Breast Cancer ICYMI

Andrew Solomon, MD, is a neurologist and Associate Professor in the Department of Neurological Sciences and Division Chief of Multiple Sclerosis at The University of Vermont. We sat down to talk with Dr. Solomon about his experience with multiple sclerosis (MS) misdiagnosis and what can be done to improve MS diagnosis going forward.

How prevalent is the misdiagnosis of MS and what are the effects that it has on patients?

The first thing to clarify is what we mean by MS misdiagnosis. In this case, we’re talking about patients who are incorrectly assigned a diagnosis of MS. MS is hard to diagnose. Sometimes we take too long to diagnose people who have MS, sometimes we incorrectly diagnose MS in people who don’t have it.

We don’t have very good data in terms of how frequent misdiagnosis is, but we have some. The earliest data we have is from the 1980s. In 1988 there was a study published involving approximately 500 patients who had been diagnosed with MS in life and subsequently died between the 1960s and the 1980s and had a postmortem exam. 6% of those people who had a diagnosis of MS during their lifetime didn’t actually have MS.¹

In 2012, we did a survey of 122 MS specialists.² We asked them if they had encountered patients incorrectly assigned a diagnosis of MS in the past year, and 95% of them had seen such a patient. This was not the most scientific study because it was just a survey and subject to recall bias. Still, many of these MS providers recalled having seen three to ten such patients in the last year where they strongly felt that a pre-existing MS diagnosis made by another provider was incorrect.

Another study was recently published by Dr. Kaisey.³ She looked at referrals to two academic MS centers on the West Coast, and specifically new patient referrals over 12 months to those two MS centers.  She found that out of 241 patients referred to the two MS centers, almost one in five who was referred with a pre-existing diagnosis of MS who came to these MS centers was subsequently found not have MS. This included 17% of patients at Cedars Sinai and 19% at UCLA. That’s an alarmingly high number of patients. And that’s the best data we have right now.

We don’t know how representative that number is of other MS centers and clinical practice nationally, but the bottom line is that misdiagnosis of MS is, unfortunately, fairly common and there’s a lot of risks to patients associated with misdiagnosis, as well as costs to our health care system.

Can you elaborate on the risks to patients?

We published a study where we looked at records from 110 patients who had been incorrectly assigned a diagnosis of MS. Twenty-three MS specialists from 4 different MS centers participated in this study that was published in Neurology in 2016.⁴

70% of these patients had been receiving disease modifying therapy for MS, which certainly has risks and side effects associated with it. 24% received disease modifying therapy with a known risk of PML, which is a frequently fatal brain infection associated with these therapies. Approximately 30% of these patients who did not have MS were on disease modifying therapy for in 3 to 9 years and 30% were on disease modifying therapy for 10 years or more.

Dr. Kaisey’s study also supports our findings. She found approximately 110 patient-years of exposure to unnecessary disease modifying therapy in the misdiagnosed patients in her study.³ Patients suffer side effects in addition to unnecessary risk related to these therapies.

It’s also important to emphasize that many of these patients also received inadequate treatment for their correct diagnoses.

How did the 2017 revision to the McDonald criteria address the challenge of MS diagnosis?

The problem of MS misdiagnosis is prominently discussed in the 2017 McDonald criteria.⁵ Unfortunately, one of the likely causes of misdiagnosis is that many clinicians may not read the full manuscript of the McDonald criteria itself. They instead rely on summary cards or reproductions—condensed versions of how to diagnose MS—which often don’t really provide the full context that would allow physicians to think critically and avoid a misdiagnosis.

MS is still a clinical diagnosis, which means we’re reliant on physician decision-making to confirm a diagnosis of MS. There are multiple steps to it.

First, we must determine if somebody has a syndrome typical for MS and they have objective evidence of a CNS lesion. After that the McDonald criteria can be applied to determine if they meet dissemination in time, dissemination in space, and have no other explanation for this syndrome before making a diagnosis of MS. Each one of those steps is reliant on thoughtful clinical decision-making and may be prone to potential error.

Knowing the ins and outs and the details of each of those steps is important. Reading the diagnostic criteria is probably the first step in becoming skilled at MS diagnosis. It’s important to know the criteria were not developed as a screening tool.  The neurologist is essentially the screening tool. The diagnostic criteria can’t be used until a MS-typical syndrome with objective evidence of a CNS lesion is confirmed.

In what way was the previous criteria flawed?

I wouldn’t say any of the MS diagnostic criteria were flawed; they have evolved along with data in our field that has helped us make diagnosis of MS earlier in many patients. When using the criteria, it’s important to understand the types of patients in the cohorts used to validate our diagnostic criteria. They were primarily younger than 50, and usually Caucasian. They had only syndromes typical for MS with objective evidence of CNS damage corroborating these syndromes.  Using the criteria more broadly in patients who do not fit this profile can reduce its specificity and lead to misdiagnosis.  

For determination of MRI dissemination in time and dissemination space, there are also some misconceptions that frequently lead to misdiagnosis. Knowing which areas are required for dissemination in space in crucial. For example, the optic nerve currently is not an area that can be used to fulfill dissemination in space, which is a mistake people frequently make. Knowing that the terms “juxtacortical” and “periventricular” means touching the ventricle and touching the cortex is very important. This is a mistake that’s often made as well, and many disorders present with MRI lesions near but not touching the cortex or ventricle. Knowing each element of our diagnostic criteria and what those terms specifically mean is important. In the 2017 McDonald criteria there’s an excellent glossary that helps clinicians understand these terms and how to use them appropriately.⁵

What more needs to be done to prevent MS misdiagnosis?

First, we need to figure out how to better educate clinicians on how to use our diagnostic criteria appropriately.

We recently completed a study that suggests that residents in training, and even MS specialists, have trouble using the diagnostic criteria. This study was presented at the American Academy of Neurology Annual meeting but has not been published yet. Education on how to use the diagnostic criteria, and in which patients to use the criteria (and in which patients the criteria do not apply) is important, particularly when new revisions to the diagnostic criteria are published.

We published a paper recently that provided guidance on how to avoid misdiagnosis using the 2017 McDonald criteria, and how to approach patients where the diagnostic criteria didn’t apply.⁶ Sometimes additional clinical, laboratory, or MRI evaluation and monitoring is required in such patients to either confirm a diagnosis of MS, or determine that a patient does not have MS.

We also desperately need biomarkers that may help us diagnose MS more accurately in patients who have neurological symptoms and an abnormal MRI and are seeing a neurologist for the first time. There’s research going on now to find relevant biomarkers in the form of blood tests, as well as MRI assessments. In particular, ongoing research focused on the MRI finding we have termed the “central vein sign” suggests this approach may be helpful as a MRI-specific biomarker for MS.^7,8 We need multicenter studies evaluating this and other biomarkers in patients who come to our clinics for a new evaluation for MS, to confirm that they are accurate. We need more researchers working on how to improve diagnosis of MS.

References:

1. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.

2. Solomon AJ, Klein EP, Bourdette D. "Undiagnosing" multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.

3. Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019;30:51-56.

4. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.

5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173..

6. Solomon AJ, Naismith RT, Cross AH. Misdiagnosis of multiple sclerosis: impact of the 2017 McDonald criteria on clinical practice. Neurology. 2019;92(1):26-33.

7. Sati P, Oh J, Constable RT, et al; NAIMS Cooperative. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.

8. Sinnecker T, Clarke MA, Meier D, et al. Evaluation of the central vein sign as a diagnostic imaging biomarker in multiple sclerosis [published online ahead of print August 19, 2019]. JAMA Neurology.  2019: doi: 10.1001/jamaneurol.2019.2478.

Andrew Solomon, MD, is a neurologist and Associate Professor in the Department of Neurological Sciences and Division Chief of Multiple Sclerosis at The University of Vermont. We sat down to talk with Dr. Solomon about his experience with multiple sclerosis (MS) misdiagnosis and what can be done to improve MS diagnosis going forward.

How prevalent is the misdiagnosis of MS and what are the effects that it has on patients?

The first thing to clarify is what we mean by MS misdiagnosis. In this case, we’re talking about patients who are incorrectly assigned a diagnosis of MS. MS is hard to diagnose. Sometimes we take too long to diagnose people who have MS, sometimes we incorrectly diagnose MS in people who don’t have it.

We don’t have very good data in terms of how frequent misdiagnosis is, but we have some. The earliest data we have is from the 1980s. In 1988 there was a study published involving approximately 500 patients who had been diagnosed with MS in life and subsequently died between the 1960s and the 1980s and had a postmortem exam. 6% of those people who had a diagnosis of MS during their lifetime didn’t actually have MS.¹

In 2012, we did a survey of 122 MS specialists.² We asked them if they had encountered patients incorrectly assigned a diagnosis of MS in the past year, and 95% of them had seen such a patient. This was not the most scientific study because it was just a survey and subject to recall bias. Still, many of these MS providers recalled having seen three to ten such patients in the last year where they strongly felt that a pre-existing MS diagnosis made by another provider was incorrect.

Another study was recently published by Dr. Kaisey.³ She looked at referrals to two academic MS centers on the West Coast, and specifically new patient referrals over 12 months to those two MS centers.  She found that out of 241 patients referred to the two MS centers, almost one in five who was referred with a pre-existing diagnosis of MS who came to these MS centers was subsequently found not have MS. This included 17% of patients at Cedars Sinai and 19% at UCLA. That’s an alarmingly high number of patients. And that’s the best data we have right now.

We don’t know how representative that number is of other MS centers and clinical practice nationally, but the bottom line is that misdiagnosis of MS is, unfortunately, fairly common and there’s a lot of risks to patients associated with misdiagnosis, as well as costs to our health care system.

Can you elaborate on the risks to patients?

We published a study where we looked at records from 110 patients who had been incorrectly assigned a diagnosis of MS. Twenty-three MS specialists from 4 different MS centers participated in this study that was published in Neurology in 2016.⁴

70% of these patients had been receiving disease modifying therapy for MS, which certainly has risks and side effects associated with it. 24% received disease modifying therapy with a known risk of PML, which is a frequently fatal brain infection associated with these therapies. Approximately 30% of these patients who did not have MS were on disease modifying therapy for in 3 to 9 years and 30% were on disease modifying therapy for 10 years or more.

Dr. Kaisey’s study also supports our findings. She found approximately 110 patient-years of exposure to unnecessary disease modifying therapy in the misdiagnosed patients in her study.³ Patients suffer side effects in addition to unnecessary risk related to these therapies.

It’s also important to emphasize that many of these patients also received inadequate treatment for their correct diagnoses.

How did the 2017 revision to the McDonald criteria address the challenge of MS diagnosis?

The problem of MS misdiagnosis is prominently discussed in the 2017 McDonald criteria.⁵ Unfortunately, one of the likely causes of misdiagnosis is that many clinicians may not read the full manuscript of the McDonald criteria itself. They instead rely on summary cards or reproductions—condensed versions of how to diagnose MS—which often don’t really provide the full context that would allow physicians to think critically and avoid a misdiagnosis.

MS is still a clinical diagnosis, which means we’re reliant on physician decision-making to confirm a diagnosis of MS. There are multiple steps to it.

First, we must determine if somebody has a syndrome typical for MS and they have objective evidence of a CNS lesion. After that the McDonald criteria can be applied to determine if they meet dissemination in time, dissemination in space, and have no other explanation for this syndrome before making a diagnosis of MS. Each one of those steps is reliant on thoughtful clinical decision-making and may be prone to potential error.

Knowing the ins and outs and the details of each of those steps is important. Reading the diagnostic criteria is probably the first step in becoming skilled at MS diagnosis. It’s important to know the criteria were not developed as a screening tool.  The neurologist is essentially the screening tool. The diagnostic criteria can’t be used until a MS-typical syndrome with objective evidence of a CNS lesion is confirmed.

In what way was the previous criteria flawed?

I wouldn’t say any of the MS diagnostic criteria were flawed; they have evolved along with data in our field that has helped us make diagnosis of MS earlier in many patients. When using the criteria, it’s important to understand the types of patients in the cohorts used to validate our diagnostic criteria. They were primarily younger than 50, and usually Caucasian. They had only syndromes typical for MS with objective evidence of CNS damage corroborating these syndromes.  Using the criteria more broadly in patients who do not fit this profile can reduce its specificity and lead to misdiagnosis.  

For determination of MRI dissemination in time and dissemination space, there are also some misconceptions that frequently lead to misdiagnosis. Knowing which areas are required for dissemination in space in crucial. For example, the optic nerve currently is not an area that can be used to fulfill dissemination in space, which is a mistake people frequently make. Knowing that the terms “juxtacortical” and “periventricular” means touching the ventricle and touching the cortex is very important. This is a mistake that’s often made as well, and many disorders present with MRI lesions near but not touching the cortex or ventricle. Knowing each element of our diagnostic criteria and what those terms specifically mean is important. In the 2017 McDonald criteria there’s an excellent glossary that helps clinicians understand these terms and how to use them appropriately.⁵

What more needs to be done to prevent MS misdiagnosis?

First, we need to figure out how to better educate clinicians on how to use our diagnostic criteria appropriately.

We recently completed a study that suggests that residents in training, and even MS specialists, have trouble using the diagnostic criteria. This study was presented at the American Academy of Neurology Annual meeting but has not been published yet. Education on how to use the diagnostic criteria, and in which patients to use the criteria (and in which patients the criteria do not apply) is important, particularly when new revisions to the diagnostic criteria are published.

We published a paper recently that provided guidance on how to avoid misdiagnosis using the 2017 McDonald criteria, and how to approach patients where the diagnostic criteria didn’t apply.⁶ Sometimes additional clinical, laboratory, or MRI evaluation and monitoring is required in such patients to either confirm a diagnosis of MS, or determine that a patient does not have MS.

We also desperately need biomarkers that may help us diagnose MS more accurately in patients who have neurological symptoms and an abnormal MRI and are seeing a neurologist for the first time. There’s research going on now to find relevant biomarkers in the form of blood tests, as well as MRI assessments. In particular, ongoing research focused on the MRI finding we have termed the “central vein sign” suggests this approach may be helpful as a MRI-specific biomarker for MS.^7,8 We need multicenter studies evaluating this and other biomarkers in patients who come to our clinics for a new evaluation for MS, to confirm that they are accurate. We need more researchers working on how to improve diagnosis of MS.

References:

1. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.

2. Solomon AJ, Klein EP, Bourdette D. "Undiagnosing" multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.

3. Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019;30:51-56.

4. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.

5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173..

6. Solomon AJ, Naismith RT, Cross AH. Misdiagnosis of multiple sclerosis: impact of the 2017 McDonald criteria on clinical practice. Neurology. 2019;92(1):26-33.

7. Sati P, Oh J, Constable RT, et al; NAIMS Cooperative. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.

8. Sinnecker T, Clarke MA, Meier D, et al. Evaluation of the central vein sign as a diagnostic imaging biomarker in multiple sclerosis [published online ahead of print August 19, 2019]. JAMA Neurology.  2019: doi: 10.1001/jamaneurol.2019.2478.

Andrew Solomon, MD, is a neurologist and Associate Professor in the Department of Neurological Sciences and Division Chief of Multiple Sclerosis at The University of Vermont. We sat down to talk with Dr. Solomon about his experience with multiple sclerosis (MS) misdiagnosis and what can be done to improve MS diagnosis going forward.

How prevalent is the misdiagnosis of MS and what are the effects that it has on patients?

The first thing to clarify is what we mean by MS misdiagnosis. In this case, we’re talking about patients who are incorrectly assigned a diagnosis of MS. MS is hard to diagnose. Sometimes we take too long to diagnose people who have MS, sometimes we incorrectly diagnose MS in people who don’t have it.

We don’t have very good data in terms of how frequent misdiagnosis is, but we have some. The earliest data we have is from the 1980s. In 1988 there was a study published involving approximately 500 patients who had been diagnosed with MS in life and subsequently died between the 1960s and the 1980s and had a postmortem exam. 6% of those people who had a diagnosis of MS during their lifetime didn’t actually have MS.¹

In 2012, we did a survey of 122 MS specialists.² We asked them if they had encountered patients incorrectly assigned a diagnosis of MS in the past year, and 95% of them had seen such a patient. This was not the most scientific study because it was just a survey and subject to recall bias. Still, many of these MS providers recalled having seen three to ten such patients in the last year where they strongly felt that a pre-existing MS diagnosis made by another provider was incorrect.

Another study was recently published by Dr. Kaisey.³ She looked at referrals to two academic MS centers on the West Coast, and specifically new patient referrals over 12 months to those two MS centers.  She found that out of 241 patients referred to the two MS centers, almost one in five who was referred with a pre-existing diagnosis of MS who came to these MS centers was subsequently found not have MS. This included 17% of patients at Cedars Sinai and 19% at UCLA. That’s an alarmingly high number of patients. And that’s the best data we have right now.

We don’t know how representative that number is of other MS centers and clinical practice nationally, but the bottom line is that misdiagnosis of MS is, unfortunately, fairly common and there’s a lot of risks to patients associated with misdiagnosis, as well as costs to our health care system.

Can you elaborate on the risks to patients?

We published a study where we looked at records from 110 patients who had been incorrectly assigned a diagnosis of MS. Twenty-three MS specialists from 4 different MS centers participated in this study that was published in Neurology in 2016.⁴

70% of these patients had been receiving disease modifying therapy for MS, which certainly has risks and side effects associated with it. 24% received disease modifying therapy with a known risk of PML, which is a frequently fatal brain infection associated with these therapies. Approximately 30% of these patients who did not have MS were on disease modifying therapy for in 3 to 9 years and 30% were on disease modifying therapy for 10 years or more.

Dr. Kaisey’s study also supports our findings. She found approximately 110 patient-years of exposure to unnecessary disease modifying therapy in the misdiagnosed patients in her study.³ Patients suffer side effects in addition to unnecessary risk related to these therapies.

It’s also important to emphasize that many of these patients also received inadequate treatment for their correct diagnoses.

How did the 2017 revision to the McDonald criteria address the challenge of MS diagnosis?

The problem of MS misdiagnosis is prominently discussed in the 2017 McDonald criteria.⁵ Unfortunately, one of the likely causes of misdiagnosis is that many clinicians may not read the full manuscript of the McDonald criteria itself. They instead rely on summary cards or reproductions—condensed versions of how to diagnose MS—which often don’t really provide the full context that would allow physicians to think critically and avoid a misdiagnosis.

MS is still a clinical diagnosis, which means we’re reliant on physician decision-making to confirm a diagnosis of MS. There are multiple steps to it.

First, we must determine if somebody has a syndrome typical for MS and they have objective evidence of a CNS lesion. After that the McDonald criteria can be applied to determine if they meet dissemination in time, dissemination in space, and have no other explanation for this syndrome before making a diagnosis of MS. Each one of those steps is reliant on thoughtful clinical decision-making and may be prone to potential error.

Knowing the ins and outs and the details of each of those steps is important. Reading the diagnostic criteria is probably the first step in becoming skilled at MS diagnosis. It’s important to know the criteria were not developed as a screening tool.  The neurologist is essentially the screening tool. The diagnostic criteria can’t be used until a MS-typical syndrome with objective evidence of a CNS lesion is confirmed.

In what way was the previous criteria flawed?

I wouldn’t say any of the MS diagnostic criteria were flawed; they have evolved along with data in our field that has helped us make diagnosis of MS earlier in many patients. When using the criteria, it’s important to understand the types of patients in the cohorts used to validate our diagnostic criteria. They were primarily younger than 50, and usually Caucasian. They had only syndromes typical for MS with objective evidence of CNS damage corroborating these syndromes.  Using the criteria more broadly in patients who do not fit this profile can reduce its specificity and lead to misdiagnosis.  

For determination of MRI dissemination in time and dissemination space, there are also some misconceptions that frequently lead to misdiagnosis. Knowing which areas are required for dissemination in space in crucial. For example, the optic nerve currently is not an area that can be used to fulfill dissemination in space, which is a mistake people frequently make. Knowing that the terms “juxtacortical” and “periventricular” means touching the ventricle and touching the cortex is very important. This is a mistake that’s often made as well, and many disorders present with MRI lesions near but not touching the cortex or ventricle. Knowing each element of our diagnostic criteria and what those terms specifically mean is important. In the 2017 McDonald criteria there’s an excellent glossary that helps clinicians understand these terms and how to use them appropriately.⁵

What more needs to be done to prevent MS misdiagnosis?

First, we need to figure out how to better educate clinicians on how to use our diagnostic criteria appropriately.

We recently completed a study that suggests that residents in training, and even MS specialists, have trouble using the diagnostic criteria. This study was presented at the American Academy of Neurology Annual meeting but has not been published yet. Education on how to use the diagnostic criteria, and in which patients to use the criteria (and in which patients the criteria do not apply) is important, particularly when new revisions to the diagnostic criteria are published.

We published a paper recently that provided guidance on how to avoid misdiagnosis using the 2017 McDonald criteria, and how to approach patients where the diagnostic criteria didn’t apply.⁶ Sometimes additional clinical, laboratory, or MRI evaluation and monitoring is required in such patients to either confirm a diagnosis of MS, or determine that a patient does not have MS.

We also desperately need biomarkers that may help us diagnose MS more accurately in patients who have neurological symptoms and an abnormal MRI and are seeing a neurologist for the first time. There’s research going on now to find relevant biomarkers in the form of blood tests, as well as MRI assessments. In particular, ongoing research focused on the MRI finding we have termed the “central vein sign” suggests this approach may be helpful as a MRI-specific biomarker for MS.^7,8 We need multicenter studies evaluating this and other biomarkers in patients who come to our clinics for a new evaluation for MS, to confirm that they are accurate. We need more researchers working on how to improve diagnosis of MS.

References:

1. Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988;78(1):39-44.

2. Solomon AJ, Klein EP, Bourdette D. "Undiagnosing" multiple sclerosis: the challenge of misdiagnosis in MS. Neurology. 2012;78(24):1986-1991.

3. Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord. 2019;30:51-56.

4. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology. 2016;87(13):1393-1399.

5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173..

6. Solomon AJ, Naismith RT, Cross AH. Misdiagnosis of multiple sclerosis: impact of the 2017 McDonald criteria on clinical practice. Neurology. 2019;92(1):26-33.

7. Sati P, Oh J, Constable RT, et al; NAIMS Cooperative. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.

8. Sinnecker T, Clarke MA, Meier D, et al. Evaluation of the central vein sign as a diagnostic imaging biomarker in multiple sclerosis [published online ahead of print August 19, 2019]. JAMA Neurology.  2019: doi: 10.1001/jamaneurol.2019.2478.

Migraines are associated with a significantly greater risk of Alzheimer’s disease and all forms of dementia except vascular dementia, according to research published online Sept. 4 in the International Journal of Geriatric Psychiatry.

In the Manitoba Study of Health and Aging, a population-based, prospective cohort study, 679 community-dwelling adults with a mean age of 75.9 years were followed for 5 years. Participants screened as cognitively intact at baseline had complete data on migraine history and all covariates at baseline and were assessed for cognitive outcomes 5 years later.

The study showed that a history of migraines was associated with a 2.97-fold greater likelihood of dementia, after adjustment for age, education, and a history of stroke, compared with individuals without a history of migraine. Individuals with Alzheimer’s disease were more than four times more likely to have a history of migraines (odds ratio 4.22).

However, researchers found no significant association between vascular dementia and a history of migraines, either before or after adjusting for confounders but particularly after incorporating a history of stroke into the model.

Lead investigator Suzanne L. Tyas, PhD, associate professor in the School of Public Health and Health Systems at the University of Waterloo, Ont., and coauthors suggested that the association between migraine and dementia was largely driven by the strong association between migraines and Alzheimer’s disease.

“This interpretation is supported by the weaker association for dementia than for Alzheimer’s disease, reflecting a dilution of the association with migraines across all types of dementia including vascular dementia, where a significant association was not found,” the researchers wrote.

The study population was 61.9% female, and no men reporting a history of migraine were diagnosed with dementia. While the study reflected a strong association between migraine and dementia in women, the researchers said they were unable to assess potential gender differences in this association.

Commenting on possible mechanisms behind the association, the authors wrote that there were overlaps underlying the biological mechanisms of migraine and dementia. Vascular risk factors such as diabetes, hypertension, heart attack, and stroke are associated with the development of dementia, and a relationship of these risk factors and migraine also has been seen.

“Many of the mechanisms involved in migraine neurophysiology, such as inflammation and reduced cerebral blood flow, are also underlying causes of dementia,” they wrote. “Repeated activation of these pathways in chronic migraineurs has been shown to cause permanent neurological and vascular damage.”

They also observed that the association could be influenced by genetic factors, as individuals with presenilin-1 mutations, which predispose them to Alzheimer’s disease, are more likely to experience migraines or recurrent headaches.

They suggested their findings could inform preventive strategies and treatments for Alzheimer’s disease, as well as interventions such as earlier screening for cognitive decline in individuals who experience migraines.

The study was funded by Manitoba Health and the National Health Research and Development Program of Health Canada. No conflicts of interest were declared.
 

SOURCE: Morton R et al. Int J Geriatr Psychiatry, 2019 Sep 4. doi: 10.1002/gps.5180.

Migraines are associated with a significantly greater risk of Alzheimer’s disease and all forms of dementia except vascular dementia, according to research published online Sept. 4 in the International Journal of Geriatric Psychiatry.

In the Manitoba Study of Health and Aging, a population-based, prospective cohort study, 679 community-dwelling adults with a mean age of 75.9 years were followed for 5 years. Participants screened as cognitively intact at baseline had complete data on migraine history and all covariates at baseline and were assessed for cognitive outcomes 5 years later.

The study showed that a history of migraines was associated with a 2.97-fold greater likelihood of dementia, after adjustment for age, education, and a history of stroke, compared with individuals without a history of migraine. Individuals with Alzheimer’s disease were more than four times more likely to have a history of migraines (odds ratio 4.22).

However, researchers found no significant association between vascular dementia and a history of migraines, either before or after adjusting for confounders but particularly after incorporating a history of stroke into the model.

Lead investigator Suzanne L. Tyas, PhD, associate professor in the School of Public Health and Health Systems at the University of Waterloo, Ont., and coauthors suggested that the association between migraine and dementia was largely driven by the strong association between migraines and Alzheimer’s disease.

“This interpretation is supported by the weaker association for dementia than for Alzheimer’s disease, reflecting a dilution of the association with migraines across all types of dementia including vascular dementia, where a significant association was not found,” the researchers wrote.

The study population was 61.9% female, and no men reporting a history of migraine were diagnosed with dementia. While the study reflected a strong association between migraine and dementia in women, the researchers said they were unable to assess potential gender differences in this association.

Commenting on possible mechanisms behind the association, the authors wrote that there were overlaps underlying the biological mechanisms of migraine and dementia. Vascular risk factors such as diabetes, hypertension, heart attack, and stroke are associated with the development of dementia, and a relationship of these risk factors and migraine also has been seen.

“Many of the mechanisms involved in migraine neurophysiology, such as inflammation and reduced cerebral blood flow, are also underlying causes of dementia,” they wrote. “Repeated activation of these pathways in chronic migraineurs has been shown to cause permanent neurological and vascular damage.”

They also observed that the association could be influenced by genetic factors, as individuals with presenilin-1 mutations, which predispose them to Alzheimer’s disease, are more likely to experience migraines or recurrent headaches.

They suggested their findings could inform preventive strategies and treatments for Alzheimer’s disease, as well as interventions such as earlier screening for cognitive decline in individuals who experience migraines.

The study was funded by Manitoba Health and the National Health Research and Development Program of Health Canada. No conflicts of interest were declared.
 

SOURCE: Morton R et al. Int J Geriatr Psychiatry, 2019 Sep 4. doi: 10.1002/gps.5180.

Migraines are associated with a significantly greater risk of Alzheimer’s disease and all forms of dementia except vascular dementia, according to research published online Sept. 4 in the International Journal of Geriatric Psychiatry.

In the Manitoba Study of Health and Aging, a population-based, prospective cohort study, 679 community-dwelling adults with a mean age of 75.9 years were followed for 5 years. Participants screened as cognitively intact at baseline had complete data on migraine history and all covariates at baseline and were assessed for cognitive outcomes 5 years later.

The study showed that a history of migraines was associated with a 2.97-fold greater likelihood of dementia, after adjustment for age, education, and a history of stroke, compared with individuals without a history of migraine. Individuals with Alzheimer’s disease were more than four times more likely to have a history of migraines (odds ratio 4.22).

However, researchers found no significant association between vascular dementia and a history of migraines, either before or after adjusting for confounders but particularly after incorporating a history of stroke into the model.

Lead investigator Suzanne L. Tyas, PhD, associate professor in the School of Public Health and Health Systems at the University of Waterloo, Ont., and coauthors suggested that the association between migraine and dementia was largely driven by the strong association between migraines and Alzheimer’s disease.

“This interpretation is supported by the weaker association for dementia than for Alzheimer’s disease, reflecting a dilution of the association with migraines across all types of dementia including vascular dementia, where a significant association was not found,” the researchers wrote.

The study population was 61.9% female, and no men reporting a history of migraine were diagnosed with dementia. While the study reflected a strong association between migraine and dementia in women, the researchers said they were unable to assess potential gender differences in this association.

Commenting on possible mechanisms behind the association, the authors wrote that there were overlaps underlying the biological mechanisms of migraine and dementia. Vascular risk factors such as diabetes, hypertension, heart attack, and stroke are associated with the development of dementia, and a relationship of these risk factors and migraine also has been seen.

“Many of the mechanisms involved in migraine neurophysiology, such as inflammation and reduced cerebral blood flow, are also underlying causes of dementia,” they wrote. “Repeated activation of these pathways in chronic migraineurs has been shown to cause permanent neurological and vascular damage.”

They also observed that the association could be influenced by genetic factors, as individuals with presenilin-1 mutations, which predispose them to Alzheimer’s disease, are more likely to experience migraines or recurrent headaches.

They suggested their findings could inform preventive strategies and treatments for Alzheimer’s disease, as well as interventions such as earlier screening for cognitive decline in individuals who experience migraines.

The study was funded by Manitoba Health and the National Health Research and Development Program of Health Canada. No conflicts of interest were declared.
 

SOURCE: Morton R et al. Int J Geriatr Psychiatry, 2019 Sep 4. doi: 10.1002/gps.5180.

Significant increases in serum serotonin levels after seizures are associated with lower incidence of seizure-related breathing dysfunction in patients with epilepsy, according to research published online Sept. 4 in Neurology. The change in serotonin level may reflect physiologic changes that protect against harmful processes that promote sudden unexpected death in epilepsy (SUDEP), the authors wrote.

“Our results give new insight into a possible link between serotonin levels and breathing during and after seizure,” Samden D. Lhatoo, MD, professor of neurology at McGovern Medical School at the University of Texas Health Science Center in Houston, said in a press release. “This may give hope that perhaps someday new therapies could be developed that may help prevent SUDEP. However, our study was small, and much more research is needed to confirm our findings in larger groups before any treatment decisions can be made. It is also important to note that excess serotonin can be harmful, so we strongly recommend against anyone trying to find ways to increase their serotonin levels in response to our study findings.”

Animal and human studies have indicated that breathing dysfunction related to SUDEP may involve serotonergic pathways. Compared with controls, patients with SUDEP have fewer midline serotonergic neurons. Furthermore, a 2018 study suggested an association between severe seizures and decreased serotonergic tone in the postictal state.

Dr. Lhatoo and colleagues examined a prospective cohort of patients with intractable epilepsy to understand the relationship between serum serotonin levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA). Patients were aged 18 years or older, were admitted to the epilepsy monitoring unit from January 2015 to April 2018, and agreed to take part in an investigation of SUDEP biomarkers. Dr. Lhatoo and colleagues evaluated video EEG, plethysmography, capillary oxygen saturation, and ECG for 49 patients. After a patient had a clinical seizure, the researchers collected postictal and interictal venous blood samples from him or her to measure serum serotonin levels. They classified seizures using the International League Against Epilepsy 2017 seizure classification. Dr. Lhatoo and colleagues analyzed 49 seizures with and without ICA and 27 generalized convulsive seizures with and without PCCA.

Of the 49 patients, 29 were female. Participants’ mean age was 42 years, mean age at epilepsy onset was 25.2 years, and mean epilepsy duration was 16.8 years. The population’s mean body mass index was 28.9. Dr. Lhatoo and colleagues observed ICA in 17 of 49 (34.7%) seizures and PCCA in 8 of 27 (29.6%) seizures.

Postictal serum serotonin levels were significantly higher than interictal levels for seizures without ICA, but not for seizures with ICA. Among patients with generalized convulsive seizures without PCCA, serum serotonin levels were significantly increased postictally, compared with interictal levels, but not among patients with seizures with PCCA. The change in postictal and interictal serotonin levels also differed significantly between participants with and without PCCA. In patients without PCCA, an increase in serotonin was associated with an increase in heart rate, but not in patients with PCCA.

“Large postictal increases in serum serotonin may play a role in modulation of respiration in these patients,” wrote Dr. Lhatoo and colleagues. “Alternatively, the increase in serum serotonin that we measured may be a surrogate for an increase in brain serotonin levels that may depend on similar physiologic mechanisms, rather than serum serotonin directly stimulating breathing.” Low levels of postictal serum serotonin are associated with potentially harmful breathing phenomena that should be investigated in larger studies, the investigators concluded.

The study was funded by a grant from the National Institutes of Health. One author received a laboratory research grant from Zogenix.

[email protected]

SOURCE: Murugesan A et al. Neurology. 2019 Sep 3. doi: 10.1212/WNL.0000000000008244.

Significant increases in serum serotonin levels after seizures are associated with lower incidence of seizure-related breathing dysfunction in patients with epilepsy, according to research published online Sept. 4 in Neurology. The change in serotonin level may reflect physiologic changes that protect against harmful processes that promote sudden unexpected death in epilepsy (SUDEP), the authors wrote.

“Our results give new insight into a possible link between serotonin levels and breathing during and after seizure,” Samden D. Lhatoo, MD, professor of neurology at McGovern Medical School at the University of Texas Health Science Center in Houston, said in a press release. “This may give hope that perhaps someday new therapies could be developed that may help prevent SUDEP. However, our study was small, and much more research is needed to confirm our findings in larger groups before any treatment decisions can be made. It is also important to note that excess serotonin can be harmful, so we strongly recommend against anyone trying to find ways to increase their serotonin levels in response to our study findings.”

Animal and human studies have indicated that breathing dysfunction related to SUDEP may involve serotonergic pathways. Compared with controls, patients with SUDEP have fewer midline serotonergic neurons. Furthermore, a 2018 study suggested an association between severe seizures and decreased serotonergic tone in the postictal state.

Dr. Lhatoo and colleagues examined a prospective cohort of patients with intractable epilepsy to understand the relationship between serum serotonin levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA). Patients were aged 18 years or older, were admitted to the epilepsy monitoring unit from January 2015 to April 2018, and agreed to take part in an investigation of SUDEP biomarkers. Dr. Lhatoo and colleagues evaluated video EEG, plethysmography, capillary oxygen saturation, and ECG for 49 patients. After a patient had a clinical seizure, the researchers collected postictal and interictal venous blood samples from him or her to measure serum serotonin levels. They classified seizures using the International League Against Epilepsy 2017 seizure classification. Dr. Lhatoo and colleagues analyzed 49 seizures with and without ICA and 27 generalized convulsive seizures with and without PCCA.

Of the 49 patients, 29 were female. Participants’ mean age was 42 years, mean age at epilepsy onset was 25.2 years, and mean epilepsy duration was 16.8 years. The population’s mean body mass index was 28.9. Dr. Lhatoo and colleagues observed ICA in 17 of 49 (34.7%) seizures and PCCA in 8 of 27 (29.6%) seizures.

Postictal serum serotonin levels were significantly higher than interictal levels for seizures without ICA, but not for seizures with ICA. Among patients with generalized convulsive seizures without PCCA, serum serotonin levels were significantly increased postictally, compared with interictal levels, but not among patients with seizures with PCCA. The change in postictal and interictal serotonin levels also differed significantly between participants with and without PCCA. In patients without PCCA, an increase in serotonin was associated with an increase in heart rate, but not in patients with PCCA.

“Large postictal increases in serum serotonin may play a role in modulation of respiration in these patients,” wrote Dr. Lhatoo and colleagues. “Alternatively, the increase in serum serotonin that we measured may be a surrogate for an increase in brain serotonin levels that may depend on similar physiologic mechanisms, rather than serum serotonin directly stimulating breathing.” Low levels of postictal serum serotonin are associated with potentially harmful breathing phenomena that should be investigated in larger studies, the investigators concluded.

The study was funded by a grant from the National Institutes of Health. One author received a laboratory research grant from Zogenix.

[email protected]

SOURCE: Murugesan A et al. Neurology. 2019 Sep 3. doi: 10.1212/WNL.0000000000008244.

Significant increases in serum serotonin levels after seizures are associated with lower incidence of seizure-related breathing dysfunction in patients with epilepsy, according to research published online Sept. 4 in Neurology. The change in serotonin level may reflect physiologic changes that protect against harmful processes that promote sudden unexpected death in epilepsy (SUDEP), the authors wrote.

“Our results give new insight into a possible link between serotonin levels and breathing during and after seizure,” Samden D. Lhatoo, MD, professor of neurology at McGovern Medical School at the University of Texas Health Science Center in Houston, said in a press release. “This may give hope that perhaps someday new therapies could be developed that may help prevent SUDEP. However, our study was small, and much more research is needed to confirm our findings in larger groups before any treatment decisions can be made. It is also important to note that excess serotonin can be harmful, so we strongly recommend against anyone trying to find ways to increase their serotonin levels in response to our study findings.”

Animal and human studies have indicated that breathing dysfunction related to SUDEP may involve serotonergic pathways. Compared with controls, patients with SUDEP have fewer midline serotonergic neurons. Furthermore, a 2018 study suggested an association between severe seizures and decreased serotonergic tone in the postictal state.

Dr. Lhatoo and colleagues examined a prospective cohort of patients with intractable epilepsy to understand the relationship between serum serotonin levels, ictal central apnea (ICA), and postconvulsive central apnea (PCCA). Patients were aged 18 years or older, were admitted to the epilepsy monitoring unit from January 2015 to April 2018, and agreed to take part in an investigation of SUDEP biomarkers. Dr. Lhatoo and colleagues evaluated video EEG, plethysmography, capillary oxygen saturation, and ECG for 49 patients. After a patient had a clinical seizure, the researchers collected postictal and interictal venous blood samples from him or her to measure serum serotonin levels. They classified seizures using the International League Against Epilepsy 2017 seizure classification. Dr. Lhatoo and colleagues analyzed 49 seizures with and without ICA and 27 generalized convulsive seizures with and without PCCA.

Of the 49 patients, 29 were female. Participants’ mean age was 42 years, mean age at epilepsy onset was 25.2 years, and mean epilepsy duration was 16.8 years. The population’s mean body mass index was 28.9. Dr. Lhatoo and colleagues observed ICA in 17 of 49 (34.7%) seizures and PCCA in 8 of 27 (29.6%) seizures.

Postictal serum serotonin levels were significantly higher than interictal levels for seizures without ICA, but not for seizures with ICA. Among patients with generalized convulsive seizures without PCCA, serum serotonin levels were significantly increased postictally, compared with interictal levels, but not among patients with seizures with PCCA. The change in postictal and interictal serotonin levels also differed significantly between participants with and without PCCA. In patients without PCCA, an increase in serotonin was associated with an increase in heart rate, but not in patients with PCCA.

“Large postictal increases in serum serotonin may play a role in modulation of respiration in these patients,” wrote Dr. Lhatoo and colleagues. “Alternatively, the increase in serum serotonin that we measured may be a surrogate for an increase in brain serotonin levels that may depend on similar physiologic mechanisms, rather than serum serotonin directly stimulating breathing.” Low levels of postictal serum serotonin are associated with potentially harmful breathing phenomena that should be investigated in larger studies, the investigators concluded.

The study was funded by a grant from the National Institutes of Health. One author received a laboratory research grant from Zogenix.

[email protected]

SOURCE: Murugesan A et al. Neurology. 2019 Sep 3. doi: 10.1212/WNL.0000000000008244.

Among women with HER2-positive metastatic breast cancer enrolled in a phase 2 randomized trial, the pan-ErbB inhibitor pyrotinib plus capecitabine had manageable toxicity and a significantly higher overall response rate (ORR) than lapatinib plus capecitabine, investigators reported.

The pyrotinib/capecitabine combination also led to significantly longer progression-free survival (PFS) versus that of standard lapatinib/capecitabine treatment in these women, who had previously received treatment with taxanes, anthracyclines, and in some cases trastuzumab, the investigators wrote in the Journal of Clinical Oncology.

“To our knowledge, this is the first trial to demonstrate that a novel epidermal growth factor receptor/HER2–targeting tyrosine kinase inhibitor provides ORR and PFS benefits over lapatinib,” wrote Fei Ma, MD, of the National Cancer Center, State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking, and colleagues.

In the phase 2 study, a total of 128 Chinese women with histologically confirmed relapsed or metastatic breast cancer were randomized to receive the pyrotinib- or lapatinib-containing regimens given in 21-day cycles.

Overall response rates, the primary end point, were 78% (51 of 65 patients) in the pyrotinib arm and 57.1% (36 of 63 patients) in the lapatinib arm (P = .01), Dr. Yu and colleagues reported.

Median PFS was 18.1 months versus 7.0 months in the pyrotinib and lapatinib arms, respectively (P less than .001). A “potential trend” toward improved overall survival was noted in the pyrotinib arm, though the data were premature and not statistically significant at the time of data analysis, according to the investigators.

Altogether, these efficacy results tracked with those of an earlier phase 1 investigation, and currently, a randomized phase 3 study is underway to confirm the findings, reported Dr. Yu and coauthors.

Hand-foot syndrome and diarrhea were the most common grade 3 adverse events seen with pyrotinib. The rate of grade 3 hand-foot syndrome wit pyrotinib was 24.6% versus 20.6% for the lapatinib group, and the rate of grade 3 diarrhea for the two groups was 15.4% and 4.8%, respectively.

Overall, grade 3 or 4 adverse events were seen in 61% of patients receiving pyrotinib, of which 3.1% were grade 4; they were seen in 47.6% of patients receiving lapatinib, of which 3.2% were grade 4.

Diarrhea of grade 3 severity occurred mainly in the first treatment cycle for both the pyrotinib and lapatinib groups, investigators said.

While the protocol for this randomized phase 2 study did not permit diarrhea prophylaxis, the use of prophylactic loperamide is being studied in a phase 3 study of pyrotinib plus trastuzumab and docetaxel in women with HER2-positive metastatic disease and no prior systemic therapy

Investigators said patients are told to interrupt capecitabine if they experience ongoing grade 3 diarrhea or grade 1 or 2 diarrhea with complications such as dehydration, nausea, vomiting, or fever. If the diarrhea persists after 3 days, pyrotinib should then be interrupted, they said.

Similar advice was given for hand-foot syndrome.

“To date, the only method proven to effectively manage hand-foot syndrome is interruption of treatment and, if necessary, dose reduction,” said the investigators, who recommended first interrupting capecitabine and later pyrotinib.

The study was sponsored by Jiangsu Hengrui Medicine and supported by the CAMS Initiative for Innovative Medicine and the National Science and Technology Major Project of the Ministry of Science and Technology in China. The corresponding author of this study, Binghe Xu, MD, PHD, reported institutional research funding from Jiangsu Hengrui Medicine and other disclosures related to AstraZeneca, Pfizer, Roche, and Eisai. Two study coauthors reported employment with Jiangsu Hengrui Medicine.

SOURCE: Ma F et al. J Clin Oncol. 2019 Aug 20. doi: 10.1200/JCO.19.00108.

Among women with HER2-positive metastatic breast cancer enrolled in a phase 2 randomized trial, the pan-ErbB inhibitor pyrotinib plus capecitabine had manageable toxicity and a significantly higher overall response rate (ORR) than lapatinib plus capecitabine, investigators reported.

The pyrotinib/capecitabine combination also led to significantly longer progression-free survival (PFS) versus that of standard lapatinib/capecitabine treatment in these women, who had previously received treatment with taxanes, anthracyclines, and in some cases trastuzumab, the investigators wrote in the Journal of Clinical Oncology.

“To our knowledge, this is the first trial to demonstrate that a novel epidermal growth factor receptor/HER2–targeting tyrosine kinase inhibitor provides ORR and PFS benefits over lapatinib,” wrote Fei Ma, MD, of the National Cancer Center, State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking, and colleagues.

In the phase 2 study, a total of 128 Chinese women with histologically confirmed relapsed or metastatic breast cancer were randomized to receive the pyrotinib- or lapatinib-containing regimens given in 21-day cycles.

Overall response rates, the primary end point, were 78% (51 of 65 patients) in the pyrotinib arm and 57.1% (36 of 63 patients) in the lapatinib arm (P = .01), Dr. Yu and colleagues reported.

Median PFS was 18.1 months versus 7.0 months in the pyrotinib and lapatinib arms, respectively (P less than .001). A “potential trend” toward improved overall survival was noted in the pyrotinib arm, though the data were premature and not statistically significant at the time of data analysis, according to the investigators.

Altogether, these efficacy results tracked with those of an earlier phase 1 investigation, and currently, a randomized phase 3 study is underway to confirm the findings, reported Dr. Yu and coauthors.

Hand-foot syndrome and diarrhea were the most common grade 3 adverse events seen with pyrotinib. The rate of grade 3 hand-foot syndrome wit pyrotinib was 24.6% versus 20.6% for the lapatinib group, and the rate of grade 3 diarrhea for the two groups was 15.4% and 4.8%, respectively.

Overall, grade 3 or 4 adverse events were seen in 61% of patients receiving pyrotinib, of which 3.1% were grade 4; they were seen in 47.6% of patients receiving lapatinib, of which 3.2% were grade 4.

Diarrhea of grade 3 severity occurred mainly in the first treatment cycle for both the pyrotinib and lapatinib groups, investigators said.

While the protocol for this randomized phase 2 study did not permit diarrhea prophylaxis, the use of prophylactic loperamide is being studied in a phase 3 study of pyrotinib plus trastuzumab and docetaxel in women with HER2-positive metastatic disease and no prior systemic therapy

Investigators said patients are told to interrupt capecitabine if they experience ongoing grade 3 diarrhea or grade 1 or 2 diarrhea with complications such as dehydration, nausea, vomiting, or fever. If the diarrhea persists after 3 days, pyrotinib should then be interrupted, they said.

Similar advice was given for hand-foot syndrome.

“To date, the only method proven to effectively manage hand-foot syndrome is interruption of treatment and, if necessary, dose reduction,” said the investigators, who recommended first interrupting capecitabine and later pyrotinib.

The study was sponsored by Jiangsu Hengrui Medicine and supported by the CAMS Initiative for Innovative Medicine and the National Science and Technology Major Project of the Ministry of Science and Technology in China. The corresponding author of this study, Binghe Xu, MD, PHD, reported institutional research funding from Jiangsu Hengrui Medicine and other disclosures related to AstraZeneca, Pfizer, Roche, and Eisai. Two study coauthors reported employment with Jiangsu Hengrui Medicine.

SOURCE: Ma F et al. J Clin Oncol. 2019 Aug 20. doi: 10.1200/JCO.19.00108.

Among women with HER2-positive metastatic breast cancer enrolled in a phase 2 randomized trial, the pan-ErbB inhibitor pyrotinib plus capecitabine had manageable toxicity and a significantly higher overall response rate (ORR) than lapatinib plus capecitabine, investigators reported.

The pyrotinib/capecitabine combination also led to significantly longer progression-free survival (PFS) versus that of standard lapatinib/capecitabine treatment in these women, who had previously received treatment with taxanes, anthracyclines, and in some cases trastuzumab, the investigators wrote in the Journal of Clinical Oncology.

“To our knowledge, this is the first trial to demonstrate that a novel epidermal growth factor receptor/HER2–targeting tyrosine kinase inhibitor provides ORR and PFS benefits over lapatinib,” wrote Fei Ma, MD, of the National Cancer Center, State Key Laboratory of Molecular Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking, and colleagues.

In the phase 2 study, a total of 128 Chinese women with histologically confirmed relapsed or metastatic breast cancer were randomized to receive the pyrotinib- or lapatinib-containing regimens given in 21-day cycles.

Overall response rates, the primary end point, were 78% (51 of 65 patients) in the pyrotinib arm and 57.1% (36 of 63 patients) in the lapatinib arm (P = .01), Dr. Yu and colleagues reported.

Median PFS was 18.1 months versus 7.0 months in the pyrotinib and lapatinib arms, respectively (P less than .001). A “potential trend” toward improved overall survival was noted in the pyrotinib arm, though the data were premature and not statistically significant at the time of data analysis, according to the investigators.

Altogether, these efficacy results tracked with those of an earlier phase 1 investigation, and currently, a randomized phase 3 study is underway to confirm the findings, reported Dr. Yu and coauthors.

Hand-foot syndrome and diarrhea were the most common grade 3 adverse events seen with pyrotinib. The rate of grade 3 hand-foot syndrome wit pyrotinib was 24.6% versus 20.6% for the lapatinib group, and the rate of grade 3 diarrhea for the two groups was 15.4% and 4.8%, respectively.

Overall, grade 3 or 4 adverse events were seen in 61% of patients receiving pyrotinib, of which 3.1% were grade 4; they were seen in 47.6% of patients receiving lapatinib, of which 3.2% were grade 4.

Diarrhea of grade 3 severity occurred mainly in the first treatment cycle for both the pyrotinib and lapatinib groups, investigators said.

While the protocol for this randomized phase 2 study did not permit diarrhea prophylaxis, the use of prophylactic loperamide is being studied in a phase 3 study of pyrotinib plus trastuzumab and docetaxel in women with HER2-positive metastatic disease and no prior systemic therapy

Investigators said patients are told to interrupt capecitabine if they experience ongoing grade 3 diarrhea or grade 1 or 2 diarrhea with complications such as dehydration, nausea, vomiting, or fever. If the diarrhea persists after 3 days, pyrotinib should then be interrupted, they said.

Similar advice was given for hand-foot syndrome.

“To date, the only method proven to effectively manage hand-foot syndrome is interruption of treatment and, if necessary, dose reduction,” said the investigators, who recommended first interrupting capecitabine and later pyrotinib.

The study was sponsored by Jiangsu Hengrui Medicine and supported by the CAMS Initiative for Innovative Medicine and the National Science and Technology Major Project of the Ministry of Science and Technology in China. The corresponding author of this study, Binghe Xu, MD, PHD, reported institutional research funding from Jiangsu Hengrui Medicine and other disclosures related to AstraZeneca, Pfizer, Roche, and Eisai. Two study coauthors reported employment with Jiangsu Hengrui Medicine.

SOURCE: Ma F et al. J Clin Oncol. 2019 Aug 20. doi: 10.1200/JCO.19.00108.

Medication to help prevent breast cancer is not recommended for women without increased risk, but could benefit women at increased risk for the disease, according to an update from the U.S. Preventive Services Task Force.

Dr. Cecil Fox/National Cancer Institute

SOURCEs: Owens DK et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.11885; Nelson HD et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.5780.

Medication to help prevent breast cancer is not recommended for women without increased risk, but could benefit women at increased risk for the disease, according to an update from the U.S. Preventive Services Task Force.

Dr. Cecil Fox/National Cancer Institute

SOURCEs: Owens DK et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.11885; Nelson HD et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.5780.

Medication to help prevent breast cancer is not recommended for women without increased risk, but could benefit women at increased risk for the disease, according to an update from the U.S. Preventive Services Task Force.

Dr. Cecil Fox/National Cancer Institute

SOURCEs: Owens DK et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.11885; Nelson HD et al. JAMA. 2019 Sept 3. doi: 10.1001/jama.2019.5780.

In women with nonmetastatic breast cancer, postoperative regional node irradiation with proton-beam radiation was associated with low rates of toxicity and with disease control rates similar to those reported with conventional photon-based radiation therapy (RT), investigators in a small prospective clinical study reported.

Among 62 survivors of a cohort of 69 women with nonmetastatic breast cancer who required postoperative radiation to the internal mammary nodes (IMN) and for whom conventional radiation was thought to pose excess risks of toxicity, there were no cases of the primary endpoint of grade 3 or greater radiation pneumonitis and no grade 4 toxicities within 3 months of therapy, reported Rachel B. Jimenez, MD, of the Massachusetts General Hospital Cancer Center in Boston and colleagues.

“In our prospective trial of women with locally advanced breast cancer who required treatment of the IMNs, proton beam RT was safe and effective. Future research will provide needed information about the potential long-term normal tissue–sparing benefits of this complex treatment modality compared with conventional radiation,” they wrote in the Journal of Clinical Oncology.

Protons offer the theoretic advantage over photons of minimizing radiation dose to the heart and lungs when treating the breast, chest wall, or regional lymph nodes. Protons, unlike photons, deliver their maximum ionizing energy to tissues immediately before they come to rest, allowing for a more precise dose of radiation to local tissues.

“Multiple dosimetric planning studies that compared proton RT with photon RT have demonstrated superior delivery to targeted areas while sparing more of the heart and lungs. However, prospective clinical data are lacking to support the safety and efficacy of proton RT for breast cancer,” the investigators wrote.

To rectify this, they enrolled adult patients with nonmetastatic breast cancer who required postoperative radiation therapy inclusive of the IMNs and for whom the treating physician determined that either breast reconstruction would prevent adequate target coverage or conventional radiation would deliver 20 Gy or more to 5% or more of the heart and/or the left anterior descending artery (LAD).

A total of 69 patients (median age 45 years) were evaluable for the primary endpoint. In all, 63 of the 70 enrolled patients had left-sided breast cancer, 5 had right-sided breast cancer, and 2 had bilateral breast cancer. The majority of patients (65) had stage II-III disease. All but 2 patients underwent systemic chemotherapy, and 50 underwent immediate reconstruction.

The median of the mean proton radiation dose to the chest wall/breast was 49.7 Gy (relative biological effectiveness) and to the IMN was 48.8 Gy (relative biological effectiveness), indicating comprehensive coverage. The mean heart dose was a median of 0.50 Gy, and the mean dose to the LAD was a median of 1.16 Gy.

After a median follow-up of 55 months, the 5-year rate for locoregional failure among 62 surviving patients was 1.5%

As noted before, there were no cases of grade 3 radiation pneumonitis and no grade 4 toxicities of any type within 3 months of radiation therapy. One patient developed grade 2 radiation pneumonitis 4 months after therapy and was successfully treated with oral corticosteroids, and one developed a severe infection of the bilateral chest wall 4 months after radiation to the left-side chest wall. She was treated with intravenous antibiotics.

There were no significant changes in either echocardiography or cardiac biomarkers after radiotherapy.

The authors noted that the toxicity and disease control rates compared favorably with those of historical data on conventional radiation therapy from two studies published in 2015 (N Engl J Med. 2015;373:307-16; N Engl J Med. 2015;373:317-27).

The study was supported by a grant from the National Institutes of Health. Dr. Jimenez disclosed research funding from Focal Therapeutics.

SOURCE: Jimenez RB et al. J Clin Oncol 2019 Aug 26. doi: 10.1200/JCO.18.02366.

In women with nonmetastatic breast cancer, postoperative regional node irradiation with proton-beam radiation was associated with low rates of toxicity and with disease control rates similar to those reported with conventional photon-based radiation therapy (RT), investigators in a small prospective clinical study reported.

Among 62 survivors of a cohort of 69 women with nonmetastatic breast cancer who required postoperative radiation to the internal mammary nodes (IMN) and for whom conventional radiation was thought to pose excess risks of toxicity, there were no cases of the primary endpoint of grade 3 or greater radiation pneumonitis and no grade 4 toxicities within 3 months of therapy, reported Rachel B. Jimenez, MD, of the Massachusetts General Hospital Cancer Center in Boston and colleagues.

“In our prospective trial of women with locally advanced breast cancer who required treatment of the IMNs, proton beam RT was safe and effective. Future research will provide needed information about the potential long-term normal tissue–sparing benefits of this complex treatment modality compared with conventional radiation,” they wrote in the Journal of Clinical Oncology.

Protons offer the theoretic advantage over photons of minimizing radiation dose to the heart and lungs when treating the breast, chest wall, or regional lymph nodes. Protons, unlike photons, deliver their maximum ionizing energy to tissues immediately before they come to rest, allowing for a more precise dose of radiation to local tissues.

“Multiple dosimetric planning studies that compared proton RT with photon RT have demonstrated superior delivery to targeted areas while sparing more of the heart and lungs. However, prospective clinical data are lacking to support the safety and efficacy of proton RT for breast cancer,” the investigators wrote.

To rectify this, they enrolled adult patients with nonmetastatic breast cancer who required postoperative radiation therapy inclusive of the IMNs and for whom the treating physician determined that either breast reconstruction would prevent adequate target coverage or conventional radiation would deliver 20 Gy or more to 5% or more of the heart and/or the left anterior descending artery (LAD).

A total of 69 patients (median age 45 years) were evaluable for the primary endpoint. In all, 63 of the 70 enrolled patients had left-sided breast cancer, 5 had right-sided breast cancer, and 2 had bilateral breast cancer. The majority of patients (65) had stage II-III disease. All but 2 patients underwent systemic chemotherapy, and 50 underwent immediate reconstruction.

The median of the mean proton radiation dose to the chest wall/breast was 49.7 Gy (relative biological effectiveness) and to the IMN was 48.8 Gy (relative biological effectiveness), indicating comprehensive coverage. The mean heart dose was a median of 0.50 Gy, and the mean dose to the LAD was a median of 1.16 Gy.

After a median follow-up of 55 months, the 5-year rate for locoregional failure among 62 surviving patients was 1.5%

As noted before, there were no cases of grade 3 radiation pneumonitis and no grade 4 toxicities of any type within 3 months of radiation therapy. One patient developed grade 2 radiation pneumonitis 4 months after therapy and was successfully treated with oral corticosteroids, and one developed a severe infection of the bilateral chest wall 4 months after radiation to the left-side chest wall. She was treated with intravenous antibiotics.

There were no significant changes in either echocardiography or cardiac biomarkers after radiotherapy.

The authors noted that the toxicity and disease control rates compared favorably with those of historical data on conventional radiation therapy from two studies published in 2015 (N Engl J Med. 2015;373:307-16; N Engl J Med. 2015;373:317-27).

The study was supported by a grant from the National Institutes of Health. Dr. Jimenez disclosed research funding from Focal Therapeutics.

SOURCE: Jimenez RB et al. J Clin Oncol 2019 Aug 26. doi: 10.1200/JCO.18.02366.

In women with nonmetastatic breast cancer, postoperative regional node irradiation with proton-beam radiation was associated with low rates of toxicity and with disease control rates similar to those reported with conventional photon-based radiation therapy (RT), investigators in a small prospective clinical study reported.

Among 62 survivors of a cohort of 69 women with nonmetastatic breast cancer who required postoperative radiation to the internal mammary nodes (IMN) and for whom conventional radiation was thought to pose excess risks of toxicity, there were no cases of the primary endpoint of grade 3 or greater radiation pneumonitis and no grade 4 toxicities within 3 months of therapy, reported Rachel B. Jimenez, MD, of the Massachusetts General Hospital Cancer Center in Boston and colleagues.

“In our prospective trial of women with locally advanced breast cancer who required treatment of the IMNs, proton beam RT was safe and effective. Future research will provide needed information about the potential long-term normal tissue–sparing benefits of this complex treatment modality compared with conventional radiation,” they wrote in the Journal of Clinical Oncology.

Protons offer the theoretic advantage over photons of minimizing radiation dose to the heart and lungs when treating the breast, chest wall, or regional lymph nodes. Protons, unlike photons, deliver their maximum ionizing energy to tissues immediately before they come to rest, allowing for a more precise dose of radiation to local tissues.

“Multiple dosimetric planning studies that compared proton RT with photon RT have demonstrated superior delivery to targeted areas while sparing more of the heart and lungs. However, prospective clinical data are lacking to support the safety and efficacy of proton RT for breast cancer,” the investigators wrote.

To rectify this, they enrolled adult patients with nonmetastatic breast cancer who required postoperative radiation therapy inclusive of the IMNs and for whom the treating physician determined that either breast reconstruction would prevent adequate target coverage or conventional radiation would deliver 20 Gy or more to 5% or more of the heart and/or the left anterior descending artery (LAD).

A total of 69 patients (median age 45 years) were evaluable for the primary endpoint. In all, 63 of the 70 enrolled patients had left-sided breast cancer, 5 had right-sided breast cancer, and 2 had bilateral breast cancer. The majority of patients (65) had stage II-III disease. All but 2 patients underwent systemic chemotherapy, and 50 underwent immediate reconstruction.

The median of the mean proton radiation dose to the chest wall/breast was 49.7 Gy (relative biological effectiveness) and to the IMN was 48.8 Gy (relative biological effectiveness), indicating comprehensive coverage. The mean heart dose was a median of 0.50 Gy, and the mean dose to the LAD was a median of 1.16 Gy.

After a median follow-up of 55 months, the 5-year rate for locoregional failure among 62 surviving patients was 1.5%

As noted before, there were no cases of grade 3 radiation pneumonitis and no grade 4 toxicities of any type within 3 months of radiation therapy. One patient developed grade 2 radiation pneumonitis 4 months after therapy and was successfully treated with oral corticosteroids, and one developed a severe infection of the bilateral chest wall 4 months after radiation to the left-side chest wall. She was treated with intravenous antibiotics.

There were no significant changes in either echocardiography or cardiac biomarkers after radiotherapy.

The authors noted that the toxicity and disease control rates compared favorably with those of historical data on conventional radiation therapy from two studies published in 2015 (N Engl J Med. 2015;373:307-16; N Engl J Med. 2015;373:317-27).

The study was supported by a grant from the National Institutes of Health. Dr. Jimenez disclosed research funding from Focal Therapeutics.

SOURCE: Jimenez RB et al. J Clin Oncol 2019 Aug 26. doi: 10.1200/JCO.18.02366.

Providing access to clinical trials for veteran and active-duty military patients can be a challenge, but a significant number of trials are now recruiting patients from those patient populations. Many trials explicitly recruit patients from the VA, the military, and IHS. The VA Office of Research and Development alone sponsors or cosponsors nearly 1,000 research initiatives, and many more are sponsored by Walter Reed National Medical Center and other major defense and VA facilities. The clinical trials listed below are all open as of August 1, 201 8 ; have at least 1 VA, DoD, or IHS location recruiting patients; and are focused on treatment for colorectal cancer. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.

Lung-MAP (multiple trials)

Lung-MAP (SWOG S1400) is a multidrug, multi-substudy, biomarker-driven squamous cell lung cancer clinical trial that uses state-of-the-art genomic profiling to match patients to substudies testing investigational treatments that may target the genomic alterations, or mutations, found to be driving the growth of their cancer.

ID: NCT02154490, NCT02595944, NCT02766335, NCT02785913, NCT02785939, NCT02926638, NCT02965378, NCT03373760, NCT03377556
Sponsor: Southwest Oncology Group
Locations: VA Connecticut Healthcare System-West Haven Campus; Hines VA Hospital, Illinois; Richard L. Roudebush VAMC, Indianapolis, Indiana; Ann Arbor VAMC, Michigan; Kansas City VAMC, Missouri; VA New Jersey Health Care System, East Orange; Michael E. DeBakey VAMC Houston, Texas

ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (multiple trials)

A group of randomized clinical trials for patients with early-stage non-small cell lung cancer whose tumors have been completely removed by surgery.

ID: NCT02193282, NCT02194738, NCT02201992, NCT02595944
Sponsor: National Cancer Institute
Locations: Little Rock VAMC, Arkansas; VA Connecticut Healthcare System West Haven Campus; Atlanta VAMC, Decatur, Georgia; Hines VA Hospital, Illinois; Richard L. Roudebush VAMC, Indianapolis, Indiana; Minneapolis VAMC, Minnesota; Saint Louis VAMC, Missouri; Veterans Affairs New York Harbor Healthcare System-Brooklyn Campus; Dayton VAMC, Ohio; William S. Middleton VAMC, Madison, Wisconsin

Veterans Affairs Lung Cancer Or Stereotactic Radiotherapy (VALOR)

The standard of care for stage I non-small cell lung cancer has historically been surgical resection in patients who are medically fit to tolerate an operation. Recent data now suggests that stereotactic radiotherapy may be a suitable alternative. This includes the results from a pooled analysis of two incomplete phase III studies that reported a 15% overall survival advantage with stereotactic radiotherapy at 3 years. While these data are promising, the median follow-up period was short, the results underpowered, and the findings were in contradiction to multiple retrospective studies that demonstrate the outcomes with surgery are likely equal or superior. Therefore, the herein trial aims to evaluate these two treatments in a prospective randomized fashion with a goal to compare the overall survival beyond 5 years. It has been designed to enroll patients who have a long life-expectancy, and are fit enough to tolerate an anatomic pulmonary resection with intraoperative lymph node sampling.

ID: NCT02984761
Sponsor: VA Office of Research and Development
Locations: Edward Hines Jr. VA Hospital, Hines, Illinois; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Minneapolis VA Health Care System, Minnesota; Durham VAMC, North Carolina; Michael E. DeBakey VAMC, Houston, Texas; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia

Naloxegol in Treating Patients With Stage IIIB-IV Non-Small Cell Lung Cancer

This randomized pilot clinical trial studies the side effects and best dose of naloxegol and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer. Naloxegol may relieve some of the side effects of opioid pain medication and fight off future growth in the cancer.

ID: NCT03087708
Sponsor: Alliance for Clinical Trials in Oncology
Locations: Minneapolis VAMC, Minnesota; Kansas City VAMC, Missouri; VA Western New York Health Care System-Buffalo; Salisbury VAMC, North Carolina

Palliative Care Interventions for Outpatients Newly Diagnosed With Lung Cancer: Phase II (PCI2)

The focus of the study is to test a nurse-led telephone-based palliative care intervention on improving the delivery of care for patients with newly diagnosed lung cancer. The study is a three site randomized control trial to determine the efficacy of the intervention on improving patients’ quality of life, symptom burden, and satisfaction of care. Additionally, the study will test an innovative care delivery model to improve patients’ access to palliative care. The investigators will also determine the effect of the intervention on patient activation to discuss treatment preferences with their clinician and on clinician knowledge of patients’ goals of care.

ID: NCT03007953
Sponsor: VA Office of Research and Development
Locations: Birmingham VAMC, Alabama; VA Portland Health Care System, Oregon; VA Puget Sound Health Care System Seattle Division, Washington

Radiation Therapy Regimens in Treating Patients With Limited-Stage Small Cell Lung Cancer Receiving Cisplatin and Etoposide

Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as etoposide, carboplatin and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known which radiation therapy regimen is more effective when given together with chemotherapy in treating patients with limited-stage small cell lung cancer. This randomized phase III trial is comparing different chest radiation therapy regimens to see how well they work in treating patients with limited-stage small cell lung cancer.

ID: NCT00632853
Sponsor: Alliance for Clinical Trials in Oncology
Locations: Baltimore VAMC, Maryland; Kansas City VAMC, Missouri; VA Western New York Health Care System, Buffalo, New York; Dayton VAMC, Ohio; Zablocki VAMC, Milwaukee, Wisconsin

Comparison of Different Types of Surgery in Treating Patients With Stage IA Non-Small Cell Lung Cancer

Wedge resection or segmentectomy may be less invasive types of surgery than lobectomy for non-small cell lung cancer and may have fewer side effects and improve recovery. It is not yet known whether wedge resection or segmentectomy are more effective than lobectomy in treating stage IA non-small cell lung cancer.

ID: NCT00499330
Sponsor: Alliance for Clinical Trials in Oncology
Locations: VA Loma Linda Healthcare System, California; VA Long Beach Medical Center, California; Richard L. Roudebush VAMC, Indianapolis, Indiana; Portland VAMC, Oregon

Lung Cancer Screening Decisions (VA-LCSDecTool)

Veterans have a high risk of developing lung in comparison to general populations due to their older age and smoking history. Recent evidence indicates that lung cancer screening with low dose CT scan reduces lung cancer mortality among older heavy smokers. However, the rates of false positive findings are high, requiring further testing and evaluation. Preliminary studies report that while some Veterans are enthusiastic about screening, others are highly reluctant. Patient preferences should be considered as part of an informed decision making process for this emerging paradigm of lung cancer control. Effective methods for preference assessment among Veterans have not yet been developed, evaluated, and integrated into clinical practice. The specific aims of this study are to 1) elicit patient and provider stakeholder input to inform the development of a lung cancer screening decision tool, 2) develop a web based Lung Cancer Screening Decision Tool (LCSDecTool) that incorporates patient and provider input, and 3) evaluate the impact of the LCSDecTool compared to usual care on the decision process, clinical outcomes, and quality of life.

ID: NCT02899754
Sponsor: VA Office of Research and Development
Locations: VA Connecticut Healthcare System West Haven Campus; Corporal Michael J. Crescenz VAMC Philadelphia, Pennsylvania

Molecular Predictors of Cancer in Patients at High Risk of Lung Cancer

Using samples of blood, urine, sputum, and lung tissue from patients at high risk of cancer for laboratory studies may help doctors learn more about changes that may occur in DNA and identify biomarkers related to cancer.

ID: NCT00898313
Sponsor: Vanderbilt-Ingram Cancer Center
Location: VAMC Nashville, Tennessee

Improving Supportive Care for Patients With Thoracic Malignancies

The purpose of this study is to use a proactive approach to improve symptom management of patients with thoracic malignancies. In this pilot study, the investigators propose to evaluate the feasibility of using outbound, proactive telephone symptom assessment strategies and measure the efficacy of this approach on patient satisfaction with their care, patient activation, quality of life and use of healthcare resources.

ID: NCT03216109
Sponsor: Palo Alto Veterans Institute for Research
Location: VA Palo Alto Health Care System, California

Providing access to clinical trials for veteran and active-duty military patients can be a challenge, but a significant number of trials are now recruiting patients from those patient populations. Many trials explicitly recruit patients from the VA, the military, and IHS. The VA Office of Research and Development alone sponsors or cosponsors nearly 1,000 research initiatives, and many more are sponsored by Walter Reed National Medical Center and other major defense and VA facilities. The clinical trials listed below are all open as of August 1, 201 8 ; have at least 1 VA, DoD, or IHS location recruiting patients; and are focused on treatment for colorectal cancer. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.

Lung-MAP (multiple trials)

Lung-MAP (SWOG S1400) is a multidrug, multi-substudy, biomarker-driven squamous cell lung cancer clinical trial that uses state-of-the-art genomic profiling to match patients to substudies testing investigational treatments that may target the genomic alterations, or mutations, found to be driving the growth of their cancer.

ID: NCT02154490, NCT02595944, NCT02766335, NCT02785913, NCT02785939, NCT02926638, NCT02965378, NCT03373760, NCT03377556
Sponsor: Southwest Oncology Group
Locations: VA Connecticut Healthcare System-West Haven Campus; Hines VA Hospital, Illinois; Richard L. Roudebush VAMC, Indianapolis, Indiana; Ann Arbor VAMC, Michigan; Kansas City VAMC, Missouri; VA New Jersey Health Care System, East Orange; Michael E. DeBakey VAMC Houston, Texas

ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (multiple trials)

A group of randomized clinical trials for patients with early-stage non-small cell lung cancer whose tumors have been completely removed by surgery.

ID: NCT02193282, NCT02194738, NCT02201992, NCT02595944
Sponsor: National Cancer Institute
Locations: Little Rock VAMC, Arkansas; VA Connecticut Healthcare System West Haven Campus; Atlanta VAMC, Decatur, Georgia; Hines VA Hospital, Illinois; Richard L. Roudebush VAMC, Indianapolis, Indiana; Minneapolis VAMC, Minnesota; Saint Louis VAMC, Missouri; Veterans Affairs New York Harbor Healthcare System-Brooklyn Campus; Dayton VAMC, Ohio; William S. Middleton VAMC, Madison, Wisconsin

Veterans Affairs Lung Cancer Or Stereotactic Radiotherapy (VALOR)

The standard of care for stage I non-small cell lung cancer has historically been surgical resection in patients who are medically fit to tolerate an operation. Recent data now suggests that stereotactic radiotherapy may be a suitable alternative. This includes the results from a pooled analysis of two incomplete phase III studies that reported a 15% overall survival advantage with stereotactic radiotherapy at 3 years. While these data are promising, the median follow-up period was short, the results underpowered, and the findings were in contradiction to multiple retrospective studies that demonstrate the outcomes with surgery are likely equal or superior. Therefore, the herein trial aims to evaluate these two treatments in a prospective randomized fashion with a goal to compare the overall survival beyond 5 years. It has been designed to enroll patients who have a long life-expectancy, and are fit enough to tolerate an anatomic pulmonary resection with intraoperative lymph node sampling.

ID: NCT02984761
Sponsor: VA Office of Research and Development
Locations: Edward Hines Jr. VA Hospital, Hines, Illinois; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Minneapolis VA Health Care System, Minnesota; Durham VAMC, North Carolina; Michael E. DeBakey VAMC, Houston, Texas; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia

Naloxegol in Treating Patients With Stage IIIB-IV Non-Small Cell Lung Cancer

This randomized pilot clinical trial studies the side effects and best dose of naloxegol and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer. Naloxegol may relieve some of the side effects of opioid pain medication and fight off future growth in the cancer.

ID: NCT03087708
Sponsor: Alliance for Clinical Trials in Oncology
Locations: Minneapolis VAMC, Minnesota; Kansas City VAMC, Missouri; VA Western New York Health Care System-Buffalo; Salisbury VAMC, North Carolina

Palliative Care Interventions for Outpatients Newly Diagnosed With Lung Cancer: Phase II (PCI2)

The focus of the study is to test a nurse-led telephone-based palliative care intervention on improving the delivery of care for patients with newly diagnosed lung cancer. The study is a three site randomized control trial to determine the efficacy of the intervention on improving patients’ quality of life, symptom burden, and satisfaction of care. Additionally, the study will test an innovative care delivery model to improve patients’ access to palliative care. The investigators will also determine the effect of the intervention on patient activation to discuss treatment preferences with their clinician and on clinician knowledge of patients’ goals of care.

ID: NCT03007953
Sponsor: VA Office of Research and Development
Locations: Birmingham VAMC, Alabama; VA Portland Health Care System, Oregon; VA Puget Sound Health Care System Seattle Division, Washington

Radiation Therapy Regimens in Treating Patients With Limited-Stage Small Cell Lung Cancer Receiving Cisplatin and Etoposide

Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as etoposide, carboplatin and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known which radiation therapy regimen is more effective when given together with chemotherapy in treating patients with limited-stage small cell lung cancer. This randomized phase III trial is comparing different chest radiation therapy regimens to see how well they work in treating patients with limited-stage small cell lung cancer.

ID: NCT00632853
Sponsor: Alliance for Clinical Trials in Oncology
Locations: Baltimore VAMC, Maryland; Kansas City VAMC, Missouri; VA Western New York Health Care System, Buffalo, New York; Dayton VAMC, Ohio; Zablocki VAMC, Milwaukee, Wisconsin

Comparison of Different Types of Surgery in Treating Patients With Stage IA Non-Small Cell Lung Cancer

Wedge resection or segmentectomy may be less invasive types of surgery than lobectomy for non-small cell lung cancer and may have fewer side effects and improve recovery. It is not yet known whether wedge resection or segmentectomy are more effective than lobectomy in treating stage IA non-small cell lung cancer.

ID: NCT00499330
Sponsor: Alliance for Clinical Trials in Oncology
Locations: VA Loma Linda Healthcare System, California; VA Long Beach Medical Center, California; Richard L. Roudebush VAMC, Indianapolis, Indiana; Portland VAMC, Oregon

Lung Cancer Screening Decisions (VA-LCSDecTool)

Veterans have a high risk of developing lung in comparison to general populations due to their older age and smoking history. Recent evidence indicates that lung cancer screening with low dose CT scan reduces lung cancer mortality among older heavy smokers. However, the rates of false positive findings are high, requiring further testing and evaluation. Preliminary studies report that while some Veterans are enthusiastic about screening, others are highly reluctant. Patient preferences should be considered as part of an informed decision making process for this emerging paradigm of lung cancer control. Effective methods for preference assessment among Veterans have not yet been developed, evaluated, and integrated into clinical practice. The specific aims of this study are to 1) elicit patient and provider stakeholder input to inform the development of a lung cancer screening decision tool, 2) develop a web based Lung Cancer Screening Decision Tool (LCSDecTool) that incorporates patient and provider input, and 3) evaluate the impact of the LCSDecTool compared to usual care on the decision process, clinical outcomes, and quality of life.

ID: NCT02899754
Sponsor: VA Office of Research and Development
Locations: VA Connecticut Healthcare System West Haven Campus; Corporal Michael J. Crescenz VAMC Philadelphia, Pennsylvania

Molecular Predictors of Cancer in Patients at High Risk of Lung Cancer

Using samples of blood, urine, sputum, and lung tissue from patients at high risk of cancer for laboratory studies may help doctors learn more about changes that may occur in DNA and identify biomarkers related to cancer.

ID: NCT00898313
Sponsor: Vanderbilt-Ingram Cancer Center
Location: VAMC Nashville, Tennessee

Improving Supportive Care for Patients With Thoracic Malignancies

The purpose of this study is to use a proactive approach to improve symptom management of patients with thoracic malignancies. In this pilot study, the investigators propose to evaluate the feasibility of using outbound, proactive telephone symptom assessment strategies and measure the efficacy of this approach on patient satisfaction with their care, patient activation, quality of life and use of healthcare resources.

ID: NCT03216109
Sponsor: Palo Alto Veterans Institute for Research
Location: VA Palo Alto Health Care System, California

Providing access to clinical trials for veteran and active-duty military patients can be a challenge, but a significant number of trials are now recruiting patients from those patient populations. Many trials explicitly recruit patients from the VA, the military, and IHS. The VA Office of Research and Development alone sponsors or cosponsors nearly 1,000 research initiatives, and many more are sponsored by Walter Reed National Medical Center and other major defense and VA facilities. The clinical trials listed below are all open as of August 1, 201 8 ; have at least 1 VA, DoD, or IHS location recruiting patients; and are focused on treatment for colorectal cancer. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials.gov.

Lung-MAP (multiple trials)

Lung-MAP (SWOG S1400) is a multidrug, multi-substudy, biomarker-driven squamous cell lung cancer clinical trial that uses state-of-the-art genomic profiling to match patients to substudies testing investigational treatments that may target the genomic alterations, or mutations, found to be driving the growth of their cancer.

ID: NCT02154490, NCT02595944, NCT02766335, NCT02785913, NCT02785939, NCT02926638, NCT02965378, NCT03373760, NCT03377556
Sponsor: Southwest Oncology Group
Locations: VA Connecticut Healthcare System-West Haven Campus; Hines VA Hospital, Illinois; Richard L. Roudebush VAMC, Indianapolis, Indiana; Ann Arbor VAMC, Michigan; Kansas City VAMC, Missouri; VA New Jersey Health Care System, East Orange; Michael E. DeBakey VAMC Houston, Texas

ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (multiple trials)

A group of randomized clinical trials for patients with early-stage non-small cell lung cancer whose tumors have been completely removed by surgery.

ID: NCT02193282, NCT02194738, NCT02201992, NCT02595944
Sponsor: National Cancer Institute
Locations: Little Rock VAMC, Arkansas; VA Connecticut Healthcare System West Haven Campus; Atlanta VAMC, Decatur, Georgia; Hines VA Hospital, Illinois; Richard L. Roudebush VAMC, Indianapolis, Indiana; Minneapolis VAMC, Minnesota; Saint Louis VAMC, Missouri; Veterans Affairs New York Harbor Healthcare System-Brooklyn Campus; Dayton VAMC, Ohio; William S. Middleton VAMC, Madison, Wisconsin

Veterans Affairs Lung Cancer Or Stereotactic Radiotherapy (VALOR)

The standard of care for stage I non-small cell lung cancer has historically been surgical resection in patients who are medically fit to tolerate an operation. Recent data now suggests that stereotactic radiotherapy may be a suitable alternative. This includes the results from a pooled analysis of two incomplete phase III studies that reported a 15% overall survival advantage with stereotactic radiotherapy at 3 years. While these data are promising, the median follow-up period was short, the results underpowered, and the findings were in contradiction to multiple retrospective studies that demonstrate the outcomes with surgery are likely equal or superior. Therefore, the herein trial aims to evaluate these two treatments in a prospective randomized fashion with a goal to compare the overall survival beyond 5 years. It has been designed to enroll patients who have a long life-expectancy, and are fit enough to tolerate an anatomic pulmonary resection with intraoperative lymph node sampling.

ID: NCT02984761
Sponsor: VA Office of Research and Development
Locations: Edward Hines Jr. VA Hospital, Hines, Illinois; Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Minneapolis VA Health Care System, Minnesota; Durham VAMC, North Carolina; Michael E. DeBakey VAMC, Houston, Texas; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia

Naloxegol in Treating Patients With Stage IIIB-IV Non-Small Cell Lung Cancer

This randomized pilot clinical trial studies the side effects and best dose of naloxegol and to see how well it works in treating patients with stage IIIB-IV non-small cell lung cancer. Naloxegol may relieve some of the side effects of opioid pain medication and fight off future growth in the cancer.

ID: NCT03087708
Sponsor: Alliance for Clinical Trials in Oncology
Locations: Minneapolis VAMC, Minnesota; Kansas City VAMC, Missouri; VA Western New York Health Care System-Buffalo; Salisbury VAMC, North Carolina

Palliative Care Interventions for Outpatients Newly Diagnosed With Lung Cancer: Phase II (PCI2)

The focus of the study is to test a nurse-led telephone-based palliative care intervention on improving the delivery of care for patients with newly diagnosed lung cancer. The study is a three site randomized control trial to determine the efficacy of the intervention on improving patients’ quality of life, symptom burden, and satisfaction of care. Additionally, the study will test an innovative care delivery model to improve patients’ access to palliative care. The investigators will also determine the effect of the intervention on patient activation to discuss treatment preferences with their clinician and on clinician knowledge of patients’ goals of care.

ID: NCT03007953
Sponsor: VA Office of Research and Development
Locations: Birmingham VAMC, Alabama; VA Portland Health Care System, Oregon; VA Puget Sound Health Care System Seattle Division, Washington

Radiation Therapy Regimens in Treating Patients With Limited-Stage Small Cell Lung Cancer Receiving Cisplatin and Etoposide

Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as etoposide, carboplatin and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known which radiation therapy regimen is more effective when given together with chemotherapy in treating patients with limited-stage small cell lung cancer. This randomized phase III trial is comparing different chest radiation therapy regimens to see how well they work in treating patients with limited-stage small cell lung cancer.

ID: NCT00632853
Sponsor: Alliance for Clinical Trials in Oncology
Locations: Baltimore VAMC, Maryland; Kansas City VAMC, Missouri; VA Western New York Health Care System, Buffalo, New York; Dayton VAMC, Ohio; Zablocki VAMC, Milwaukee, Wisconsin

Comparison of Different Types of Surgery in Treating Patients With Stage IA Non-Small Cell Lung Cancer

Wedge resection or segmentectomy may be less invasive types of surgery than lobectomy for non-small cell lung cancer and may have fewer side effects and improve recovery. It is not yet known whether wedge resection or segmentectomy are more effective than lobectomy in treating stage IA non-small cell lung cancer.

ID: NCT00499330
Sponsor: Alliance for Clinical Trials in Oncology
Locations: VA Loma Linda Healthcare System, California; VA Long Beach Medical Center, California; Richard L. Roudebush VAMC, Indianapolis, Indiana; Portland VAMC, Oregon

Lung Cancer Screening Decisions (VA-LCSDecTool)

Veterans have a high risk of developing lung in comparison to general populations due to their older age and smoking history. Recent evidence indicates that lung cancer screening with low dose CT scan reduces lung cancer mortality among older heavy smokers. However, the rates of false positive findings are high, requiring further testing and evaluation. Preliminary studies report that while some Veterans are enthusiastic about screening, others are highly reluctant. Patient preferences should be considered as part of an informed decision making process for this emerging paradigm of lung cancer control. Effective methods for preference assessment among Veterans have not yet been developed, evaluated, and integrated into clinical practice. The specific aims of this study are to 1) elicit patient and provider stakeholder input to inform the development of a lung cancer screening decision tool, 2) develop a web based Lung Cancer Screening Decision Tool (LCSDecTool) that incorporates patient and provider input, and 3) evaluate the impact of the LCSDecTool compared to usual care on the decision process, clinical outcomes, and quality of life.

ID: NCT02899754
Sponsor: VA Office of Research and Development
Locations: VA Connecticut Healthcare System West Haven Campus; Corporal Michael J. Crescenz VAMC Philadelphia, Pennsylvania

Molecular Predictors of Cancer in Patients at High Risk of Lung Cancer

Using samples of blood, urine, sputum, and lung tissue from patients at high risk of cancer for laboratory studies may help doctors learn more about changes that may occur in DNA and identify biomarkers related to cancer.

ID: NCT00898313
Sponsor: Vanderbilt-Ingram Cancer Center
Location: VAMC Nashville, Tennessee

Improving Supportive Care for Patients With Thoracic Malignancies

The purpose of this study is to use a proactive approach to improve symptom management of patients with thoracic malignancies. In this pilot study, the investigators propose to evaluate the feasibility of using outbound, proactive telephone symptom assessment strategies and measure the efficacy of this approach on patient satisfaction with their care, patient activation, quality of life and use of healthcare resources.

ID: NCT03216109
Sponsor: Palo Alto Veterans Institute for Research
Location: VA Palo Alto Health Care System, California

The combination of ado-trastuzumab emtansine (T-DM1) and neratinib shows promise in patients with HER2-positive metastatic breast cancer, according to results from a phase 1b trial.

“The purpose of this study was to determine the safety and preliminary efficacy of the combination in patients previously treated with trastuzumab plus pertuzumab,” wrote Jame Abraham, MD, of the Cleveland Clinic and colleagues in the Journal of Clinical Oncology.

The open-label, dose-escalation study included 27 women with HER2-positive metastatic breast cancer who had hormone receptor–positive or hormone receptor–negative disease. All participants had demonstrated disease progression, despite prior treatment with combination pertuzumab and trastuzumab, plus a taxane. Among 19 response-evaluable patients, 12 patients (63%) had an objective response. Responses were observed across all neratinib doses, including a complete response in three patients, and partial response in nine patients.

“Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification,” Dr. Abraham and associates noted.

“Alterations in the expression of specific HER2 species in ERBB2-amplified cancers, including p95HER2, may have therapeutic implications and require further investigation,” they wrote.

With respect to neratinib dosing, the initial cohort was started at 120 mg daily, which was increased to 240 mg daily in successive cohorts using a 3+3 design. T-DM1 was administered every 3 weeks at 3.6 mg/kg.

After analysis, the researchers proposed a phase 2 dose of neratinib 160 mg once daily and T-DM1 3.6 mg/kg for the combination.

Dose-limiting grade 3 diarrhea was reported in a total of six patients, which was most pronounced in cycle 1. At the phase 2 recommended dose of neratinib, 7 of 10 patients had early-onset diarrhea, which resolved within 24 hours. No grade 4-5 diarrheal toxicities were reported.

Other grade 3-4 adverse events observed were electrolyte abnormalities, thrombocytopenia, nausea, and dehydration.

Phase 2 studies are currently ongoing in order to better characterize the activity of combination T-DM1 and neratinib.

The study was funded by PUMA Biotechnology and the University of Pittsburgh. The authors reported financial affiliations with AstraZeneca, Eisai, Genentech, Guardant Health, Pfizer, Roche, Seattle Genetics, and several others.

SOURCE: Abraham J et al. J Clin Oncol. 2019 Aug 23. doi: 10.1200/JCO.19.00858.

The combination of ado-trastuzumab emtansine (T-DM1) and neratinib shows promise in patients with HER2-positive metastatic breast cancer, according to results from a phase 1b trial.

“The purpose of this study was to determine the safety and preliminary efficacy of the combination in patients previously treated with trastuzumab plus pertuzumab,” wrote Jame Abraham, MD, of the Cleveland Clinic and colleagues in the Journal of Clinical Oncology.

The open-label, dose-escalation study included 27 women with HER2-positive metastatic breast cancer who had hormone receptor–positive or hormone receptor–negative disease. All participants had demonstrated disease progression, despite prior treatment with combination pertuzumab and trastuzumab, plus a taxane. Among 19 response-evaluable patients, 12 patients (63%) had an objective response. Responses were observed across all neratinib doses, including a complete response in three patients, and partial response in nine patients.

“Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification,” Dr. Abraham and associates noted.

“Alterations in the expression of specific HER2 species in ERBB2-amplified cancers, including p95HER2, may have therapeutic implications and require further investigation,” they wrote.

With respect to neratinib dosing, the initial cohort was started at 120 mg daily, which was increased to 240 mg daily in successive cohorts using a 3+3 design. T-DM1 was administered every 3 weeks at 3.6 mg/kg.

After analysis, the researchers proposed a phase 2 dose of neratinib 160 mg once daily and T-DM1 3.6 mg/kg for the combination.

Dose-limiting grade 3 diarrhea was reported in a total of six patients, which was most pronounced in cycle 1. At the phase 2 recommended dose of neratinib, 7 of 10 patients had early-onset diarrhea, which resolved within 24 hours. No grade 4-5 diarrheal toxicities were reported.

Other grade 3-4 adverse events observed were electrolyte abnormalities, thrombocytopenia, nausea, and dehydration.

Phase 2 studies are currently ongoing in order to better characterize the activity of combination T-DM1 and neratinib.

The study was funded by PUMA Biotechnology and the University of Pittsburgh. The authors reported financial affiliations with AstraZeneca, Eisai, Genentech, Guardant Health, Pfizer, Roche, Seattle Genetics, and several others.

SOURCE: Abraham J et al. J Clin Oncol. 2019 Aug 23. doi: 10.1200/JCO.19.00858.

The combination of ado-trastuzumab emtansine (T-DM1) and neratinib shows promise in patients with HER2-positive metastatic breast cancer, according to results from a phase 1b trial.

“The purpose of this study was to determine the safety and preliminary efficacy of the combination in patients previously treated with trastuzumab plus pertuzumab,” wrote Jame Abraham, MD, of the Cleveland Clinic and colleagues in the Journal of Clinical Oncology.

The open-label, dose-escalation study included 27 women with HER2-positive metastatic breast cancer who had hormone receptor–positive or hormone receptor–negative disease. All participants had demonstrated disease progression, despite prior treatment with combination pertuzumab and trastuzumab, plus a taxane. Among 19 response-evaluable patients, 12 patients (63%) had an objective response. Responses were observed across all neratinib doses, including a complete response in three patients, and partial response in nine patients.

“Deep and more durable responses occurred in patients with cell-free DNA ERBB2 amplification,” Dr. Abraham and associates noted.

“Alterations in the expression of specific HER2 species in ERBB2-amplified cancers, including p95HER2, may have therapeutic implications and require further investigation,” they wrote.

With respect to neratinib dosing, the initial cohort was started at 120 mg daily, which was increased to 240 mg daily in successive cohorts using a 3+3 design. T-DM1 was administered every 3 weeks at 3.6 mg/kg.

After analysis, the researchers proposed a phase 2 dose of neratinib 160 mg once daily and T-DM1 3.6 mg/kg for the combination.

Dose-limiting grade 3 diarrhea was reported in a total of six patients, which was most pronounced in cycle 1. At the phase 2 recommended dose of neratinib, 7 of 10 patients had early-onset diarrhea, which resolved within 24 hours. No grade 4-5 diarrheal toxicities were reported.

Other grade 3-4 adverse events observed were electrolyte abnormalities, thrombocytopenia, nausea, and dehydration.

Phase 2 studies are currently ongoing in order to better characterize the activity of combination T-DM1 and neratinib.

The study was funded by PUMA Biotechnology and the University of Pittsburgh. The authors reported financial affiliations with AstraZeneca, Eisai, Genentech, Guardant Health, Pfizer, Roche, Seattle Genetics, and several others.

SOURCE: Abraham J et al. J Clin Oncol. 2019 Aug 23. doi: 10.1200/JCO.19.00858.