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Florbetapir PET may rule out amyloidosis and Alzheimer’s disease
BOSTON – Brain amyloid imaging may help clinicians to rule Alzheimer’s disease in or out and spare patients with other forms of dementia from the possibly harmful effects of antiamyloid therapies, a small study has shown.
In a case series of 20 patients who were given clinical diagnoses that included frontotemporal dementia, Alzheimer’s disease (AD), Parkinson’s disease, and mild cognitive impairment, PET scanning with the radiotracer florbetapir 18F (Amyvid) was positive and consistent in scans of patients with diagnoses of AD or amnestic mild cognitive impairment, and was negative in scans of patients with Parkinson’s disease, delayed post-traumatic cognitive impairment, depression, and normal cognition.
One of the patients was a retired National Football League player with a history of multiple concussions. Although neuropsychologists and neurologists disagreed on a diagnosis of possible AD, florbetapir 18F PET imaging helped them confirm a diagnosis of delayed post-traumatic cognitive impairment without amyloidosis and with possible chronic traumatic encephalopathy, said Effie Mitsis, Ph.D., of the department of psychiatry at Mount Sinai School of Medicine in New York.
"If this guy came to our Alzheimer’s disease research center without the scan, undoubtedly one of the neurologists would have put him on an antiamyloid agent and put him into a clinical trial," she said in an interview.
Florbetapir is a radioligand that attaches to amyloid plaques in the brain. Dr. Mitsis and her colleagues use the agent as part of a comprehensive clinical dementia evaluation.
In the series she reported, florbetapir PET scans were negative in all of three patients diagnosed with frontotemporal dementia and primary progressive aphasia, and in two of three patients with behavioral variant frontotemporal dementia.
In one patient diagnosed with Parkinson’s disease and AD, the scans were positive, and in another diagnosed with Parkinson’s disease and depression, the scans were negative, the investigators found.
Of four patients with a diagnosis of amnestic mild cognitive impairment and five with a diagnosis of AD alone, all scans were positive. In contrast, in the one patient with a diagnosis of depression but no neurodegenerative disease, the scans were negative.
Dazed and confused after games
Scans were negative in two patients with normal cognition, and in the former NFL player.
He had retired from the game after a 10-year professional career, during which time he had multiple concussions.
"By 12 hours post game, he was at times unable to name which team he had just played against. He does not recall loss of consciousness, but was dazed and confused sometimes up to a full day afterward. On several occasions, the player had difficulty finding his way home after a game," Dr. Mitsis reported in a poster presentation at the Alzheimer’s Association International Conference 2013.
A designated NFL Neurological Care Program team consisting of a neurologist, a neurologic psychiatrist, a neuropsychologist, neuroradiologists, and nuclear medicine physicians had evaluated him with validated cognitive and memory instruments, and determined that he had impairments in information-processing speed, verbal comprehension, and immediate and delayed word recall, but still had intellectual function and learning ability.
Dr. Mitsis and another neuropsychologist independently reviewed the test results and agreed on the inclusion of possible AD in the diagnosis, a finding that was opposed by all but one member of the original evaluation team.
With florbetapir PET scanning, however, they were able to exclude a diagnosis of cerebral amyloidosis, thereby ruling out AD, Dr. Mitsis said.
The research was supported by grants from the U.S. Department of Veterans Affairs. Dr. Mitsis reported having no relevant financial disclosures.
BOSTON – Brain amyloid imaging may help clinicians to rule Alzheimer’s disease in or out and spare patients with other forms of dementia from the possibly harmful effects of antiamyloid therapies, a small study has shown.
In a case series of 20 patients who were given clinical diagnoses that included frontotemporal dementia, Alzheimer’s disease (AD), Parkinson’s disease, and mild cognitive impairment, PET scanning with the radiotracer florbetapir 18F (Amyvid) was positive and consistent in scans of patients with diagnoses of AD or amnestic mild cognitive impairment, and was negative in scans of patients with Parkinson’s disease, delayed post-traumatic cognitive impairment, depression, and normal cognition.
One of the patients was a retired National Football League player with a history of multiple concussions. Although neuropsychologists and neurologists disagreed on a diagnosis of possible AD, florbetapir 18F PET imaging helped them confirm a diagnosis of delayed post-traumatic cognitive impairment without amyloidosis and with possible chronic traumatic encephalopathy, said Effie Mitsis, Ph.D., of the department of psychiatry at Mount Sinai School of Medicine in New York.
"If this guy came to our Alzheimer’s disease research center without the scan, undoubtedly one of the neurologists would have put him on an antiamyloid agent and put him into a clinical trial," she said in an interview.
Florbetapir is a radioligand that attaches to amyloid plaques in the brain. Dr. Mitsis and her colleagues use the agent as part of a comprehensive clinical dementia evaluation.
In the series she reported, florbetapir PET scans were negative in all of three patients diagnosed with frontotemporal dementia and primary progressive aphasia, and in two of three patients with behavioral variant frontotemporal dementia.
In one patient diagnosed with Parkinson’s disease and AD, the scans were positive, and in another diagnosed with Parkinson’s disease and depression, the scans were negative, the investigators found.
Of four patients with a diagnosis of amnestic mild cognitive impairment and five with a diagnosis of AD alone, all scans were positive. In contrast, in the one patient with a diagnosis of depression but no neurodegenerative disease, the scans were negative.
Dazed and confused after games
Scans were negative in two patients with normal cognition, and in the former NFL player.
He had retired from the game after a 10-year professional career, during which time he had multiple concussions.
"By 12 hours post game, he was at times unable to name which team he had just played against. He does not recall loss of consciousness, but was dazed and confused sometimes up to a full day afterward. On several occasions, the player had difficulty finding his way home after a game," Dr. Mitsis reported in a poster presentation at the Alzheimer’s Association International Conference 2013.
A designated NFL Neurological Care Program team consisting of a neurologist, a neurologic psychiatrist, a neuropsychologist, neuroradiologists, and nuclear medicine physicians had evaluated him with validated cognitive and memory instruments, and determined that he had impairments in information-processing speed, verbal comprehension, and immediate and delayed word recall, but still had intellectual function and learning ability.
Dr. Mitsis and another neuropsychologist independently reviewed the test results and agreed on the inclusion of possible AD in the diagnosis, a finding that was opposed by all but one member of the original evaluation team.
With florbetapir PET scanning, however, they were able to exclude a diagnosis of cerebral amyloidosis, thereby ruling out AD, Dr. Mitsis said.
The research was supported by grants from the U.S. Department of Veterans Affairs. Dr. Mitsis reported having no relevant financial disclosures.
BOSTON – Brain amyloid imaging may help clinicians to rule Alzheimer’s disease in or out and spare patients with other forms of dementia from the possibly harmful effects of antiamyloid therapies, a small study has shown.
In a case series of 20 patients who were given clinical diagnoses that included frontotemporal dementia, Alzheimer’s disease (AD), Parkinson’s disease, and mild cognitive impairment, PET scanning with the radiotracer florbetapir 18F (Amyvid) was positive and consistent in scans of patients with diagnoses of AD or amnestic mild cognitive impairment, and was negative in scans of patients with Parkinson’s disease, delayed post-traumatic cognitive impairment, depression, and normal cognition.
One of the patients was a retired National Football League player with a history of multiple concussions. Although neuropsychologists and neurologists disagreed on a diagnosis of possible AD, florbetapir 18F PET imaging helped them confirm a diagnosis of delayed post-traumatic cognitive impairment without amyloidosis and with possible chronic traumatic encephalopathy, said Effie Mitsis, Ph.D., of the department of psychiatry at Mount Sinai School of Medicine in New York.
"If this guy came to our Alzheimer’s disease research center without the scan, undoubtedly one of the neurologists would have put him on an antiamyloid agent and put him into a clinical trial," she said in an interview.
Florbetapir is a radioligand that attaches to amyloid plaques in the brain. Dr. Mitsis and her colleagues use the agent as part of a comprehensive clinical dementia evaluation.
In the series she reported, florbetapir PET scans were negative in all of three patients diagnosed with frontotemporal dementia and primary progressive aphasia, and in two of three patients with behavioral variant frontotemporal dementia.
In one patient diagnosed with Parkinson’s disease and AD, the scans were positive, and in another diagnosed with Parkinson’s disease and depression, the scans were negative, the investigators found.
Of four patients with a diagnosis of amnestic mild cognitive impairment and five with a diagnosis of AD alone, all scans were positive. In contrast, in the one patient with a diagnosis of depression but no neurodegenerative disease, the scans were negative.
Dazed and confused after games
Scans were negative in two patients with normal cognition, and in the former NFL player.
He had retired from the game after a 10-year professional career, during which time he had multiple concussions.
"By 12 hours post game, he was at times unable to name which team he had just played against. He does not recall loss of consciousness, but was dazed and confused sometimes up to a full day afterward. On several occasions, the player had difficulty finding his way home after a game," Dr. Mitsis reported in a poster presentation at the Alzheimer’s Association International Conference 2013.
A designated NFL Neurological Care Program team consisting of a neurologist, a neurologic psychiatrist, a neuropsychologist, neuroradiologists, and nuclear medicine physicians had evaluated him with validated cognitive and memory instruments, and determined that he had impairments in information-processing speed, verbal comprehension, and immediate and delayed word recall, but still had intellectual function and learning ability.
Dr. Mitsis and another neuropsychologist independently reviewed the test results and agreed on the inclusion of possible AD in the diagnosis, a finding that was opposed by all but one member of the original evaluation team.
With florbetapir PET scanning, however, they were able to exclude a diagnosis of cerebral amyloidosis, thereby ruling out AD, Dr. Mitsis said.
The research was supported by grants from the U.S. Department of Veterans Affairs. Dr. Mitsis reported having no relevant financial disclosures.
AT AAIC 2013
Major finding: Brain amyloid imaging with florbetapir 18F PET was consistently positive in patients with amyloid pathology, and negative in patients without cerebral amyloidosis except in one case.
Data source: A case series of 20 patients with various clinical diagnoses of dementia or cognitive problems.
Disclosures: The research was supported by a grant from the U.S. Department of Veterans Affairs. Dr. Mitsis reported having no relevant financial disclosures.
Two-minute Alzheimer’s test? Not so fast!
BOSTON – The quality of websites that purport to help visitors or other people acting on their behalf to diagnose Alzheimer’s disease are very low and should not be used for such a purpose, cautioned an investigator at the Alzheimer’s Association International Conference 2013.
Independent panelists who reviewed 16 online tests for Alzheimer’s disease (AD) found that none provided validated results, and all were sorely lacking in ethical standards, reported Julie Robillard, Ph.D., a postdoctoral fellow at the National Core for Neuroethics at the University of British Columbia in Vancouver, Canada.
More than half of all Americans aged 65 years and older use the Internet, and approximately 80% of all adults find health information online, Dr. Robillard noted.
"There’s an increasingly popular behavior online, which is self-diagnosis, and the truth is we have almost no information about the quality of information about Alzheimer’s online," she said.
To at least partially fill in this knowledge gap, she and her colleagues conducted a keyword search to identify 16 freely available online tests purporting to be for Alzheimer’s disease and asked two independent panels of expert reviewers to rate each test on a scale of 1 (very poor) to 10 (excellent) for content, breadth, peer review, and reliability.
The tests were found on news, not-for-profit, academic, commercial, and entertainment sites, with monthly traffic ranging from 200 to 8.8 million unique visits. At least one test could be completed in about 2 minutes; others took as long as 1 hour to complete, Dr. Robillard estimated.
"So, in 2 minutes, you can go online and find out if you have Alzheimer’s disease," she joked.
Thirteen were designed to be self tests, and three were designed to be filled out by a proxy such as a relative or friend. Six sites relied primarily on questionnaires asking about risk factors and symptoms, and 10 used performance measures.
The tests gave users a variety of possible outcomes. For example, nine tests classified users as not at risk, at risk, or as already having AD. Another three rated responses on a continuum based on test answers. Of the four remaining tests, two were pass/fail, one was fail only, and one offered no outcomes.
The scientific validity and reliability of the tests were rated as mediocre at best by the panelists, indicating that the tests were generally poor at achieving their stated goals. The tests were generally poor at including current peer-reviewed evidence, and the experts also said that test/retest reliability was also quite poor.
Experts in human-computer interaction gave decent marks (scores of about 7) for their ease of use. But clinicians, ethicists, and neuropsychologists were less forgiving on whether the tests could detect if the user was performing properly or merely playing around and how easy the tests were to use for those with lower levels of computer literacy. None rated the usability of any test much higher than 5.
None of the tests rated better than poor for meeting various ethical standards, such as providing upfront information about the nature and scope of the test, informed consent, and privacy discussions. The panelists also gave poor ratings to the tests’ wording of outcomes, the clarity of their interpretation, and their provision of appropriate advice for follow-up. Conflict-of-interest disclosures were not present, either.
"Is self-diagnosis appropriate at all? I think that professional consensus is that it’s not, so we have to wonder how we handle these tests being online and people doing them," Dr. Robillard said.
Her next step will be to explore in depth the potential harms or benefits of online dementia screening and to evaluate how such testing may affect clinician/patient relationships.
The study was supported by the Canadian Institute for Health Research and the Canadian Dementia Knowledge Translation Network. Dr. Robillard disclosed that two of her coauthors are involved in developing a computerized testing tool for mild cognitive impairment and dementia for use in specialty-care settings. Dr. Robillard reported having no personal disclosures.
BOSTON – The quality of websites that purport to help visitors or other people acting on their behalf to diagnose Alzheimer’s disease are very low and should not be used for such a purpose, cautioned an investigator at the Alzheimer’s Association International Conference 2013.
Independent panelists who reviewed 16 online tests for Alzheimer’s disease (AD) found that none provided validated results, and all were sorely lacking in ethical standards, reported Julie Robillard, Ph.D., a postdoctoral fellow at the National Core for Neuroethics at the University of British Columbia in Vancouver, Canada.
More than half of all Americans aged 65 years and older use the Internet, and approximately 80% of all adults find health information online, Dr. Robillard noted.
"There’s an increasingly popular behavior online, which is self-diagnosis, and the truth is we have almost no information about the quality of information about Alzheimer’s online," she said.
To at least partially fill in this knowledge gap, she and her colleagues conducted a keyword search to identify 16 freely available online tests purporting to be for Alzheimer’s disease and asked two independent panels of expert reviewers to rate each test on a scale of 1 (very poor) to 10 (excellent) for content, breadth, peer review, and reliability.
The tests were found on news, not-for-profit, academic, commercial, and entertainment sites, with monthly traffic ranging from 200 to 8.8 million unique visits. At least one test could be completed in about 2 minutes; others took as long as 1 hour to complete, Dr. Robillard estimated.
"So, in 2 minutes, you can go online and find out if you have Alzheimer’s disease," she joked.
Thirteen were designed to be self tests, and three were designed to be filled out by a proxy such as a relative or friend. Six sites relied primarily on questionnaires asking about risk factors and symptoms, and 10 used performance measures.
The tests gave users a variety of possible outcomes. For example, nine tests classified users as not at risk, at risk, or as already having AD. Another three rated responses on a continuum based on test answers. Of the four remaining tests, two were pass/fail, one was fail only, and one offered no outcomes.
The scientific validity and reliability of the tests were rated as mediocre at best by the panelists, indicating that the tests were generally poor at achieving their stated goals. The tests were generally poor at including current peer-reviewed evidence, and the experts also said that test/retest reliability was also quite poor.
Experts in human-computer interaction gave decent marks (scores of about 7) for their ease of use. But clinicians, ethicists, and neuropsychologists were less forgiving on whether the tests could detect if the user was performing properly or merely playing around and how easy the tests were to use for those with lower levels of computer literacy. None rated the usability of any test much higher than 5.
None of the tests rated better than poor for meeting various ethical standards, such as providing upfront information about the nature and scope of the test, informed consent, and privacy discussions. The panelists also gave poor ratings to the tests’ wording of outcomes, the clarity of their interpretation, and their provision of appropriate advice for follow-up. Conflict-of-interest disclosures were not present, either.
"Is self-diagnosis appropriate at all? I think that professional consensus is that it’s not, so we have to wonder how we handle these tests being online and people doing them," Dr. Robillard said.
Her next step will be to explore in depth the potential harms or benefits of online dementia screening and to evaluate how such testing may affect clinician/patient relationships.
The study was supported by the Canadian Institute for Health Research and the Canadian Dementia Knowledge Translation Network. Dr. Robillard disclosed that two of her coauthors are involved in developing a computerized testing tool for mild cognitive impairment and dementia for use in specialty-care settings. Dr. Robillard reported having no personal disclosures.
BOSTON – The quality of websites that purport to help visitors or other people acting on their behalf to diagnose Alzheimer’s disease are very low and should not be used for such a purpose, cautioned an investigator at the Alzheimer’s Association International Conference 2013.
Independent panelists who reviewed 16 online tests for Alzheimer’s disease (AD) found that none provided validated results, and all were sorely lacking in ethical standards, reported Julie Robillard, Ph.D., a postdoctoral fellow at the National Core for Neuroethics at the University of British Columbia in Vancouver, Canada.
More than half of all Americans aged 65 years and older use the Internet, and approximately 80% of all adults find health information online, Dr. Robillard noted.
"There’s an increasingly popular behavior online, which is self-diagnosis, and the truth is we have almost no information about the quality of information about Alzheimer’s online," she said.
To at least partially fill in this knowledge gap, she and her colleagues conducted a keyword search to identify 16 freely available online tests purporting to be for Alzheimer’s disease and asked two independent panels of expert reviewers to rate each test on a scale of 1 (very poor) to 10 (excellent) for content, breadth, peer review, and reliability.
The tests were found on news, not-for-profit, academic, commercial, and entertainment sites, with monthly traffic ranging from 200 to 8.8 million unique visits. At least one test could be completed in about 2 minutes; others took as long as 1 hour to complete, Dr. Robillard estimated.
"So, in 2 minutes, you can go online and find out if you have Alzheimer’s disease," she joked.
Thirteen were designed to be self tests, and three were designed to be filled out by a proxy such as a relative or friend. Six sites relied primarily on questionnaires asking about risk factors and symptoms, and 10 used performance measures.
The tests gave users a variety of possible outcomes. For example, nine tests classified users as not at risk, at risk, or as already having AD. Another three rated responses on a continuum based on test answers. Of the four remaining tests, two were pass/fail, one was fail only, and one offered no outcomes.
The scientific validity and reliability of the tests were rated as mediocre at best by the panelists, indicating that the tests were generally poor at achieving their stated goals. The tests were generally poor at including current peer-reviewed evidence, and the experts also said that test/retest reliability was also quite poor.
Experts in human-computer interaction gave decent marks (scores of about 7) for their ease of use. But clinicians, ethicists, and neuropsychologists were less forgiving on whether the tests could detect if the user was performing properly or merely playing around and how easy the tests were to use for those with lower levels of computer literacy. None rated the usability of any test much higher than 5.
None of the tests rated better than poor for meeting various ethical standards, such as providing upfront information about the nature and scope of the test, informed consent, and privacy discussions. The panelists also gave poor ratings to the tests’ wording of outcomes, the clarity of their interpretation, and their provision of appropriate advice for follow-up. Conflict-of-interest disclosures were not present, either.
"Is self-diagnosis appropriate at all? I think that professional consensus is that it’s not, so we have to wonder how we handle these tests being online and people doing them," Dr. Robillard said.
Her next step will be to explore in depth the potential harms or benefits of online dementia screening and to evaluate how such testing may affect clinician/patient relationships.
The study was supported by the Canadian Institute for Health Research and the Canadian Dementia Knowledge Translation Network. Dr. Robillard disclosed that two of her coauthors are involved in developing a computerized testing tool for mild cognitive impairment and dementia for use in specialty-care settings. Dr. Robillard reported having no personal disclosures.
AT AAIC 2013
Major finding: All of 16 online tests for Alzheimer’s disease were rated as poor in all respects by two expert panels.
Data source: Evaluation of 16 freely available Internet-based tests purported to screen for Alzheimer’s disease.
Disclosures: The study was supported by the Canadian Institute for Health Research and the Canadian Dementia Knowledge Translation Network. Dr. Robillard disclosed that two of her coauthors are involved in developing a computerized testing tool for mild cognitive impairment and dementia for use in specialty-care settings. Dr. Robillard reported having no personal disclosures.
Subjective cognitive decline may be early omen of Alzheimer’s
BOSTON – Patients who complain of memory and cognition problems may be experiencing early, subtle signs of Alzheimer’s disease, according to findings from four separate studies presented at the Alzheimer’s Association International Conference 2013.
A study of 2,319 elderly patients with no dementia at baseline and no mild cognitive impairment (MCI) showed that patients who reported subjective memory impairment (SMI) had a significantly greater decline than control subjects in episodic memory (immediate and delayed recall), and that patients with SMI with self-reported concerns about memory had a greater slope of decline, reported Alexander Koppara, a PhD candidate at the Universitätsklinikum Bonn in Germany.
Depression also was associated with cognitive performance at baseline, but the effects of SMI remained when the investigators controlled for depression, he said.
"Even if we introduce depression as a covariate of development over time, depression is not a significant predictor of cognitive decline, which is in line with a lot of findings in psychiatry. That is why subjects who report subjective memory impairment should be tracked over a long period of time," Mr. Koppara said.
He added that a multimodal approach combining studies of biomarkers with experimental assessment tools could help to further objectify clinical impressions from subjective memory and cognition symptoms.
Amyloid mirrors memory concerns
The findings of Mr. Koppara’s group were supported by a second study indicating that, among 200 healthy, clinically normal older adults, those who reported more concerns than their nonworried peers about problems with cognition and memory had more evidence of beta-amyloid protein buildup in the brain, as seen with PET scans with the amyloid tracing agent 11C-labeled Pittsburgh Compound B.
In addition, among subjects with higher levels of education and reading ability, the greater the level of concern, the greater the degree of amyloid deposition, said Rebecca E. Amariglio, Ph.D., a clinical neuropsychologist at Brigham & Women’s Hospital and Massachusetts General Hospital in Boston.
"We also took a look at reports of concerns by an informant, or somebody who knew these subjects well, like a family member or a friend, and we did not see a relationship with amyloid," she said at a media briefing. "There seems to be something specific to someone’s own knowledge of their abilities that isn’t quite captured by an informant at this stage, the preclinical stage of Alzheimer’s disease."
Dr. Amariglio emphasized that many subjective memory changes should not be cause for concern. For example, it’s normal for an older person to walk into a room and forget why he or she went there, have difficulty retrieving names of unfamiliar people, or have changes in memory, compared with young adulthood.
What is abnormal, and may be a trigger for clinical evaluation, is getting lost in familiar surroundings, having difficulty remembering important details of recent events, trouble following the plot of a TV program or book because of memory, or having noticeably worse memory than friends of the same age, she said.
Subjective symptoms in high-risk allele carriers
Dr. Amariglio was coauthor of a second study looking at women aged 70 years and older with no history of stroke who were participants in the Nurses Health Study. The investigators looked at a subjective memory symptom score based on self-report of up to seven specific, subjective memory symptoms and compared it with verbal memory decline over 6 years among 889 women with one or two copies of the high-risk apolipoprotein E epsilon-4 (APOE epsilon-4) allele and 2,972 APOE epsilon-4 noncarriers.
They found that, for both APOE epsilon-4 carriers and noncarriers, higher numbers of subjective memory symptoms at baseline were related to poorer verbal memory scores (P for trend less than .001 for both groups). In addition, after adjusting for age and the presence of depression, women with more subjective memory symptoms at baseline also had higher rates of verbal memory decline over time (P for trend = .006 for APOE epsilon-4 carriers and less than .001 for noncarriers).
Interestingly, only one subjective memory symptom at baseline was needed to accurately predict verbal memory decline over time among APOE epsilon-4 carriers, compared with three or more needed to predict decline in noncarriers.
"Self-report of memory concerns may be useful for identifying individuals at greater risk of memory decline, particularly within [APOE epsilon-4] carriers, a group at higher risk of memory decline and Alzheimer’s disease dementia," said lead author Cecilia Samieri, Ph.D., an epidemiologist and researcher at the University of Bordeaux in France.
Self-reported symptoms during longitudinal study
Additional evidence for the link between subjective cognitive decline and MCI or dementia comes from the BRAINS (Biologically Resilient Adults in Neurological Studies) longitudinal study. Richard J. Kryscio, Ph.D., a professor of statistics and faculty member in the Sanders-Brown Center on Aging at the University of Kentucky, Lexington, and his colleagues looked at 531 men and women with a mean age of 73 who underwent annual cognitive assessments for a mean of 10 years.
Before each exam, the participants were asked, "Have you noticed a change in your memory since the last visit?" More than half of the participants (55.7%) said yes, reporting subjective memory complaints during the study.
The investigators found that a person with a subjective memory complaint had 2.8-fold greater risk of developing MCI or dementia later in life, compared with someone who did not respond in the affirmative.
Dr. Kryscio cautioned, however, that a positive subjective memory complaint "is no guarantee that MCI or dementia will follow."
Dr. Koppara’s study was funded by the AgeCoDe Study Group and the German Center for Neurodegenerative Diseases. The two studies authored by Dr. Amariglio and Dr. Samieri were supported by the National Institutes of Health and France’s Institut National de la Santé et de la Recherche Médicale. Dr. Kryscio’s study was supported by the National Institute on Aging. The authors all reported having no relevant disclosures.
BOSTON – Patients who complain of memory and cognition problems may be experiencing early, subtle signs of Alzheimer’s disease, according to findings from four separate studies presented at the Alzheimer’s Association International Conference 2013.
A study of 2,319 elderly patients with no dementia at baseline and no mild cognitive impairment (MCI) showed that patients who reported subjective memory impairment (SMI) had a significantly greater decline than control subjects in episodic memory (immediate and delayed recall), and that patients with SMI with self-reported concerns about memory had a greater slope of decline, reported Alexander Koppara, a PhD candidate at the Universitätsklinikum Bonn in Germany.
Depression also was associated with cognitive performance at baseline, but the effects of SMI remained when the investigators controlled for depression, he said.
"Even if we introduce depression as a covariate of development over time, depression is not a significant predictor of cognitive decline, which is in line with a lot of findings in psychiatry. That is why subjects who report subjective memory impairment should be tracked over a long period of time," Mr. Koppara said.
He added that a multimodal approach combining studies of biomarkers with experimental assessment tools could help to further objectify clinical impressions from subjective memory and cognition symptoms.
Amyloid mirrors memory concerns
The findings of Mr. Koppara’s group were supported by a second study indicating that, among 200 healthy, clinically normal older adults, those who reported more concerns than their nonworried peers about problems with cognition and memory had more evidence of beta-amyloid protein buildup in the brain, as seen with PET scans with the amyloid tracing agent 11C-labeled Pittsburgh Compound B.
In addition, among subjects with higher levels of education and reading ability, the greater the level of concern, the greater the degree of amyloid deposition, said Rebecca E. Amariglio, Ph.D., a clinical neuropsychologist at Brigham & Women’s Hospital and Massachusetts General Hospital in Boston.
"We also took a look at reports of concerns by an informant, or somebody who knew these subjects well, like a family member or a friend, and we did not see a relationship with amyloid," she said at a media briefing. "There seems to be something specific to someone’s own knowledge of their abilities that isn’t quite captured by an informant at this stage, the preclinical stage of Alzheimer’s disease."
Dr. Amariglio emphasized that many subjective memory changes should not be cause for concern. For example, it’s normal for an older person to walk into a room and forget why he or she went there, have difficulty retrieving names of unfamiliar people, or have changes in memory, compared with young adulthood.
What is abnormal, and may be a trigger for clinical evaluation, is getting lost in familiar surroundings, having difficulty remembering important details of recent events, trouble following the plot of a TV program or book because of memory, or having noticeably worse memory than friends of the same age, she said.
Subjective symptoms in high-risk allele carriers
Dr. Amariglio was coauthor of a second study looking at women aged 70 years and older with no history of stroke who were participants in the Nurses Health Study. The investigators looked at a subjective memory symptom score based on self-report of up to seven specific, subjective memory symptoms and compared it with verbal memory decline over 6 years among 889 women with one or two copies of the high-risk apolipoprotein E epsilon-4 (APOE epsilon-4) allele and 2,972 APOE epsilon-4 noncarriers.
They found that, for both APOE epsilon-4 carriers and noncarriers, higher numbers of subjective memory symptoms at baseline were related to poorer verbal memory scores (P for trend less than .001 for both groups). In addition, after adjusting for age and the presence of depression, women with more subjective memory symptoms at baseline also had higher rates of verbal memory decline over time (P for trend = .006 for APOE epsilon-4 carriers and less than .001 for noncarriers).
Interestingly, only one subjective memory symptom at baseline was needed to accurately predict verbal memory decline over time among APOE epsilon-4 carriers, compared with three or more needed to predict decline in noncarriers.
"Self-report of memory concerns may be useful for identifying individuals at greater risk of memory decline, particularly within [APOE epsilon-4] carriers, a group at higher risk of memory decline and Alzheimer’s disease dementia," said lead author Cecilia Samieri, Ph.D., an epidemiologist and researcher at the University of Bordeaux in France.
Self-reported symptoms during longitudinal study
Additional evidence for the link between subjective cognitive decline and MCI or dementia comes from the BRAINS (Biologically Resilient Adults in Neurological Studies) longitudinal study. Richard J. Kryscio, Ph.D., a professor of statistics and faculty member in the Sanders-Brown Center on Aging at the University of Kentucky, Lexington, and his colleagues looked at 531 men and women with a mean age of 73 who underwent annual cognitive assessments for a mean of 10 years.
Before each exam, the participants were asked, "Have you noticed a change in your memory since the last visit?" More than half of the participants (55.7%) said yes, reporting subjective memory complaints during the study.
The investigators found that a person with a subjective memory complaint had 2.8-fold greater risk of developing MCI or dementia later in life, compared with someone who did not respond in the affirmative.
Dr. Kryscio cautioned, however, that a positive subjective memory complaint "is no guarantee that MCI or dementia will follow."
Dr. Koppara’s study was funded by the AgeCoDe Study Group and the German Center for Neurodegenerative Diseases. The two studies authored by Dr. Amariglio and Dr. Samieri were supported by the National Institutes of Health and France’s Institut National de la Santé et de la Recherche Médicale. Dr. Kryscio’s study was supported by the National Institute on Aging. The authors all reported having no relevant disclosures.
BOSTON – Patients who complain of memory and cognition problems may be experiencing early, subtle signs of Alzheimer’s disease, according to findings from four separate studies presented at the Alzheimer’s Association International Conference 2013.
A study of 2,319 elderly patients with no dementia at baseline and no mild cognitive impairment (MCI) showed that patients who reported subjective memory impairment (SMI) had a significantly greater decline than control subjects in episodic memory (immediate and delayed recall), and that patients with SMI with self-reported concerns about memory had a greater slope of decline, reported Alexander Koppara, a PhD candidate at the Universitätsklinikum Bonn in Germany.
Depression also was associated with cognitive performance at baseline, but the effects of SMI remained when the investigators controlled for depression, he said.
"Even if we introduce depression as a covariate of development over time, depression is not a significant predictor of cognitive decline, which is in line with a lot of findings in psychiatry. That is why subjects who report subjective memory impairment should be tracked over a long period of time," Mr. Koppara said.
He added that a multimodal approach combining studies of biomarkers with experimental assessment tools could help to further objectify clinical impressions from subjective memory and cognition symptoms.
Amyloid mirrors memory concerns
The findings of Mr. Koppara’s group were supported by a second study indicating that, among 200 healthy, clinically normal older adults, those who reported more concerns than their nonworried peers about problems with cognition and memory had more evidence of beta-amyloid protein buildup in the brain, as seen with PET scans with the amyloid tracing agent 11C-labeled Pittsburgh Compound B.
In addition, among subjects with higher levels of education and reading ability, the greater the level of concern, the greater the degree of amyloid deposition, said Rebecca E. Amariglio, Ph.D., a clinical neuropsychologist at Brigham & Women’s Hospital and Massachusetts General Hospital in Boston.
"We also took a look at reports of concerns by an informant, or somebody who knew these subjects well, like a family member or a friend, and we did not see a relationship with amyloid," she said at a media briefing. "There seems to be something specific to someone’s own knowledge of their abilities that isn’t quite captured by an informant at this stage, the preclinical stage of Alzheimer’s disease."
Dr. Amariglio emphasized that many subjective memory changes should not be cause for concern. For example, it’s normal for an older person to walk into a room and forget why he or she went there, have difficulty retrieving names of unfamiliar people, or have changes in memory, compared with young adulthood.
What is abnormal, and may be a trigger for clinical evaluation, is getting lost in familiar surroundings, having difficulty remembering important details of recent events, trouble following the plot of a TV program or book because of memory, or having noticeably worse memory than friends of the same age, she said.
Subjective symptoms in high-risk allele carriers
Dr. Amariglio was coauthor of a second study looking at women aged 70 years and older with no history of stroke who were participants in the Nurses Health Study. The investigators looked at a subjective memory symptom score based on self-report of up to seven specific, subjective memory symptoms and compared it with verbal memory decline over 6 years among 889 women with one or two copies of the high-risk apolipoprotein E epsilon-4 (APOE epsilon-4) allele and 2,972 APOE epsilon-4 noncarriers.
They found that, for both APOE epsilon-4 carriers and noncarriers, higher numbers of subjective memory symptoms at baseline were related to poorer verbal memory scores (P for trend less than .001 for both groups). In addition, after adjusting for age and the presence of depression, women with more subjective memory symptoms at baseline also had higher rates of verbal memory decline over time (P for trend = .006 for APOE epsilon-4 carriers and less than .001 for noncarriers).
Interestingly, only one subjective memory symptom at baseline was needed to accurately predict verbal memory decline over time among APOE epsilon-4 carriers, compared with three or more needed to predict decline in noncarriers.
"Self-report of memory concerns may be useful for identifying individuals at greater risk of memory decline, particularly within [APOE epsilon-4] carriers, a group at higher risk of memory decline and Alzheimer’s disease dementia," said lead author Cecilia Samieri, Ph.D., an epidemiologist and researcher at the University of Bordeaux in France.
Self-reported symptoms during longitudinal study
Additional evidence for the link between subjective cognitive decline and MCI or dementia comes from the BRAINS (Biologically Resilient Adults in Neurological Studies) longitudinal study. Richard J. Kryscio, Ph.D., a professor of statistics and faculty member in the Sanders-Brown Center on Aging at the University of Kentucky, Lexington, and his colleagues looked at 531 men and women with a mean age of 73 who underwent annual cognitive assessments for a mean of 10 years.
Before each exam, the participants were asked, "Have you noticed a change in your memory since the last visit?" More than half of the participants (55.7%) said yes, reporting subjective memory complaints during the study.
The investigators found that a person with a subjective memory complaint had 2.8-fold greater risk of developing MCI or dementia later in life, compared with someone who did not respond in the affirmative.
Dr. Kryscio cautioned, however, that a positive subjective memory complaint "is no guarantee that MCI or dementia will follow."
Dr. Koppara’s study was funded by the AgeCoDe Study Group and the German Center for Neurodegenerative Diseases. The two studies authored by Dr. Amariglio and Dr. Samieri were supported by the National Institutes of Health and France’s Institut National de la Santé et de la Recherche Médicale. Dr. Kryscio’s study was supported by the National Institute on Aging. The authors all reported having no relevant disclosures.
AT AAIC 2013
Cancer survivors may have lower Alzheimer’s risk
BOSTON – It’s a trade-off that few people would be likely to make, but having cancer – particularly a type treated by chemotherapy – is associated with a significantly decreased risk for developing Alzheimer’s disease, a retrospective study has shown.
An inverse relationship was found between the incidence of the majority of different types of cancer and Alzheimer’s disease (AD) risk, in a review of the records of nearly 3.5 million U.S. veterans.
Liver cancer survivors had the lowest risk for AD (hazard ratio = 0.49), followed by survivors of pancreatic cancer (HR = 0.56), esophageal cancer (0.67), and multiple myeloma (0.74), reported Dr. Laura Frain of the geriatric research education and clinical center at Boston VA Medical Center.
However, survivors of prostate cancer had a small but significantly higher risk for AD (HR = 1.11), and other screening-detected cancers (colorectal cancer, melanoma) were not associated with a reduced risk, Dr. Frain and her associates found.
"There may be something different about prostate cancer survivors, but whether that’s biologic or related to the way that they’re screened is unclear," Dr. Frain said in an interview.
Many types of cancer were associated with an increased risk for non-AD dementias, with increased risks ranging from an HR of 1.11 for head and neck cancer to 2.64 for brain cancer.
The investigators attempted to control for the possibility that people with cancer may not survive long enough to develop frank dementia by looking at other age-related conditions, including stroke, osteoarthritis, cataracts, and macular degeneration. They found that all cancers were associated with an increased risk for other age-related conditions, suggesting that their findings of reduced AD risk were valid, Dr. Frain said at the Alzheimer’s Association International Conference 2013.
Findings corroborated
The findings parallel those of a recently published study of more than 1 million residents of Northern Italy (Neurology 2013 July 10 [doi:10.1212/WNL.0b013e31829c5ec1]). The investigators in that study found that "[t]he risk of cancer in patients with AD dementia was halved, and the risk of AD dementia in patients with cancer was 35% reduced. This relationship was observed in almost all subgroup analyses, suggesting that some anticipated potential confounding factors did not significantly influence the results."
Dr. Frain noted that three previous prospective cohort studies had found that older adults with cancer had a reduction in risk for incident AD, ranging from a 33% to a 60% decline. Those studies, however, were limited by small numbers of patients with cancer, limiting the ability to look for associations with specific cancer or treatment types.
The current study drew on data from the massive U.S. National Veterans Affairs Healthcare System to assemble a cohort of 3,499,378 veterans who received outpatient care within the system from 1997 to 2011. The investigators used regression analysis models adjusted for cancer treatment, multiple comorbidities, follow-up time, and number of visits per year before baseline. In addition, the researchers performed subanalyses of patients with diagnoses of prostate, lung, colorectal, and bladder cancers and lymphoma, with the models adjusted for cancer stage and grade.
The median age of the cohort was 71 years, 98% were males, and 66% were white. A total of 771,285 veterans (22%) had a cancer diagnosis. Of the 82,028 veterans who developed AD (2.3% of the entire cohort), 24% were cancer survivors, and the remainder had no cancer history.
The investigators also found that "treatment with chemotherapy conferred additional protection against AD in nearly all cancer types, suggesting that some forms of chemotherapy may have neuroprotective action."
Chemotherapy lowered the risk of AD associated with all cancers except prostate cancer by 20%-45%.
The investigators plan to look at individual categories of anticancer agents, and to see whether they may be common factors between cancer and AD in regard to proteins, genes, and biochemical pathways.
One intriguing target for exploration, Dr. Frain said, is peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), an enzyme that when upregulated has been associated with the pathogenesis of some forms of cancer, and when downregulated may be associated with the development of AD.
The study was supported by grants from the Department of Veterans Affairs. Dr. Frain is supported by a VA Special Fellowship in geriatrics.
BOSTON – It’s a trade-off that few people would be likely to make, but having cancer – particularly a type treated by chemotherapy – is associated with a significantly decreased risk for developing Alzheimer’s disease, a retrospective study has shown.
An inverse relationship was found between the incidence of the majority of different types of cancer and Alzheimer’s disease (AD) risk, in a review of the records of nearly 3.5 million U.S. veterans.
Liver cancer survivors had the lowest risk for AD (hazard ratio = 0.49), followed by survivors of pancreatic cancer (HR = 0.56), esophageal cancer (0.67), and multiple myeloma (0.74), reported Dr. Laura Frain of the geriatric research education and clinical center at Boston VA Medical Center.
However, survivors of prostate cancer had a small but significantly higher risk for AD (HR = 1.11), and other screening-detected cancers (colorectal cancer, melanoma) were not associated with a reduced risk, Dr. Frain and her associates found.
"There may be something different about prostate cancer survivors, but whether that’s biologic or related to the way that they’re screened is unclear," Dr. Frain said in an interview.
Many types of cancer were associated with an increased risk for non-AD dementias, with increased risks ranging from an HR of 1.11 for head and neck cancer to 2.64 for brain cancer.
The investigators attempted to control for the possibility that people with cancer may not survive long enough to develop frank dementia by looking at other age-related conditions, including stroke, osteoarthritis, cataracts, and macular degeneration. They found that all cancers were associated with an increased risk for other age-related conditions, suggesting that their findings of reduced AD risk were valid, Dr. Frain said at the Alzheimer’s Association International Conference 2013.
Findings corroborated
The findings parallel those of a recently published study of more than 1 million residents of Northern Italy (Neurology 2013 July 10 [doi:10.1212/WNL.0b013e31829c5ec1]). The investigators in that study found that "[t]he risk of cancer in patients with AD dementia was halved, and the risk of AD dementia in patients with cancer was 35% reduced. This relationship was observed in almost all subgroup analyses, suggesting that some anticipated potential confounding factors did not significantly influence the results."
Dr. Frain noted that three previous prospective cohort studies had found that older adults with cancer had a reduction in risk for incident AD, ranging from a 33% to a 60% decline. Those studies, however, were limited by small numbers of patients with cancer, limiting the ability to look for associations with specific cancer or treatment types.
The current study drew on data from the massive U.S. National Veterans Affairs Healthcare System to assemble a cohort of 3,499,378 veterans who received outpatient care within the system from 1997 to 2011. The investigators used regression analysis models adjusted for cancer treatment, multiple comorbidities, follow-up time, and number of visits per year before baseline. In addition, the researchers performed subanalyses of patients with diagnoses of prostate, lung, colorectal, and bladder cancers and lymphoma, with the models adjusted for cancer stage and grade.
The median age of the cohort was 71 years, 98% were males, and 66% were white. A total of 771,285 veterans (22%) had a cancer diagnosis. Of the 82,028 veterans who developed AD (2.3% of the entire cohort), 24% were cancer survivors, and the remainder had no cancer history.
The investigators also found that "treatment with chemotherapy conferred additional protection against AD in nearly all cancer types, suggesting that some forms of chemotherapy may have neuroprotective action."
Chemotherapy lowered the risk of AD associated with all cancers except prostate cancer by 20%-45%.
The investigators plan to look at individual categories of anticancer agents, and to see whether they may be common factors between cancer and AD in regard to proteins, genes, and biochemical pathways.
One intriguing target for exploration, Dr. Frain said, is peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), an enzyme that when upregulated has been associated with the pathogenesis of some forms of cancer, and when downregulated may be associated with the development of AD.
The study was supported by grants from the Department of Veterans Affairs. Dr. Frain is supported by a VA Special Fellowship in geriatrics.
BOSTON – It’s a trade-off that few people would be likely to make, but having cancer – particularly a type treated by chemotherapy – is associated with a significantly decreased risk for developing Alzheimer’s disease, a retrospective study has shown.
An inverse relationship was found between the incidence of the majority of different types of cancer and Alzheimer’s disease (AD) risk, in a review of the records of nearly 3.5 million U.S. veterans.
Liver cancer survivors had the lowest risk for AD (hazard ratio = 0.49), followed by survivors of pancreatic cancer (HR = 0.56), esophageal cancer (0.67), and multiple myeloma (0.74), reported Dr. Laura Frain of the geriatric research education and clinical center at Boston VA Medical Center.
However, survivors of prostate cancer had a small but significantly higher risk for AD (HR = 1.11), and other screening-detected cancers (colorectal cancer, melanoma) were not associated with a reduced risk, Dr. Frain and her associates found.
"There may be something different about prostate cancer survivors, but whether that’s biologic or related to the way that they’re screened is unclear," Dr. Frain said in an interview.
Many types of cancer were associated with an increased risk for non-AD dementias, with increased risks ranging from an HR of 1.11 for head and neck cancer to 2.64 for brain cancer.
The investigators attempted to control for the possibility that people with cancer may not survive long enough to develop frank dementia by looking at other age-related conditions, including stroke, osteoarthritis, cataracts, and macular degeneration. They found that all cancers were associated with an increased risk for other age-related conditions, suggesting that their findings of reduced AD risk were valid, Dr. Frain said at the Alzheimer’s Association International Conference 2013.
Findings corroborated
The findings parallel those of a recently published study of more than 1 million residents of Northern Italy (Neurology 2013 July 10 [doi:10.1212/WNL.0b013e31829c5ec1]). The investigators in that study found that "[t]he risk of cancer in patients with AD dementia was halved, and the risk of AD dementia in patients with cancer was 35% reduced. This relationship was observed in almost all subgroup analyses, suggesting that some anticipated potential confounding factors did not significantly influence the results."
Dr. Frain noted that three previous prospective cohort studies had found that older adults with cancer had a reduction in risk for incident AD, ranging from a 33% to a 60% decline. Those studies, however, were limited by small numbers of patients with cancer, limiting the ability to look for associations with specific cancer or treatment types.
The current study drew on data from the massive U.S. National Veterans Affairs Healthcare System to assemble a cohort of 3,499,378 veterans who received outpatient care within the system from 1997 to 2011. The investigators used regression analysis models adjusted for cancer treatment, multiple comorbidities, follow-up time, and number of visits per year before baseline. In addition, the researchers performed subanalyses of patients with diagnoses of prostate, lung, colorectal, and bladder cancers and lymphoma, with the models adjusted for cancer stage and grade.
The median age of the cohort was 71 years, 98% were males, and 66% were white. A total of 771,285 veterans (22%) had a cancer diagnosis. Of the 82,028 veterans who developed AD (2.3% of the entire cohort), 24% were cancer survivors, and the remainder had no cancer history.
The investigators also found that "treatment with chemotherapy conferred additional protection against AD in nearly all cancer types, suggesting that some forms of chemotherapy may have neuroprotective action."
Chemotherapy lowered the risk of AD associated with all cancers except prostate cancer by 20%-45%.
The investigators plan to look at individual categories of anticancer agents, and to see whether they may be common factors between cancer and AD in regard to proteins, genes, and biochemical pathways.
One intriguing target for exploration, Dr. Frain said, is peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), an enzyme that when upregulated has been associated with the pathogenesis of some forms of cancer, and when downregulated may be associated with the development of AD.
The study was supported by grants from the Department of Veterans Affairs. Dr. Frain is supported by a VA Special Fellowship in geriatrics.
AT AAIC 2013
Major finding: The risk for incident Alzheimer’s disease was reduced by 51% in liver cancer survivors, 44% in survivors of pancreatic cancer, and 23% in survivors of esophageal cancer.
Data source: A retrospective cohort study of 3,499,378 U.S. veterans.
Disclosures: The study was supported by grants from the Department of Veterans Affairs. Dr. Frain is supported by a VA Special Fellowship in geriatrics.
CSF findings boost confidence in dementia diagnosis
BOSTON – Like a belt and suspenders, the presence of measurable biomarkers in cerebrospinal fluid gives clinicians added confidence, even when they are already comfortable with a diagnosis of dementia, reported investigators at the Alzheimer’s Association International Conference 2013.
A study of how neurologists incorporate biomarkers such as amyloid-beta 42, tau, and phosphorylated tau into their diagnostic practice found that in a substantial proportion of patients, cerebrospinal fluid (CSF) results prompted some type of change in patient management, such as a different diagnosis or additional studies, reported Wiesje van der Flier, Ph.D., senior researcher in neurology at the VU University Medical Center in Amsterdam.
"Countless studies have shown that these biomarkers have good discriminatory value for identifying Alzheimer’s disease [AD], but almost all of these studies have been performed in selected research populations. Nevertheless, these biomarkers are increasingly being used in regular clinical practice," Dr. van der Flier said.
She noted that the 2011 recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for AD state that "the use of biomarkers to enhance certainty of AD pathophysiological process may be useful in three circumstances: investigational studies, clinical trials, and as optional clinical tools for use where available and when deemed appropriate by the clinician."
Despite these recommendations, there are still no clear guidelines for clinicians and considerable variability in interpretation of results, she said.
To see how clinicians were using biomarkers in their center, they conducted a prospective study during June 2011-May 2012.
A total of 438 patients, 351 of whom underwent lumbar puncture for CSF screening, were included. The patients were diagnosed by a multidisciplinary team blinded to each patient’s biomarker status, and neurologists were asked to fill out questionnaires both before and after disclosure of CSF status. The primary outcome measure was change in diagnosis, and the neurologist’s confidence in that diagnosis.
The majority of neurologists (74%) said that they wanted to know the results of the lumbar puncture before they were disclosed, with 46% saying they hoped it would confirm the diagnosis, 36% saying they wished to exclude a diagnosis of AD, 11% hoping to reassure the patient, 24% saying they wanted to assess prognosis, and 11% saying they wanted to select patients for possible clinical trials.
Neurologists tended to be more confident with their diagnoses when they felt it wasn’t necessary to have CSF findings first (90% vs. 82%; P less than .001).
CSF results caused a change of diagnosis in 7% of all patients with CSF tests (23 cases).
The findings bolstered clinician confidence in the diagnosis in the majority of cases where the results did not change diagnosis, from 84% before disclosure, to 89% after (P = .001). The increase was significant for individual diagnoses of AD (P less than .001), other dementia (P less than .01) and mild cognitive impairment (P less than .001).
In 13% of patients with CSF findings and unchanged diagnosis (40 patients), the physicians reported losing confidence in the diagnosis because the CSF findings were discordant with the clinical diagnosis. Many of these had more intensive clinical follow-up or additional studies, Dr. van der Flier said.
The study was funded by Dutch public agencies, and the VU Medical Center has received support for imaging studies and clinical trials from Nutricia, Lilly, Merck, Novartis, Roche, and Janssen-Pfizer. Dr. van der Flier reported having no personal conflicts of interest.
BOSTON – Like a belt and suspenders, the presence of measurable biomarkers in cerebrospinal fluid gives clinicians added confidence, even when they are already comfortable with a diagnosis of dementia, reported investigators at the Alzheimer’s Association International Conference 2013.
A study of how neurologists incorporate biomarkers such as amyloid-beta 42, tau, and phosphorylated tau into their diagnostic practice found that in a substantial proportion of patients, cerebrospinal fluid (CSF) results prompted some type of change in patient management, such as a different diagnosis or additional studies, reported Wiesje van der Flier, Ph.D., senior researcher in neurology at the VU University Medical Center in Amsterdam.
"Countless studies have shown that these biomarkers have good discriminatory value for identifying Alzheimer’s disease [AD], but almost all of these studies have been performed in selected research populations. Nevertheless, these biomarkers are increasingly being used in regular clinical practice," Dr. van der Flier said.
She noted that the 2011 recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for AD state that "the use of biomarkers to enhance certainty of AD pathophysiological process may be useful in three circumstances: investigational studies, clinical trials, and as optional clinical tools for use where available and when deemed appropriate by the clinician."
Despite these recommendations, there are still no clear guidelines for clinicians and considerable variability in interpretation of results, she said.
To see how clinicians were using biomarkers in their center, they conducted a prospective study during June 2011-May 2012.
A total of 438 patients, 351 of whom underwent lumbar puncture for CSF screening, were included. The patients were diagnosed by a multidisciplinary team blinded to each patient’s biomarker status, and neurologists were asked to fill out questionnaires both before and after disclosure of CSF status. The primary outcome measure was change in diagnosis, and the neurologist’s confidence in that diagnosis.
The majority of neurologists (74%) said that they wanted to know the results of the lumbar puncture before they were disclosed, with 46% saying they hoped it would confirm the diagnosis, 36% saying they wished to exclude a diagnosis of AD, 11% hoping to reassure the patient, 24% saying they wanted to assess prognosis, and 11% saying they wanted to select patients for possible clinical trials.
Neurologists tended to be more confident with their diagnoses when they felt it wasn’t necessary to have CSF findings first (90% vs. 82%; P less than .001).
CSF results caused a change of diagnosis in 7% of all patients with CSF tests (23 cases).
The findings bolstered clinician confidence in the diagnosis in the majority of cases where the results did not change diagnosis, from 84% before disclosure, to 89% after (P = .001). The increase was significant for individual diagnoses of AD (P less than .001), other dementia (P less than .01) and mild cognitive impairment (P less than .001).
In 13% of patients with CSF findings and unchanged diagnosis (40 patients), the physicians reported losing confidence in the diagnosis because the CSF findings were discordant with the clinical diagnosis. Many of these had more intensive clinical follow-up or additional studies, Dr. van der Flier said.
The study was funded by Dutch public agencies, and the VU Medical Center has received support for imaging studies and clinical trials from Nutricia, Lilly, Merck, Novartis, Roche, and Janssen-Pfizer. Dr. van der Flier reported having no personal conflicts of interest.
BOSTON – Like a belt and suspenders, the presence of measurable biomarkers in cerebrospinal fluid gives clinicians added confidence, even when they are already comfortable with a diagnosis of dementia, reported investigators at the Alzheimer’s Association International Conference 2013.
A study of how neurologists incorporate biomarkers such as amyloid-beta 42, tau, and phosphorylated tau into their diagnostic practice found that in a substantial proportion of patients, cerebrospinal fluid (CSF) results prompted some type of change in patient management, such as a different diagnosis or additional studies, reported Wiesje van der Flier, Ph.D., senior researcher in neurology at the VU University Medical Center in Amsterdam.
"Countless studies have shown that these biomarkers have good discriminatory value for identifying Alzheimer’s disease [AD], but almost all of these studies have been performed in selected research populations. Nevertheless, these biomarkers are increasingly being used in regular clinical practice," Dr. van der Flier said.
She noted that the 2011 recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for AD state that "the use of biomarkers to enhance certainty of AD pathophysiological process may be useful in three circumstances: investigational studies, clinical trials, and as optional clinical tools for use where available and when deemed appropriate by the clinician."
Despite these recommendations, there are still no clear guidelines for clinicians and considerable variability in interpretation of results, she said.
To see how clinicians were using biomarkers in their center, they conducted a prospective study during June 2011-May 2012.
A total of 438 patients, 351 of whom underwent lumbar puncture for CSF screening, were included. The patients were diagnosed by a multidisciplinary team blinded to each patient’s biomarker status, and neurologists were asked to fill out questionnaires both before and after disclosure of CSF status. The primary outcome measure was change in diagnosis, and the neurologist’s confidence in that diagnosis.
The majority of neurologists (74%) said that they wanted to know the results of the lumbar puncture before they were disclosed, with 46% saying they hoped it would confirm the diagnosis, 36% saying they wished to exclude a diagnosis of AD, 11% hoping to reassure the patient, 24% saying they wanted to assess prognosis, and 11% saying they wanted to select patients for possible clinical trials.
Neurologists tended to be more confident with their diagnoses when they felt it wasn’t necessary to have CSF findings first (90% vs. 82%; P less than .001).
CSF results caused a change of diagnosis in 7% of all patients with CSF tests (23 cases).
The findings bolstered clinician confidence in the diagnosis in the majority of cases where the results did not change diagnosis, from 84% before disclosure, to 89% after (P = .001). The increase was significant for individual diagnoses of AD (P less than .001), other dementia (P less than .01) and mild cognitive impairment (P less than .001).
In 13% of patients with CSF findings and unchanged diagnosis (40 patients), the physicians reported losing confidence in the diagnosis because the CSF findings were discordant with the clinical diagnosis. Many of these had more intensive clinical follow-up or additional studies, Dr. van der Flier said.
The study was funded by Dutch public agencies, and the VU Medical Center has received support for imaging studies and clinical trials from Nutricia, Lilly, Merck, Novartis, Roche, and Janssen-Pfizer. Dr. van der Flier reported having no personal conflicts of interest.
AT AAIC 2013
Major finding: Cerebrospinal fluid (CSF) findings changed the diagnosis in 7% of patients with a clinical diagnosis of dementia.
Data source: Prospective study of diagnostic practice in a single center with 438 patients screened for dementia.
Disclosures: The study was funded by Dutch public agencies, and the VU Medical Center has received support for imaging studies and clinical trials from Nutricia, Lilly, Merck, Novartis, Roche, and Janssen-Pfizer. Dr. van der Flier reported having no personal conflicts of interest.
Exercise in young adulthood may pay dividends to brain later
BOSTON – The sedentary young adults of today may be tomorrow’s cognitively impaired middle-aged adults, investigators suggested at Alzheimer’s Association International Conference 2013.
Young adults who are sedentary and stay relatively inactive through their early adult years are significantly more likely than are their more active peers to have worse executive function and processing speed in middle age, Tina Hoang, a research associate at Veterans Health Research Institute in San Francisco, said on behalf of researchers in the CARDIA (Coronary Artery Risk Development in Young Adults) study.
"We didn’t see an association with verbal memory, but we think that these findings suggest that physical inactivity earlier in the life course may be associated with worse cognitive outcomes later in life," she said.
Although the mechanisms for the association are unclear, it is well documented that exercise decreases vascular risk factors, inflammation, and depression, and increases angiogenesis and neurogenesis, which may help to build up cognitive reserves early in the life course that can be drawn on in middle age, Ms. Hoang said.
The finding also suggest that the risks are cumulative, and that modifying cardiovascular risk factors in young adulthood may be warranted, said lead investigator Dr. Kristine Yaffe, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco.
"I think we can conclude that cardiovascular risk factors are probably very important modifiable risk factors, even early in life, for cognitive aging. But what does it mean in terms of public policy, how aggressive to be? I don’t think we really know," said Dr. Yaffe, also chief of geriatric psychiatry and director of the memory disorders clinic at the San Francisco VA Medical Center.
More longitudinal and life-course studies are needed, and it will be important for researchers to incorporate both biomarkers and neuroimaging into their studies to establish mechanisms of effect, she said.
In it for the long haul
In 1985 and 1986, black and white adults from the ages of 18 to 30 years in Birmingham, Ala.; Chicago; Minneapolis, Minn.; and Oakland, Calif., were recruited into the CARDIA longitudinal study and were followed for 25 years.
The final sample size of 3,375 participants included those with at least three assessments of physical activity and cognitive function by study year 25.
Low physical activity, the bottom quartile at baseline, was defined as less than 197 exercise units engaged in during leisure, occupational, and household activities for more than two-thirds of completed visits.
The cutoff of 197 exercise units translates into approximately 100 minutes per week of moderate-intensity physical activity. The U.S. Department of Health and Human Services and the American Heart Association generally recommend that adults get at least 300 exercise units (150 minutes) per week, the investigators said.
Sedentary participants were those with fewer than 50 exercise units on more than two-thirds of completed visits.
Investigators assessed cognitive function with the Digit Symbol Substitution Test (DSST, standard deviation [SD] = 16.16), Stroop Interference Score (S = 10.98), and Rey Auditory Verbal Learning Test (RAVLT, SD = 3.27).
The authors found that on the DSST, 14.9% of those with moderate activity levels or greater were deemed to have cognitive impairment, compared with 20.9% of those with low activity levels. In a regression analysis adjusted for age, race, sex, education, smoking, body mass index, and hypertension, low activity on the DSST had a statistically significant odds ratio (OR) of 1.93 for cognitive impairment.
Similarly, 11.6% of the more active participants were judged cognitively impaired on the STROOP test, compared with 18.9% of their less active peers (adjusted OR 1.40).
Results of the RAVLT were not significantly different between the high- and low-activity groups.
The investigators are planning to develop objective measures of sedentary behavior and physical activity, and said they hope to study cognitive function over time, coupling the data to neuroimaging and biomarker studies.
The CARDIA study was supported by the National Heart, Lung, and Blood Institute. Dr. Yaffe disclosed receiving grant support from the National Institutes of Health, and serving as a consultant to Novartis and Eli Lilly. Tina Hoang reported having no financial disclosures.
BOSTON – The sedentary young adults of today may be tomorrow’s cognitively impaired middle-aged adults, investigators suggested at Alzheimer’s Association International Conference 2013.
Young adults who are sedentary and stay relatively inactive through their early adult years are significantly more likely than are their more active peers to have worse executive function and processing speed in middle age, Tina Hoang, a research associate at Veterans Health Research Institute in San Francisco, said on behalf of researchers in the CARDIA (Coronary Artery Risk Development in Young Adults) study.
"We didn’t see an association with verbal memory, but we think that these findings suggest that physical inactivity earlier in the life course may be associated with worse cognitive outcomes later in life," she said.
Although the mechanisms for the association are unclear, it is well documented that exercise decreases vascular risk factors, inflammation, and depression, and increases angiogenesis and neurogenesis, which may help to build up cognitive reserves early in the life course that can be drawn on in middle age, Ms. Hoang said.
The finding also suggest that the risks are cumulative, and that modifying cardiovascular risk factors in young adulthood may be warranted, said lead investigator Dr. Kristine Yaffe, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco.
"I think we can conclude that cardiovascular risk factors are probably very important modifiable risk factors, even early in life, for cognitive aging. But what does it mean in terms of public policy, how aggressive to be? I don’t think we really know," said Dr. Yaffe, also chief of geriatric psychiatry and director of the memory disorders clinic at the San Francisco VA Medical Center.
More longitudinal and life-course studies are needed, and it will be important for researchers to incorporate both biomarkers and neuroimaging into their studies to establish mechanisms of effect, she said.
In it for the long haul
In 1985 and 1986, black and white adults from the ages of 18 to 30 years in Birmingham, Ala.; Chicago; Minneapolis, Minn.; and Oakland, Calif., were recruited into the CARDIA longitudinal study and were followed for 25 years.
The final sample size of 3,375 participants included those with at least three assessments of physical activity and cognitive function by study year 25.
Low physical activity, the bottom quartile at baseline, was defined as less than 197 exercise units engaged in during leisure, occupational, and household activities for more than two-thirds of completed visits.
The cutoff of 197 exercise units translates into approximately 100 minutes per week of moderate-intensity physical activity. The U.S. Department of Health and Human Services and the American Heart Association generally recommend that adults get at least 300 exercise units (150 minutes) per week, the investigators said.
Sedentary participants were those with fewer than 50 exercise units on more than two-thirds of completed visits.
Investigators assessed cognitive function with the Digit Symbol Substitution Test (DSST, standard deviation [SD] = 16.16), Stroop Interference Score (S = 10.98), and Rey Auditory Verbal Learning Test (RAVLT, SD = 3.27).
The authors found that on the DSST, 14.9% of those with moderate activity levels or greater were deemed to have cognitive impairment, compared with 20.9% of those with low activity levels. In a regression analysis adjusted for age, race, sex, education, smoking, body mass index, and hypertension, low activity on the DSST had a statistically significant odds ratio (OR) of 1.93 for cognitive impairment.
Similarly, 11.6% of the more active participants were judged cognitively impaired on the STROOP test, compared with 18.9% of their less active peers (adjusted OR 1.40).
Results of the RAVLT were not significantly different between the high- and low-activity groups.
The investigators are planning to develop objective measures of sedentary behavior and physical activity, and said they hope to study cognitive function over time, coupling the data to neuroimaging and biomarker studies.
The CARDIA study was supported by the National Heart, Lung, and Blood Institute. Dr. Yaffe disclosed receiving grant support from the National Institutes of Health, and serving as a consultant to Novartis and Eli Lilly. Tina Hoang reported having no financial disclosures.
BOSTON – The sedentary young adults of today may be tomorrow’s cognitively impaired middle-aged adults, investigators suggested at Alzheimer’s Association International Conference 2013.
Young adults who are sedentary and stay relatively inactive through their early adult years are significantly more likely than are their more active peers to have worse executive function and processing speed in middle age, Tina Hoang, a research associate at Veterans Health Research Institute in San Francisco, said on behalf of researchers in the CARDIA (Coronary Artery Risk Development in Young Adults) study.
"We didn’t see an association with verbal memory, but we think that these findings suggest that physical inactivity earlier in the life course may be associated with worse cognitive outcomes later in life," she said.
Although the mechanisms for the association are unclear, it is well documented that exercise decreases vascular risk factors, inflammation, and depression, and increases angiogenesis and neurogenesis, which may help to build up cognitive reserves early in the life course that can be drawn on in middle age, Ms. Hoang said.
The finding also suggest that the risks are cumulative, and that modifying cardiovascular risk factors in young adulthood may be warranted, said lead investigator Dr. Kristine Yaffe, professor of psychiatry, neurology, and epidemiology at the University of California, San Francisco.
"I think we can conclude that cardiovascular risk factors are probably very important modifiable risk factors, even early in life, for cognitive aging. But what does it mean in terms of public policy, how aggressive to be? I don’t think we really know," said Dr. Yaffe, also chief of geriatric psychiatry and director of the memory disorders clinic at the San Francisco VA Medical Center.
More longitudinal and life-course studies are needed, and it will be important for researchers to incorporate both biomarkers and neuroimaging into their studies to establish mechanisms of effect, she said.
In it for the long haul
In 1985 and 1986, black and white adults from the ages of 18 to 30 years in Birmingham, Ala.; Chicago; Minneapolis, Minn.; and Oakland, Calif., were recruited into the CARDIA longitudinal study and were followed for 25 years.
The final sample size of 3,375 participants included those with at least three assessments of physical activity and cognitive function by study year 25.
Low physical activity, the bottom quartile at baseline, was defined as less than 197 exercise units engaged in during leisure, occupational, and household activities for more than two-thirds of completed visits.
The cutoff of 197 exercise units translates into approximately 100 minutes per week of moderate-intensity physical activity. The U.S. Department of Health and Human Services and the American Heart Association generally recommend that adults get at least 300 exercise units (150 minutes) per week, the investigators said.
Sedentary participants were those with fewer than 50 exercise units on more than two-thirds of completed visits.
Investigators assessed cognitive function with the Digit Symbol Substitution Test (DSST, standard deviation [SD] = 16.16), Stroop Interference Score (S = 10.98), and Rey Auditory Verbal Learning Test (RAVLT, SD = 3.27).
The authors found that on the DSST, 14.9% of those with moderate activity levels or greater were deemed to have cognitive impairment, compared with 20.9% of those with low activity levels. In a regression analysis adjusted for age, race, sex, education, smoking, body mass index, and hypertension, low activity on the DSST had a statistically significant odds ratio (OR) of 1.93 for cognitive impairment.
Similarly, 11.6% of the more active participants were judged cognitively impaired on the STROOP test, compared with 18.9% of their less active peers (adjusted OR 1.40).
Results of the RAVLT were not significantly different between the high- and low-activity groups.
The investigators are planning to develop objective measures of sedentary behavior and physical activity, and said they hope to study cognitive function over time, coupling the data to neuroimaging and biomarker studies.
The CARDIA study was supported by the National Heart, Lung, and Blood Institute. Dr. Yaffe disclosed receiving grant support from the National Institutes of Health, and serving as a consultant to Novartis and Eli Lilly. Tina Hoang reported having no financial disclosures.
AT AAIC 2013
Major finding: Among adults followed for 25 years, low physical activity levels were associated with nearly twofold greater odds of cognitive impairment on the Digital Symbol Substitution Test compared with higher activity levels.
Data source: Longitudinal, biracial study of 3,375 adults from four U.S. cities.
Disclosures: The CARDIA study was supported by the National Heart, Lung, and Blood Institute. Dr. Yaffe disclosed receiving grant support from the National Institutes of Health, and serving as a consultant to Novartis and Eli Lilly. Tina Hoang reported having no financial disclosures.
Experimental agent CHF5074 improves memory tasks in mild cognitive impairment
BOSTON – Patients with mild cognitive impairment had significant improvement in both executive function and verbal memory when they were treated with CHF5074, an experimental gamma-secretase modulator that investigators claim has the potential to partially restore the brain’s innate immune response, investigators reported at Alzheimer’s Association International Conference 2013.
Among 32 patients with mild cognitive impairment (MCI) who reached 64 weeks of follow-up in an open-label extension of a double-blind, placebo-controlled trial, CHF5074 was associated with significant improvement over baseline in the Digital Symbol Substitution Test (P less than .001), Trail-Making Tests A and B (P = .002 and .004, respectively), Immediate Word Recall (P =.001), and Delayed Word Recall (P = .003), said co–principal investigator Dr. Joel Ross of the Memory Enhancement Center of America in Eatontown, N.J.
Carriers of either one or two copies of the apolipoprotein E epsilon-4 (APOE epsilon-4) allele, who are at increased risk for early-onset Alzheimer’s disease (AD), had significantly greater improvements than did noncarriers in both word recall and trail-making tests.
"We think that this medication may be a start, the first step – perhaps a baby step – in preventing the memory loss that of course is the classic hallmark that Dr. Alzheimer described in the early 1900s," Dr. Ross said at a media briefing held several days prior to the presentation of his data.
Microglia, macrophages that serve as the primary active immune response mechanism of the brain, can malfunction in the presence of beta-amyloid (A-beta) protein, releasing inflammatory cytokines such as tumor necrosis factor–alpha (TNF-alpha), which in turn can cause irreversible neural damage.
CHF5074 (1-(3\',4\'-dichloro-2-fluoro[1,1\'-biphenyl]-4-yl)-cyclopropanecarboxylic acid is a small molecule modulator of the gamma-secretase enzymatic complex involved in A-beta formation, which is believed by many to be the hallmark pathologic event of AD.
According to CHF5074’s developer, the compound does not have the anticyclooxygenase (COX) or Notch-interfering properties seen with some gamma-secretase inhibitors (JPET 2007;323:822-30). The drug has been shown to lower cerebrospinal fluid levels of both soluble CD40 ligand and TNF-alpha, which are markers of neuroinflammation.
"That’s the big selling point for gamma-secretase modulators – that they shift the types of A-betas that are produced without affecting COX, without affecting Notch signaling," said Michael Wolfe, Ph.D., professor of neurology at Harvard Medical School and Brigham and Women’s Hospital, both in Boston. Dr. Wolfe, who studies gamma-secretase pathology in dementias, was not involved in the study.
But whether the drug is actually having an effect on microglia is less clear, he said.
"That doesn’t make any sense to me, based on the molecular mechanism," Dr. Wolfe said in an interview.
CHF5074 was evaluated for safety, tolerability, and efficacy in a 14-week trial of 96 patients with MCI who were enrolled in one of three dose regimens (200, 400, or 600 mg daily). Of this group, 74 enrolled in an open-label extension phase, and 32 were available for evaluation after 64 weeks.
An interim analysis of the cognitive tests in this subgroup showed significant improvement over baseline in domains of both verbal recall and executive function, as noted before.
Fourteen patients dropped out of the study at week 40, including 2 patients in the 600-mg/day group because of worsening cognitive function and serum creatinine elevation, and 1 patient in the 400-mg group because of pneumonia.
Gastrointestinal disorders were the most frequent treatment-emergent adverse events, with diarrhea occurring in 16% of patients on the 600-mg dose, 6.3% of those on 400 mg, and 1.4% on 200 mg.
The study was sponsored by Chiesi Pharmaceuticals. Dr. Ross heads the contract research organization that conducted the study. He did not disclose whether he has additional conflicts of interest. Dr. Wolfe reported having nor relevant disclosures.
BOSTON – Patients with mild cognitive impairment had significant improvement in both executive function and verbal memory when they were treated with CHF5074, an experimental gamma-secretase modulator that investigators claim has the potential to partially restore the brain’s innate immune response, investigators reported at Alzheimer’s Association International Conference 2013.
Among 32 patients with mild cognitive impairment (MCI) who reached 64 weeks of follow-up in an open-label extension of a double-blind, placebo-controlled trial, CHF5074 was associated with significant improvement over baseline in the Digital Symbol Substitution Test (P less than .001), Trail-Making Tests A and B (P = .002 and .004, respectively), Immediate Word Recall (P =.001), and Delayed Word Recall (P = .003), said co–principal investigator Dr. Joel Ross of the Memory Enhancement Center of America in Eatontown, N.J.
Carriers of either one or two copies of the apolipoprotein E epsilon-4 (APOE epsilon-4) allele, who are at increased risk for early-onset Alzheimer’s disease (AD), had significantly greater improvements than did noncarriers in both word recall and trail-making tests.
"We think that this medication may be a start, the first step – perhaps a baby step – in preventing the memory loss that of course is the classic hallmark that Dr. Alzheimer described in the early 1900s," Dr. Ross said at a media briefing held several days prior to the presentation of his data.
Microglia, macrophages that serve as the primary active immune response mechanism of the brain, can malfunction in the presence of beta-amyloid (A-beta) protein, releasing inflammatory cytokines such as tumor necrosis factor–alpha (TNF-alpha), which in turn can cause irreversible neural damage.
CHF5074 (1-(3\',4\'-dichloro-2-fluoro[1,1\'-biphenyl]-4-yl)-cyclopropanecarboxylic acid is a small molecule modulator of the gamma-secretase enzymatic complex involved in A-beta formation, which is believed by many to be the hallmark pathologic event of AD.
According to CHF5074’s developer, the compound does not have the anticyclooxygenase (COX) or Notch-interfering properties seen with some gamma-secretase inhibitors (JPET 2007;323:822-30). The drug has been shown to lower cerebrospinal fluid levels of both soluble CD40 ligand and TNF-alpha, which are markers of neuroinflammation.
"That’s the big selling point for gamma-secretase modulators – that they shift the types of A-betas that are produced without affecting COX, without affecting Notch signaling," said Michael Wolfe, Ph.D., professor of neurology at Harvard Medical School and Brigham and Women’s Hospital, both in Boston. Dr. Wolfe, who studies gamma-secretase pathology in dementias, was not involved in the study.
But whether the drug is actually having an effect on microglia is less clear, he said.
"That doesn’t make any sense to me, based on the molecular mechanism," Dr. Wolfe said in an interview.
CHF5074 was evaluated for safety, tolerability, and efficacy in a 14-week trial of 96 patients with MCI who were enrolled in one of three dose regimens (200, 400, or 600 mg daily). Of this group, 74 enrolled in an open-label extension phase, and 32 were available for evaluation after 64 weeks.
An interim analysis of the cognitive tests in this subgroup showed significant improvement over baseline in domains of both verbal recall and executive function, as noted before.
Fourteen patients dropped out of the study at week 40, including 2 patients in the 600-mg/day group because of worsening cognitive function and serum creatinine elevation, and 1 patient in the 400-mg group because of pneumonia.
Gastrointestinal disorders were the most frequent treatment-emergent adverse events, with diarrhea occurring in 16% of patients on the 600-mg dose, 6.3% of those on 400 mg, and 1.4% on 200 mg.
The study was sponsored by Chiesi Pharmaceuticals. Dr. Ross heads the contract research organization that conducted the study. He did not disclose whether he has additional conflicts of interest. Dr. Wolfe reported having nor relevant disclosures.
BOSTON – Patients with mild cognitive impairment had significant improvement in both executive function and verbal memory when they were treated with CHF5074, an experimental gamma-secretase modulator that investigators claim has the potential to partially restore the brain’s innate immune response, investigators reported at Alzheimer’s Association International Conference 2013.
Among 32 patients with mild cognitive impairment (MCI) who reached 64 weeks of follow-up in an open-label extension of a double-blind, placebo-controlled trial, CHF5074 was associated with significant improvement over baseline in the Digital Symbol Substitution Test (P less than .001), Trail-Making Tests A and B (P = .002 and .004, respectively), Immediate Word Recall (P =.001), and Delayed Word Recall (P = .003), said co–principal investigator Dr. Joel Ross of the Memory Enhancement Center of America in Eatontown, N.J.
Carriers of either one or two copies of the apolipoprotein E epsilon-4 (APOE epsilon-4) allele, who are at increased risk for early-onset Alzheimer’s disease (AD), had significantly greater improvements than did noncarriers in both word recall and trail-making tests.
"We think that this medication may be a start, the first step – perhaps a baby step – in preventing the memory loss that of course is the classic hallmark that Dr. Alzheimer described in the early 1900s," Dr. Ross said at a media briefing held several days prior to the presentation of his data.
Microglia, macrophages that serve as the primary active immune response mechanism of the brain, can malfunction in the presence of beta-amyloid (A-beta) protein, releasing inflammatory cytokines such as tumor necrosis factor–alpha (TNF-alpha), which in turn can cause irreversible neural damage.
CHF5074 (1-(3\',4\'-dichloro-2-fluoro[1,1\'-biphenyl]-4-yl)-cyclopropanecarboxylic acid is a small molecule modulator of the gamma-secretase enzymatic complex involved in A-beta formation, which is believed by many to be the hallmark pathologic event of AD.
According to CHF5074’s developer, the compound does not have the anticyclooxygenase (COX) or Notch-interfering properties seen with some gamma-secretase inhibitors (JPET 2007;323:822-30). The drug has been shown to lower cerebrospinal fluid levels of both soluble CD40 ligand and TNF-alpha, which are markers of neuroinflammation.
"That’s the big selling point for gamma-secretase modulators – that they shift the types of A-betas that are produced without affecting COX, without affecting Notch signaling," said Michael Wolfe, Ph.D., professor of neurology at Harvard Medical School and Brigham and Women’s Hospital, both in Boston. Dr. Wolfe, who studies gamma-secretase pathology in dementias, was not involved in the study.
But whether the drug is actually having an effect on microglia is less clear, he said.
"That doesn’t make any sense to me, based on the molecular mechanism," Dr. Wolfe said in an interview.
CHF5074 was evaluated for safety, tolerability, and efficacy in a 14-week trial of 96 patients with MCI who were enrolled in one of three dose regimens (200, 400, or 600 mg daily). Of this group, 74 enrolled in an open-label extension phase, and 32 were available for evaluation after 64 weeks.
An interim analysis of the cognitive tests in this subgroup showed significant improvement over baseline in domains of both verbal recall and executive function, as noted before.
Fourteen patients dropped out of the study at week 40, including 2 patients in the 600-mg/day group because of worsening cognitive function and serum creatinine elevation, and 1 patient in the 400-mg group because of pneumonia.
Gastrointestinal disorders were the most frequent treatment-emergent adverse events, with diarrhea occurring in 16% of patients on the 600-mg dose, 6.3% of those on 400 mg, and 1.4% on 200 mg.
The study was sponsored by Chiesi Pharmaceuticals. Dr. Ross heads the contract research organization that conducted the study. He did not disclose whether he has additional conflicts of interest. Dr. Wolfe reported having nor relevant disclosures.
AT AAIC2013
Major finding: Among 32 patients with mild cognitive impairment with 64 weeks of follow-up, CHF5074 was associated with significant improvements over baseline in the Digital Symbol Substitution Test (P less than .001), Trail-Making Tests A and B (P = .002 and .004, respectively), Immediate Word Recall (P =.001), and Delayed Word Recall (P = .003).
Data source: An open-label extension phase of a 14-week, double-blind, placebo-controlled trial in 96 patients with MCI.
Disclosures: The study was sponsored by Chiesi Pharmaceuticals. Dr. Ross heads the contract research organization that conducted the study. He did not disclose whether he has additional conflicts of interest. Dr. Wolfe reported having no relevant disclosures.
Obinutuzumab plus chlorambucil packs 1-2 punch against CLL in elderly
CHICAGO – Adding an anti-CD20 antibody to chlorambucil significantly improved the progression-free survival of older patients with chronic lymphocytic leukemia and comorbidities, but it’s still unknown whether the novel agent obinutuzumab has added benefit over tried-and-true rituximab, researchers reported at the annual meeting of the American Society of Clinical Oncology.
In the phase III CLL11 study, median progression-free survival (PFS) was 23 months for patients treated with a combination of obinutuzumab (GA101) and chlorambucil (Leukeran), 15.7 months for those treated with rituximab (MabThera) and chlorambucil, and 10.9 months for chlorambucil alone. The respective PFS rates at 1 year were 84%, 63%, and 27%, reported principal investigator Dr. Valentin Goede, an oncologist at the University of Cologne, Germany.
"At this stage, my conclusion is that if an older, unfit CLL patient is put on chlorambucil treatment, then he or she in addition should receive an anti-CD20 monoclonal antibody," Dr. Goede said.
Anti-CD20 agents increased the risk of infusion reactions and neutropenias, but these side effects are manageable and should not outweigh the PFS benefits, he added.
Obinutuzumab is a type II anti-CD20 antibody with a mechanism of action that differs from that of rituximab. In preclinical models, obinutuzumab showed comparatively more direct killing action of B cells and an enhanced affinity for immunoglobulin receptors, with lower complement-dependent cytotoxicity.
The CLL11 study is a 2-stage trial asking whether chlorambucil and an anti-CD20 antibody can be superior to chlorambucil monotherapy in CLL patients with coexisting medical conditions (stage 1), and whether obinutuzumab plus chlorambucil could surpass rituximab plus chlorambucil (stage 2).
Dr. Goede reported final data from stage 1 of the trial, in which the investigators enrolled 581 adults aged 18 years and older with untreated CLL and comorbidities, defined as either a total Cumulative Illness Rating Scale score higher than 6 and/or a creatinine clearance rate lower than 70 mL/minute. An additional 190 patients are planned for stage 2 of the trial, which will be a head-to-head anti-CD20 comparison, Dr. Goede said.
The patients were randomized on a 1:2:2 ratio to either six cycles of chlorambucil 0.5 mg/kg on day 1 and day 15 of every 28-day cycle (110 patients), or to the same regimen plus either obinutuzumab 1,000 mg on days 1, 8 and 15 of the first cycle, and on day 1 of cycles two through 6 (238 patients), or to rituximab 375 mg/m2 on day 1 of cycle one, and 500 mg/m2 on day 1 of every subsequent cycle, for a total of six 28-day cycles (233 patients). Patients in the chlorambucil-only arm who experienced disease progression on treatment were allowed to cross over to the obinutuzumab combination.
The median patient age was about 73 years in each study arm and about three-fourths of patients were aged 65 years or older.
Overall response rates were 30.2% for patients assigned to chlorambucil alone, compared with 75.5% for patients assigned to obinutuzumab/chlorambucil, and 65.9% in the rituximab/chlorambucil arm. There were no complete responses (CR) in the monotherapy arm, 22.2% CR with obinutuzumab/chlorambucil, and 8.3% with rituximab/chlorambucil. Partial responses occurred in 30.2%, 53.3%, and 57.6%, respectively.
No patients on chlorambucil were found to be negative for minimal residual disease (MRD) in peripheral blood or bone marrow as assessed by a central laboratory at study end. In contrast, 31% of patients on obinutuzumab/chlorambucil and 2% of those on rituximab/chlorambucil were MRD-negative in peripheral blood; 17% and 2.8%, respectively, were MRD-negative in bone marrow.
The stratified hazard ratios for PFS with the anti-CD20 agent combinations, compared with chlorambucil monotherapy were 0.14 (P less than .0001) in the obinutuzumab/chlorambucil arm, and 0.32 (P less than .0001) in the rituximab/chlorambucil arm.
In a PFS subgroup analysis stratified by age, sex, comorbidity scores, mutational status, and other factors, both anti-CD20 agents showed a significant benefit over chlorambucil alone with the exceptions of patients with the 17p chromosomal deletion (both combination groups) and those with baseline chromosomal abnormalities (rituximab arm).
There were no significant differences in overall survival at a median follow-up of 14.2 months in the obinutuzumab group and 15.2 months in the rituximab group, but overall survival data are not yet mature, Dr. Goede noted.
Grade 3 or greater adverse events of any type occurred in 41% of patients on chlorambucil monotherapy, compared with 67% of patients on obinutuzumab, and 46% of those on rituximab.
Infusion-related reactions, neutropenia, and thrombocytopenia were more frequent with obinutuzumab than with the other two drugs, although adverse events leading to death were higher with chlorambucil monotherapy. The incidence of any new malignancy was 0.9% for patients on chlorambucil only, compared with 2.5% for obinutuzumab and 2.7% for rituximab.
The study was supported by Roche. Dr. Goede disclosed consulting to and receiving honoraria and research support from the company.
This trial was an extremely interesting, large sample size, multinational planned and executed trial.
Patients with comorbidities, the population selected for this study, are the people with chronic lymphocytic leukemia who need to be addressed. They form the largest majority of the CLL population. This study confirms that chlorambucil, which we in the United States have virtually thrown out of the window as totally ineffective, may not be so if you use it in combination with an anti-CD20 monoclonal antibody. These are excellent results that we have to keep in mind.
Dr. Kanti Rai is chief of hematology-oncology at Long Island Jewish Medical Center in New Hyde Park, N.Y. He was the invited discussant of the study and disclosed serving as a consultant or advisor to Celgene, Genentech, and Teva and receiving honoraria from Celgene, Cephalon, and Genentech.
This trial was an extremely interesting, large sample size, multinational planned and executed trial.
Patients with comorbidities, the population selected for this study, are the people with chronic lymphocytic leukemia who need to be addressed. They form the largest majority of the CLL population. This study confirms that chlorambucil, which we in the United States have virtually thrown out of the window as totally ineffective, may not be so if you use it in combination with an anti-CD20 monoclonal antibody. These are excellent results that we have to keep in mind.
Dr. Kanti Rai is chief of hematology-oncology at Long Island Jewish Medical Center in New Hyde Park, N.Y. He was the invited discussant of the study and disclosed serving as a consultant or advisor to Celgene, Genentech, and Teva and receiving honoraria from Celgene, Cephalon, and Genentech.
This trial was an extremely interesting, large sample size, multinational planned and executed trial.
Patients with comorbidities, the population selected for this study, are the people with chronic lymphocytic leukemia who need to be addressed. They form the largest majority of the CLL population. This study confirms that chlorambucil, which we in the United States have virtually thrown out of the window as totally ineffective, may not be so if you use it in combination with an anti-CD20 monoclonal antibody. These are excellent results that we have to keep in mind.
Dr. Kanti Rai is chief of hematology-oncology at Long Island Jewish Medical Center in New Hyde Park, N.Y. He was the invited discussant of the study and disclosed serving as a consultant or advisor to Celgene, Genentech, and Teva and receiving honoraria from Celgene, Cephalon, and Genentech.
CHICAGO – Adding an anti-CD20 antibody to chlorambucil significantly improved the progression-free survival of older patients with chronic lymphocytic leukemia and comorbidities, but it’s still unknown whether the novel agent obinutuzumab has added benefit over tried-and-true rituximab, researchers reported at the annual meeting of the American Society of Clinical Oncology.
In the phase III CLL11 study, median progression-free survival (PFS) was 23 months for patients treated with a combination of obinutuzumab (GA101) and chlorambucil (Leukeran), 15.7 months for those treated with rituximab (MabThera) and chlorambucil, and 10.9 months for chlorambucil alone. The respective PFS rates at 1 year were 84%, 63%, and 27%, reported principal investigator Dr. Valentin Goede, an oncologist at the University of Cologne, Germany.
"At this stage, my conclusion is that if an older, unfit CLL patient is put on chlorambucil treatment, then he or she in addition should receive an anti-CD20 monoclonal antibody," Dr. Goede said.
Anti-CD20 agents increased the risk of infusion reactions and neutropenias, but these side effects are manageable and should not outweigh the PFS benefits, he added.
Obinutuzumab is a type II anti-CD20 antibody with a mechanism of action that differs from that of rituximab. In preclinical models, obinutuzumab showed comparatively more direct killing action of B cells and an enhanced affinity for immunoglobulin receptors, with lower complement-dependent cytotoxicity.
The CLL11 study is a 2-stage trial asking whether chlorambucil and an anti-CD20 antibody can be superior to chlorambucil monotherapy in CLL patients with coexisting medical conditions (stage 1), and whether obinutuzumab plus chlorambucil could surpass rituximab plus chlorambucil (stage 2).
Dr. Goede reported final data from stage 1 of the trial, in which the investigators enrolled 581 adults aged 18 years and older with untreated CLL and comorbidities, defined as either a total Cumulative Illness Rating Scale score higher than 6 and/or a creatinine clearance rate lower than 70 mL/minute. An additional 190 patients are planned for stage 2 of the trial, which will be a head-to-head anti-CD20 comparison, Dr. Goede said.
The patients were randomized on a 1:2:2 ratio to either six cycles of chlorambucil 0.5 mg/kg on day 1 and day 15 of every 28-day cycle (110 patients), or to the same regimen plus either obinutuzumab 1,000 mg on days 1, 8 and 15 of the first cycle, and on day 1 of cycles two through 6 (238 patients), or to rituximab 375 mg/m2 on day 1 of cycle one, and 500 mg/m2 on day 1 of every subsequent cycle, for a total of six 28-day cycles (233 patients). Patients in the chlorambucil-only arm who experienced disease progression on treatment were allowed to cross over to the obinutuzumab combination.
The median patient age was about 73 years in each study arm and about three-fourths of patients were aged 65 years or older.
Overall response rates were 30.2% for patients assigned to chlorambucil alone, compared with 75.5% for patients assigned to obinutuzumab/chlorambucil, and 65.9% in the rituximab/chlorambucil arm. There were no complete responses (CR) in the monotherapy arm, 22.2% CR with obinutuzumab/chlorambucil, and 8.3% with rituximab/chlorambucil. Partial responses occurred in 30.2%, 53.3%, and 57.6%, respectively.
No patients on chlorambucil were found to be negative for minimal residual disease (MRD) in peripheral blood or bone marrow as assessed by a central laboratory at study end. In contrast, 31% of patients on obinutuzumab/chlorambucil and 2% of those on rituximab/chlorambucil were MRD-negative in peripheral blood; 17% and 2.8%, respectively, were MRD-negative in bone marrow.
The stratified hazard ratios for PFS with the anti-CD20 agent combinations, compared with chlorambucil monotherapy were 0.14 (P less than .0001) in the obinutuzumab/chlorambucil arm, and 0.32 (P less than .0001) in the rituximab/chlorambucil arm.
In a PFS subgroup analysis stratified by age, sex, comorbidity scores, mutational status, and other factors, both anti-CD20 agents showed a significant benefit over chlorambucil alone with the exceptions of patients with the 17p chromosomal deletion (both combination groups) and those with baseline chromosomal abnormalities (rituximab arm).
There were no significant differences in overall survival at a median follow-up of 14.2 months in the obinutuzumab group and 15.2 months in the rituximab group, but overall survival data are not yet mature, Dr. Goede noted.
Grade 3 or greater adverse events of any type occurred in 41% of patients on chlorambucil monotherapy, compared with 67% of patients on obinutuzumab, and 46% of those on rituximab.
Infusion-related reactions, neutropenia, and thrombocytopenia were more frequent with obinutuzumab than with the other two drugs, although adverse events leading to death were higher with chlorambucil monotherapy. The incidence of any new malignancy was 0.9% for patients on chlorambucil only, compared with 2.5% for obinutuzumab and 2.7% for rituximab.
The study was supported by Roche. Dr. Goede disclosed consulting to and receiving honoraria and research support from the company.
CHICAGO – Adding an anti-CD20 antibody to chlorambucil significantly improved the progression-free survival of older patients with chronic lymphocytic leukemia and comorbidities, but it’s still unknown whether the novel agent obinutuzumab has added benefit over tried-and-true rituximab, researchers reported at the annual meeting of the American Society of Clinical Oncology.
In the phase III CLL11 study, median progression-free survival (PFS) was 23 months for patients treated with a combination of obinutuzumab (GA101) and chlorambucil (Leukeran), 15.7 months for those treated with rituximab (MabThera) and chlorambucil, and 10.9 months for chlorambucil alone. The respective PFS rates at 1 year were 84%, 63%, and 27%, reported principal investigator Dr. Valentin Goede, an oncologist at the University of Cologne, Germany.
"At this stage, my conclusion is that if an older, unfit CLL patient is put on chlorambucil treatment, then he or she in addition should receive an anti-CD20 monoclonal antibody," Dr. Goede said.
Anti-CD20 agents increased the risk of infusion reactions and neutropenias, but these side effects are manageable and should not outweigh the PFS benefits, he added.
Obinutuzumab is a type II anti-CD20 antibody with a mechanism of action that differs from that of rituximab. In preclinical models, obinutuzumab showed comparatively more direct killing action of B cells and an enhanced affinity for immunoglobulin receptors, with lower complement-dependent cytotoxicity.
The CLL11 study is a 2-stage trial asking whether chlorambucil and an anti-CD20 antibody can be superior to chlorambucil monotherapy in CLL patients with coexisting medical conditions (stage 1), and whether obinutuzumab plus chlorambucil could surpass rituximab plus chlorambucil (stage 2).
Dr. Goede reported final data from stage 1 of the trial, in which the investigators enrolled 581 adults aged 18 years and older with untreated CLL and comorbidities, defined as either a total Cumulative Illness Rating Scale score higher than 6 and/or a creatinine clearance rate lower than 70 mL/minute. An additional 190 patients are planned for stage 2 of the trial, which will be a head-to-head anti-CD20 comparison, Dr. Goede said.
The patients were randomized on a 1:2:2 ratio to either six cycles of chlorambucil 0.5 mg/kg on day 1 and day 15 of every 28-day cycle (110 patients), or to the same regimen plus either obinutuzumab 1,000 mg on days 1, 8 and 15 of the first cycle, and on day 1 of cycles two through 6 (238 patients), or to rituximab 375 mg/m2 on day 1 of cycle one, and 500 mg/m2 on day 1 of every subsequent cycle, for a total of six 28-day cycles (233 patients). Patients in the chlorambucil-only arm who experienced disease progression on treatment were allowed to cross over to the obinutuzumab combination.
The median patient age was about 73 years in each study arm and about three-fourths of patients were aged 65 years or older.
Overall response rates were 30.2% for patients assigned to chlorambucil alone, compared with 75.5% for patients assigned to obinutuzumab/chlorambucil, and 65.9% in the rituximab/chlorambucil arm. There were no complete responses (CR) in the monotherapy arm, 22.2% CR with obinutuzumab/chlorambucil, and 8.3% with rituximab/chlorambucil. Partial responses occurred in 30.2%, 53.3%, and 57.6%, respectively.
No patients on chlorambucil were found to be negative for minimal residual disease (MRD) in peripheral blood or bone marrow as assessed by a central laboratory at study end. In contrast, 31% of patients on obinutuzumab/chlorambucil and 2% of those on rituximab/chlorambucil were MRD-negative in peripheral blood; 17% and 2.8%, respectively, were MRD-negative in bone marrow.
The stratified hazard ratios for PFS with the anti-CD20 agent combinations, compared with chlorambucil monotherapy were 0.14 (P less than .0001) in the obinutuzumab/chlorambucil arm, and 0.32 (P less than .0001) in the rituximab/chlorambucil arm.
In a PFS subgroup analysis stratified by age, sex, comorbidity scores, mutational status, and other factors, both anti-CD20 agents showed a significant benefit over chlorambucil alone with the exceptions of patients with the 17p chromosomal deletion (both combination groups) and those with baseline chromosomal abnormalities (rituximab arm).
There were no significant differences in overall survival at a median follow-up of 14.2 months in the obinutuzumab group and 15.2 months in the rituximab group, but overall survival data are not yet mature, Dr. Goede noted.
Grade 3 or greater adverse events of any type occurred in 41% of patients on chlorambucil monotherapy, compared with 67% of patients on obinutuzumab, and 46% of those on rituximab.
Infusion-related reactions, neutropenia, and thrombocytopenia were more frequent with obinutuzumab than with the other two drugs, although adverse events leading to death were higher with chlorambucil monotherapy. The incidence of any new malignancy was 0.9% for patients on chlorambucil only, compared with 2.5% for obinutuzumab and 2.7% for rituximab.
The study was supported by Roche. Dr. Goede disclosed consulting to and receiving honoraria and research support from the company.
AT THE ASCO ANNUAL MEETING 2013
Major finding: One-year progression-free survival in elderly patients with chronic lymphocytic leukemia and comorbidities was 84% with obinutuzumab and chlorambucil and 27% with chlorambucil alone.
Data source: Randomized, controlled, two-stage, phase III trial with a planned enrollment of 780 patients.
Disclosures: The study was supported by Roche. Dr. Goede disclosed consulting to and receiving honoraria and research support from the company. Dr. Rai disclosed serving as a consultant or advisor to Celgene, Genentech, and Teva and receiving honoraria from Celgene, Cephalon, and Genentech.
Nintedanib and docetaxel provide small PFS advantage in NSCLC
CHICAGO – A combination of docetaxel and nintedanib, a novel inhibitor of multiple tumor growth factors, was associated with a small but significant improvement in progression-free survival in patients with advanced non–small cell lung cancer as compared with docetaxel alone.
In the phase III LUME-Lung I trial in patients with previously treated stage IIIB/IV or recurrent non–-small cell lung cancer (NSCLC), median progression-free survival (PFS) was 3.4 months for patients randomized to nintedanib and docetaxel, compared with 2.7 months for patients assigned to placebo and docetaxel (hazard ratio, 0.79; P = .0019), reported Dr. Martin Reck of the department of thoracic oncology at Hospital Grosshansdorf, Germany.
In addition, "we have seen a significant improvement of overall survival in patients with adenocarcinoma," Dr. Reck said at the annual meeting of the American Society of Clinical Oncology.
However, when patients with squamous cell NSCLC were included in the analysis, there was no significant difference in overall survival between the treatment groups, he said.
Nintedanib is an oral kinase inhibitor that targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-3, platelet-derived growth factor receptors alpha and beta, and the RET tyrosine kinase.
In clinical trials, nintedanib has been delivered safely in combination with various chemotherapy agents, including docetaxel, paclitaxel, platinum comp2ounds, and gemcitabine, and as a single agent had clinical activity in a phase II trial against recurrent NSCLC.
Dr. Reck and his colleagues enrolled 1,314 patients with stage IIIB or IV or recurrent NSCLC after first-line chemotherapy and randomly assigned them in a double-blinded fashion to receive intravenous docetaxel 75 mg/m2 on day 1 of a 21-day cycle plus either oral nintedanib 200 mg or placebo twice daily on days 2 through 21 of each cycle. The number of potential docetaxel cycles was unlimited, and docetaxel monotherapy could continue after four cycles of the combination at the investigator’s discretion.
Patients were stratified by performance status, prior bevacizumab (Avastin) use, squamous or nonsquamous histology, and presence or absence of brain metastases.
As of the February 2013 data cutoff, 6 of the 652 patients assigned to the combination and 6 of the 655 assigned to docetaxel/placebo remained on study.
In the intention-to-treat analysis, the trial met its primary endpoint of a centrally reviewed PFS advantage for the combination.
PFS was significantly better both in patients with adenocarcinoma histologies treated with the combination (median 4.0 vs. 2.8 months; HR, 0.77; P = .0193) and with squamous cell carcinomas (2.9 vs. 2.6 months; HR, 0.77; P = .02).
Overall survival did not differ, at a median of 10.1 vs. 9.1 month. Among patients with adenocarcinomas, however, survival was significantly better, at a median of 12.6 vs. 10.3 months, respectively (HR, 0.82; P = .0359). There was also a hint of benefit in patients with adenocarcinomas refractory to prior chemotherapy with a platinum compound (median overall survival, 9.8 vs. 6.3 months; HR, 0.62; P = .0246), although this subanalysis included only 107 patients.
The combination was no better than docetaxel and placebo among patients with squamous cell cancers.
Grade 3 or greater adverse events occurred in 71% of patients on nintedanib/docetaxel, and 64% of controls. In each group, about 22% of patients had adverse events leading to discontinuation of therapy. The most common adverse events were bleeding, thromboembolic events, and hypertension, each of which occurred more frequently with the combination than with docetaxel alone.
The LUME-Lung 1 trial was sponsored by Boehringer Ingelheim. Dr. Reck disclosed serving as an advisor and lecturer for Hoffman-La Roche, Lilly, AstraZeneca, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo.
The progression-free survival analysis was performed in 1,134 (86%) of the 1,314 patients randomized, because the PFS data cutoff occurred 3 months before the actual completion of trial accrual. Also, there was a 2-year gap between the final PFS analysis and the overall survival analysis.
Although the study was reported as being positive, the lack of PFS data on 14% of the population precluded a full intention-to-treat analysis. It would be interesting to see whether the survival benefit with nintedanib in patients with adenocarcinomas would remain if this subgroup of patients were further stratified by prior bevacizumab exposure. Further, the apparent advantage for the combination in patients with platinum-refractory adenocarcinomas needs to be validated in larger studies.
Dr. Benjamin Besse is a thoracic oncologist at the Institut Gustave-Roussy in Villejuif, France. Dr. Besse, who was the invited discussant of the study, reported serving as an uncompensated advisor to Boehringer-Ingelheim.
The progression-free survival analysis was performed in 1,134 (86%) of the 1,314 patients randomized, because the PFS data cutoff occurred 3 months before the actual completion of trial accrual. Also, there was a 2-year gap between the final PFS analysis and the overall survival analysis.
Although the study was reported as being positive, the lack of PFS data on 14% of the population precluded a full intention-to-treat analysis. It would be interesting to see whether the survival benefit with nintedanib in patients with adenocarcinomas would remain if this subgroup of patients were further stratified by prior bevacizumab exposure. Further, the apparent advantage for the combination in patients with platinum-refractory adenocarcinomas needs to be validated in larger studies.
Dr. Benjamin Besse is a thoracic oncologist at the Institut Gustave-Roussy in Villejuif, France. Dr. Besse, who was the invited discussant of the study, reported serving as an uncompensated advisor to Boehringer-Ingelheim.
The progression-free survival analysis was performed in 1,134 (86%) of the 1,314 patients randomized, because the PFS data cutoff occurred 3 months before the actual completion of trial accrual. Also, there was a 2-year gap between the final PFS analysis and the overall survival analysis.
Although the study was reported as being positive, the lack of PFS data on 14% of the population precluded a full intention-to-treat analysis. It would be interesting to see whether the survival benefit with nintedanib in patients with adenocarcinomas would remain if this subgroup of patients were further stratified by prior bevacizumab exposure. Further, the apparent advantage for the combination in patients with platinum-refractory adenocarcinomas needs to be validated in larger studies.
Dr. Benjamin Besse is a thoracic oncologist at the Institut Gustave-Roussy in Villejuif, France. Dr. Besse, who was the invited discussant of the study, reported serving as an uncompensated advisor to Boehringer-Ingelheim.
CHICAGO – A combination of docetaxel and nintedanib, a novel inhibitor of multiple tumor growth factors, was associated with a small but significant improvement in progression-free survival in patients with advanced non–small cell lung cancer as compared with docetaxel alone.
In the phase III LUME-Lung I trial in patients with previously treated stage IIIB/IV or recurrent non–-small cell lung cancer (NSCLC), median progression-free survival (PFS) was 3.4 months for patients randomized to nintedanib and docetaxel, compared with 2.7 months for patients assigned to placebo and docetaxel (hazard ratio, 0.79; P = .0019), reported Dr. Martin Reck of the department of thoracic oncology at Hospital Grosshansdorf, Germany.
In addition, "we have seen a significant improvement of overall survival in patients with adenocarcinoma," Dr. Reck said at the annual meeting of the American Society of Clinical Oncology.
However, when patients with squamous cell NSCLC were included in the analysis, there was no significant difference in overall survival between the treatment groups, he said.
Nintedanib is an oral kinase inhibitor that targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-3, platelet-derived growth factor receptors alpha and beta, and the RET tyrosine kinase.
In clinical trials, nintedanib has been delivered safely in combination with various chemotherapy agents, including docetaxel, paclitaxel, platinum comp2ounds, and gemcitabine, and as a single agent had clinical activity in a phase II trial against recurrent NSCLC.
Dr. Reck and his colleagues enrolled 1,314 patients with stage IIIB or IV or recurrent NSCLC after first-line chemotherapy and randomly assigned them in a double-blinded fashion to receive intravenous docetaxel 75 mg/m2 on day 1 of a 21-day cycle plus either oral nintedanib 200 mg or placebo twice daily on days 2 through 21 of each cycle. The number of potential docetaxel cycles was unlimited, and docetaxel monotherapy could continue after four cycles of the combination at the investigator’s discretion.
Patients were stratified by performance status, prior bevacizumab (Avastin) use, squamous or nonsquamous histology, and presence or absence of brain metastases.
As of the February 2013 data cutoff, 6 of the 652 patients assigned to the combination and 6 of the 655 assigned to docetaxel/placebo remained on study.
In the intention-to-treat analysis, the trial met its primary endpoint of a centrally reviewed PFS advantage for the combination.
PFS was significantly better both in patients with adenocarcinoma histologies treated with the combination (median 4.0 vs. 2.8 months; HR, 0.77; P = .0193) and with squamous cell carcinomas (2.9 vs. 2.6 months; HR, 0.77; P = .02).
Overall survival did not differ, at a median of 10.1 vs. 9.1 month. Among patients with adenocarcinomas, however, survival was significantly better, at a median of 12.6 vs. 10.3 months, respectively (HR, 0.82; P = .0359). There was also a hint of benefit in patients with adenocarcinomas refractory to prior chemotherapy with a platinum compound (median overall survival, 9.8 vs. 6.3 months; HR, 0.62; P = .0246), although this subanalysis included only 107 patients.
The combination was no better than docetaxel and placebo among patients with squamous cell cancers.
Grade 3 or greater adverse events occurred in 71% of patients on nintedanib/docetaxel, and 64% of controls. In each group, about 22% of patients had adverse events leading to discontinuation of therapy. The most common adverse events were bleeding, thromboembolic events, and hypertension, each of which occurred more frequently with the combination than with docetaxel alone.
The LUME-Lung 1 trial was sponsored by Boehringer Ingelheim. Dr. Reck disclosed serving as an advisor and lecturer for Hoffman-La Roche, Lilly, AstraZeneca, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo.
CHICAGO – A combination of docetaxel and nintedanib, a novel inhibitor of multiple tumor growth factors, was associated with a small but significant improvement in progression-free survival in patients with advanced non–small cell lung cancer as compared with docetaxel alone.
In the phase III LUME-Lung I trial in patients with previously treated stage IIIB/IV or recurrent non–-small cell lung cancer (NSCLC), median progression-free survival (PFS) was 3.4 months for patients randomized to nintedanib and docetaxel, compared with 2.7 months for patients assigned to placebo and docetaxel (hazard ratio, 0.79; P = .0019), reported Dr. Martin Reck of the department of thoracic oncology at Hospital Grosshansdorf, Germany.
In addition, "we have seen a significant improvement of overall survival in patients with adenocarcinoma," Dr. Reck said at the annual meeting of the American Society of Clinical Oncology.
However, when patients with squamous cell NSCLC were included in the analysis, there was no significant difference in overall survival between the treatment groups, he said.
Nintedanib is an oral kinase inhibitor that targets vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-3, platelet-derived growth factor receptors alpha and beta, and the RET tyrosine kinase.
In clinical trials, nintedanib has been delivered safely in combination with various chemotherapy agents, including docetaxel, paclitaxel, platinum comp2ounds, and gemcitabine, and as a single agent had clinical activity in a phase II trial against recurrent NSCLC.
Dr. Reck and his colleagues enrolled 1,314 patients with stage IIIB or IV or recurrent NSCLC after first-line chemotherapy and randomly assigned them in a double-blinded fashion to receive intravenous docetaxel 75 mg/m2 on day 1 of a 21-day cycle plus either oral nintedanib 200 mg or placebo twice daily on days 2 through 21 of each cycle. The number of potential docetaxel cycles was unlimited, and docetaxel monotherapy could continue after four cycles of the combination at the investigator’s discretion.
Patients were stratified by performance status, prior bevacizumab (Avastin) use, squamous or nonsquamous histology, and presence or absence of brain metastases.
As of the February 2013 data cutoff, 6 of the 652 patients assigned to the combination and 6 of the 655 assigned to docetaxel/placebo remained on study.
In the intention-to-treat analysis, the trial met its primary endpoint of a centrally reviewed PFS advantage for the combination.
PFS was significantly better both in patients with adenocarcinoma histologies treated with the combination (median 4.0 vs. 2.8 months; HR, 0.77; P = .0193) and with squamous cell carcinomas (2.9 vs. 2.6 months; HR, 0.77; P = .02).
Overall survival did not differ, at a median of 10.1 vs. 9.1 month. Among patients with adenocarcinomas, however, survival was significantly better, at a median of 12.6 vs. 10.3 months, respectively (HR, 0.82; P = .0359). There was also a hint of benefit in patients with adenocarcinomas refractory to prior chemotherapy with a platinum compound (median overall survival, 9.8 vs. 6.3 months; HR, 0.62; P = .0246), although this subanalysis included only 107 patients.
The combination was no better than docetaxel and placebo among patients with squamous cell cancers.
Grade 3 or greater adverse events occurred in 71% of patients on nintedanib/docetaxel, and 64% of controls. In each group, about 22% of patients had adverse events leading to discontinuation of therapy. The most common adverse events were bleeding, thromboembolic events, and hypertension, each of which occurred more frequently with the combination than with docetaxel alone.
The LUME-Lung 1 trial was sponsored by Boehringer Ingelheim. Dr. Reck disclosed serving as an advisor and lecturer for Hoffman-La Roche, Lilly, AstraZeneca, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo.
AT THE ASCO ANNUAL MEETING 2013
Major finding: Median progression-free survival was 3.4 months for patients randomized to nintedanib and docetaxel, compared with 2.7 months for patients assigned to placebo and docetaxel (P = .019)
Data source: Randomized, placebo controlled trial in 1,314 patients, 1,134 of whom were included in the primary endpoint analysis.
Disclosures: The LUME-Lung 1 trial was sponsored by Boehringer Ingelheim. Dr. Reck disclosed serving as an advisor and lecturer for Hoffman-La Roche, Lilly, AstraZeneca, Pfizer, Bristol-Myers Squibb, and Daiichi-Sankyo. Dr. Besse reported serving as an uncompensated advisor to Boehringer Ingelheim.
Good survival rates with temozolomide CRT for high-risk, low-grade gliomas
CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.
At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.
Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.
Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.
The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.
The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).
A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m2 per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m2 per day for days 1-5 of each 28-day cycle for a total of 12 cycles.
The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.
The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.
In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).
In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.
Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.
In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."
In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.
The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.
CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.
At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.
Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.
Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.
The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.
The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).
A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m2 per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m2 per day for days 1-5 of each 28-day cycle for a total of 12 cycles.
The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.
The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.
In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).
In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.
Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.
In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."
In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.
The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.
CHICAGO – Patients with high-risk, low-grade gliomas had 3-year survival rates significantly higher than those of historical controls when they were treated with a temozolomide-based chemoradiotherapy regimen, investigators reported at the annual meeting of the American Society of Clinical Oncology.
Preliminary results from the phase II RTOG 0424 trial showed a 73% overall survival rate for patients treated with temozolomide chemoradiotherapy, compared with 54% overall survival for historical controls (P less than .001), and exceeding the study’s hypothesized 65% overall survival, reported Dr. Barbara Fisher, a radiation oncologist at the University of Western Ontario in London.
At a median follow-up of 4 years, with a minimum potential follow-up of 3 years, median survival of patients has not been reached, and the median follow-up time for surviving patients is 5 years, Dr. Fisher noted.
Median progression-free survival was 4.5 years, and 3-year PFS was 59%. In contrast to historical controls, patients with four or five risk factors appeared to have an overall survival rate similar to that of patients with three risk factors, Dr. Fisher reported.
Although the trial was originally proposed in 2000 as a randomized controlled study, "there wasn’t much information about temozolomide and radiation at that point," Dr. Fisher said.
The control population comes from a 2002 study by Francesco Pignatti and his colleagues (J. Clin. Oncol. 2002;20:2076-84), which identified prognostic factors for survival in adults with low-grade glioma, based on data from two European Organization for Research and Treatment of Cancer (EORTC) trials conducted in the 1990s.
The risk factors are age 40 years and older; astrocytoma subtype; tumor crossing the midline; largest tumor diameter more than 6 cm preoperatively; and preoperative neurological function status (neurocognitive function greater than 1: moderate impairment).
A total of 136 patients were accrued, and 129 patients were eligible for the protocol, which consisted of temozolomide 75 mg/m2 per day for 6 weeks with concurrent conformal radiotherapy, consisting of 54 Gy divided into 30 fractions delivered 5 days each week for 6 weeks, followed by temozolomide 150-200 mg/m2 per day for days 1-5 of each 28-day cycle for a total of 12 cycles.
The patients had previously untreated, histologically proven supratentorial World Health Organization grade II astrocytoma (71 patients); oligodendroglioma (29) or oligoastrocytoma (29) confirmed by central pathology; and at least three of the aforementioned risk factors. The majority of patients (80%) were aged 40 years or older, 79% had tumors greater than 6 cm in the largest diameter, 53% had tumors that crossed the midline, 66% had a dominant astrocytoma subtype, and 50% had preoperative neurological function status scores greater than 1. In all, 89 patients had three risk factors, 32 had four, and 8 had five factors.
The investigators hypothesized that they would see a 43% relative increase in median survival, from 40.5 months in controls to 57.9 months, and a 20% improvement in 3-year survival, from 54% to 65%. As noted before, the survival rates exceeded their expectations.
In an analysis of survival by risk factors 5 years after trial registration, the authors found that 35 of the 89 patients with three risk factors (39%) had died, compared with 17 of the 40 patients with four or five risk factors (43%).
In all, 55 patients had grade 3 adverse events as their worst overall events, 13 had grade 4 toxicities, and 1 patient died of herpes simplex encephalitis, possibly related to treatment.
Grade 3 adverse events were seen in 43% of patients, and grade 4 toxicities in 10%. The most common toxicities were hematologic, constitutional, or gastrointestinal, including nausea and anorexia.
In her commentary, Dr. Helen Shih, the invited discussant, said that a randomized trial would have been preferable, but she acknowledged the difficulties the investigators had in designing and implementing the trial. Dr. Shih, of the radiation oncology department at Massachusetts General Hospital in Boston, also noted that the study used for control purposes "itself was conducted in a prior decade, when the management of radiation as well as surgery were slightly different, and perhaps those advancements also have affected overall survival of patients who are treated today."
In addition, the incidences of grade 3 and 4 toxicities in the study by Dr. Fisher and her colleagues were "not trivial, and should be kept in mind," Dr. Shih said.
The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.
AT THE ASCO ANNUAL MEETING 2013
Major finding: With temozolomide chemoradiotherapy, 3-year overall survival was 73% for patients with low-grade gliomas and three or more risk factors for worse prognosis, compared with 54% for historical controls (P less than .001).
Data source: Single-arm, prospective phase II study in 129 patients compared with historical controls.
Disclosures: The study was supported by the National Cancer Institute. Dr. Fisher and Dr. Shih reported having no relevant financial disclosures.
