also showed survival plateaus “in the range of 40%.”
“So all three agents are showing that CAR T cells represent a new treatment for diffuse large B-cell lymphoma in the relapsed/refractory setting,” Dr. Zelenetz said. “And as a result, [CAR T-cell therapy has] been included in the NCCN guidelines for transformed follicular lymphoma, for transformed marginal zone lymphoma, and for diffuse large B-cell lymphoma, as well as for refractory large B-cell lymphoma.
“But are CAR T cells absolutely required? Generally what we consider these days is that if you’re not in a PET-negative CR prior to high-dose therapy stem cell rescue, you should go on to CAR T cells,” Dr. Zelenetz said.
The analysis based on the CIBMTR registry data, however, suggests there may be other alternatives.
“The bottom line is that nonrelapse mortality was very low. Progression occurred in about half of the patients, but if we look at the overall and progression-free survival curves, there’s a plateau at around 45%,” Dr. Zelenetz said, explaining that the results are “very similar to the results that we’re getting in third-line treatment with CAR T cells, and this is a very similar population [of] PET-positive patients after second-line chemotherapy.”
CAR T-cell therapy can provide a durable CR in a portion of chemorefractory patients, and although there is room for improvement, “this represents a major step forward for these patients,” he said.
However, it’s not clear that CAR T cells are clearly superior to high-dose therapy and stem cell rescue for chemosensitive patients, he added, noting that “additional randomized trials are needed to answer this question, and they are ongoing as we speak.”
Dr. Zelenetz reported clinical research support or data safety monitoring board activity for BeiGene, Genentech, Juno Therapeutics, and MEI Pharma, and scientific advisory board, consulting, or expert witness activity for Celgene Corporation, Curries, Genentech, Gilead Sciences, Janssen Pharmaceutical Products, and several other pharmaceutical and biotechnology companies.
FROM NCCN HEMATOLOGIC MALIGNANCIES