Clinical Topics & News

The Food and Drug Administration has approved diroximel fumarate (Vumerity) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, according to an Oct. 30 announcement from its developers, Biogen and Alkermes.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The approval is based on pharmacokinetic studies that established the bioequivalence of diroximel fumarate and dimethyl fumarate (Tecfidera), and it relied in part on the safety and efficacy data for dimethyl fumarate, which was approved in 2013. Diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite as dimethyl fumarate.

Diroximel fumarate may be better tolerated than dimethyl fumarate. A trial found that the newer drug has significantly better gastrointestinal tolerability, the developers of the drug announced in July. In addition, the drug application for diroximel fumarate included interim data from EVOLVE-MS-1, an ongoing, open-label, 2-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Researchers found a 6.3% rate of treatment discontinuation attributable to adverse events. Less than 1% of patients discontinued treatment because of gastrointestinal adverse events.

Serious side effects of diroximel fumarate may include allergic reaction, progressive multifocal leukoencephalopathy, decreases in white blood cell count, and liver problems. Flushing and stomach problems are the most common side effects, which may decrease over time.

Biogen plans to make diroximel fumarate available in the United States in the near future, the company said. Prescribing information is available online.

[email protected]

The Food and Drug Administration has approved diroximel fumarate (Vumerity) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, according to an Oct. 30 announcement from its developers, Biogen and Alkermes.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The approval is based on pharmacokinetic studies that established the bioequivalence of diroximel fumarate and dimethyl fumarate (Tecfidera), and it relied in part on the safety and efficacy data for dimethyl fumarate, which was approved in 2013. Diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite as dimethyl fumarate.

Diroximel fumarate may be better tolerated than dimethyl fumarate. A trial found that the newer drug has significantly better gastrointestinal tolerability, the developers of the drug announced in July. In addition, the drug application for diroximel fumarate included interim data from EVOLVE-MS-1, an ongoing, open-label, 2-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Researchers found a 6.3% rate of treatment discontinuation attributable to adverse events. Less than 1% of patients discontinued treatment because of gastrointestinal adverse events.

Serious side effects of diroximel fumarate may include allergic reaction, progressive multifocal leukoencephalopathy, decreases in white blood cell count, and liver problems. Flushing and stomach problems are the most common side effects, which may decrease over time.

Biogen plans to make diroximel fumarate available in the United States in the near future, the company said. Prescribing information is available online.

[email protected]

The Food and Drug Administration has approved diroximel fumarate (Vumerity) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, according to an Oct. 30 announcement from its developers, Biogen and Alkermes.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The approval is based on pharmacokinetic studies that established the bioequivalence of diroximel fumarate and dimethyl fumarate (Tecfidera), and it relied in part on the safety and efficacy data for dimethyl fumarate, which was approved in 2013. Diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite as dimethyl fumarate.

Diroximel fumarate may be better tolerated than dimethyl fumarate. A trial found that the newer drug has significantly better gastrointestinal tolerability, the developers of the drug announced in July. In addition, the drug application for diroximel fumarate included interim data from EVOLVE-MS-1, an ongoing, open-label, 2-year safety study evaluating diroximel fumarate in patients with relapsing-remitting MS. Researchers found a 6.3% rate of treatment discontinuation attributable to adverse events. Less than 1% of patients discontinued treatment because of gastrointestinal adverse events.

Serious side effects of diroximel fumarate may include allergic reaction, progressive multifocal leukoencephalopathy, decreases in white blood cell count, and liver problems. Flushing and stomach problems are the most common side effects, which may decrease over time.

Biogen plans to make diroximel fumarate available in the United States in the near future, the company said. Prescribing information is available online.

[email protected]

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.

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

In a sampling of 300 individuals with a mean age of 41 years and nearly 16 self-reported headache days per month over the past 6 months, respondents agreed that they were willing to trade some degree of efficacy for less severe adverse events—namely weight gain and memory problems—and that they were even willing to pay more for these tradeoffs in some cases. On average, respondents were willing to pay:

• $84 more (95% confidence interval [CI], $64‐$103) per month to avoid a 10% weight gain
• $59 more (95% CI, $42‐$76) per month to avoid memory problems
• $35 more (95% CI, $20‐$51) per month to avoid a 5% weight gain, and
• $32 (95% CI, $18‐$46) per month to avoid thinking problems.

Within the pool, 81% of respondents confirmed that they had taken a prescription medicine to prevent migraine in the past 6 months.

I think the broad message of this study is important: migraine is not just about migraine or headache days per month. This should not come as news to anyone with more than a passing interest in this condition. As an epidemiological study, it is useful to understand how migraine patients, as a group, view the relative value of cost, side effects, etc. For clinicians, the value of this study is to remind us of the complexity we need to consider when prescribing a migraine treatment. Issues of co-morbidity, economic resources, type of work or daily activities, and most bothersome symptom all play into the decision process, and it is critical to have the patient expressly involved in this process. It is not just about migraine days. It never has been.

Implicit in this article is the reality that we now have a wide variety of pharmacologic and device options for treating migraine. In the past, this was not the case. There is no clear winner among the preventives in terms of headache or migraine days per month. Rather, as the article suggests, we now have the option of selecting our preventives based on a cost-benefit analysis. Because of the near parity in terms of efficacy, the choices are often based on accessibility, financial burden, delivery system, and side effect profile. Properly presented, this can be an empowering experience for the patient. Choices may involve the need for trialing one or more treatments before gaining access to a preferred treatment, or the willingness to risk the chance of an untoward side effect against the promise of a more convivial dosing regimen. This collaborative decision-making process helps center the locus of control with the patient and secure a healthy relationship between the provider and patient.

It should also be remembered that the promise of a given side effect profile is based on the observation in trials and does not reflect the probability of a given outcome in a single patient. Neither does the side effect profile generated in a controlled trial necessarily reflect the side effect profile in any given individual. Too often we fail to stress this to patients and a 1% risk becomes an unavoidable consequence or a promise of smooth sailing. Time spent educating patients (and providers) with regard to the interpretation of efficacy and risk data, is time well spent.

Dr. Cowan is a Higgins Professor of Neurology, Chief of the Division of Headache Medicine and the Department of Neurology and Neurosciences, and Director of the Center for Headache and Facial Pain, at Stanford University School of Medicine.

In a sampling of 300 individuals with a mean age of 41 years and nearly 16 self-reported headache days per month over the past 6 months, respondents agreed that they were willing to trade some degree of efficacy for less severe adverse events—namely weight gain and memory problems—and that they were even willing to pay more for these tradeoffs in some cases. On average, respondents were willing to pay:

• $84 more (95% confidence interval [CI], $64‐$103) per month to avoid a 10% weight gain
• $59 more (95% CI, $42‐$76) per month to avoid memory problems
• $35 more (95% CI, $20‐$51) per month to avoid a 5% weight gain, and
• $32 (95% CI, $18‐$46) per month to avoid thinking problems.

Within the pool, 81% of respondents confirmed that they had taken a prescription medicine to prevent migraine in the past 6 months.

I think the broad message of this study is important: migraine is not just about migraine or headache days per month. This should not come as news to anyone with more than a passing interest in this condition. As an epidemiological study, it is useful to understand how migraine patients, as a group, view the relative value of cost, side effects, etc. For clinicians, the value of this study is to remind us of the complexity we need to consider when prescribing a migraine treatment. Issues of co-morbidity, economic resources, type of work or daily activities, and most bothersome symptom all play into the decision process, and it is critical to have the patient expressly involved in this process. It is not just about migraine days. It never has been.

Implicit in this article is the reality that we now have a wide variety of pharmacologic and device options for treating migraine. In the past, this was not the case. There is no clear winner among the preventives in terms of headache or migraine days per month. Rather, as the article suggests, we now have the option of selecting our preventives based on a cost-benefit analysis. Because of the near parity in terms of efficacy, the choices are often based on accessibility, financial burden, delivery system, and side effect profile. Properly presented, this can be an empowering experience for the patient. Choices may involve the need for trialing one or more treatments before gaining access to a preferred treatment, or the willingness to risk the chance of an untoward side effect against the promise of a more convivial dosing regimen. This collaborative decision-making process helps center the locus of control with the patient and secure a healthy relationship between the provider and patient.

It should also be remembered that the promise of a given side effect profile is based on the observation in trials and does not reflect the probability of a given outcome in a single patient. Neither does the side effect profile generated in a controlled trial necessarily reflect the side effect profile in any given individual. Too often we fail to stress this to patients and a 1% risk becomes an unavoidable consequence or a promise of smooth sailing. Time spent educating patients (and providers) with regard to the interpretation of efficacy and risk data, is time well spent.

Dr. Cowan is a Higgins Professor of Neurology, Chief of the Division of Headache Medicine and the Department of Neurology and Neurosciences, and Director of the Center for Headache and Facial Pain, at Stanford University School of Medicine.

In a sampling of 300 individuals with a mean age of 41 years and nearly 16 self-reported headache days per month over the past 6 months, respondents agreed that they were willing to trade some degree of efficacy for less severe adverse events—namely weight gain and memory problems—and that they were even willing to pay more for these tradeoffs in some cases. On average, respondents were willing to pay:

• $84 more (95% confidence interval [CI], $64‐$103) per month to avoid a 10% weight gain
• $59 more (95% CI, $42‐$76) per month to avoid memory problems
• $35 more (95% CI, $20‐$51) per month to avoid a 5% weight gain, and
• $32 (95% CI, $18‐$46) per month to avoid thinking problems.

Within the pool, 81% of respondents confirmed that they had taken a prescription medicine to prevent migraine in the past 6 months.

I think the broad message of this study is important: migraine is not just about migraine or headache days per month. This should not come as news to anyone with more than a passing interest in this condition. As an epidemiological study, it is useful to understand how migraine patients, as a group, view the relative value of cost, side effects, etc. For clinicians, the value of this study is to remind us of the complexity we need to consider when prescribing a migraine treatment. Issues of co-morbidity, economic resources, type of work or daily activities, and most bothersome symptom all play into the decision process, and it is critical to have the patient expressly involved in this process. It is not just about migraine days. It never has been.

Implicit in this article is the reality that we now have a wide variety of pharmacologic and device options for treating migraine. In the past, this was not the case. There is no clear winner among the preventives in terms of headache or migraine days per month. Rather, as the article suggests, we now have the option of selecting our preventives based on a cost-benefit analysis. Because of the near parity in terms of efficacy, the choices are often based on accessibility, financial burden, delivery system, and side effect profile. Properly presented, this can be an empowering experience for the patient. Choices may involve the need for trialing one or more treatments before gaining access to a preferred treatment, or the willingness to risk the chance of an untoward side effect against the promise of a more convivial dosing regimen. This collaborative decision-making process helps center the locus of control with the patient and secure a healthy relationship between the provider and patient.

It should also be remembered that the promise of a given side effect profile is based on the observation in trials and does not reflect the probability of a given outcome in a single patient. Neither does the side effect profile generated in a controlled trial necessarily reflect the side effect profile in any given individual. Too often we fail to stress this to patients and a 1% risk becomes an unavoidable consequence or a promise of smooth sailing. Time spent educating patients (and providers) with regard to the interpretation of efficacy and risk data, is time well spent.

Dr. Cowan is a Higgins Professor of Neurology, Chief of the Division of Headache Medicine and the Department of Neurology and Neurosciences, and Director of the Center for Headache and Facial Pain, at Stanford University School of Medicine.

The following is a lightly edited transcript of a teleconference recorded in July 2018. The teleconference brought together health care providers from the Greater Los Angeles VA Health Care System (GLAVAHCS) to discuss the real-world processes for managing the treatment of patients with prostate cancer as they move between primary and specialist care.

William J. Aronson, MD. We are fortunate in having a superb medical record system at the Department of Veterans Affairs (VA) where we can all communicate with each other through a number of methods. Let’s start our discussion by reviewing an index patient that we see in our practice who has been treated with either radical prostatectomy or radiation therapy. One question to address is: Is there a point when the Urology or Radiation Oncology service can transition the patient’s entire care back to the primary care team? And if so, what would be the optimal way to accomplish this?

Nick, is there some point at which you discharge the patient from the radiation oncology service and give specific directions to primary care, or is it primarily just back to urology in your case?

Nicholas G. Nickols, MD, PhD. I have not discharged any patient from my clinic after definitive prostate cancer treatment. During treatment, patients are seen every week. Subsequently, I see them 6 weeks posttreatment, and then every 4 months for the first year, then every 6 months for the next 4 years, and then yearly after that. Although I never formally discharged a patient from my clinic, you can see based on the frequency of visits, that the patient will see more often than their primary care provider (PCP) toward the beginning. And then, after some years, the patient sees their primary more than they me. So it’s not an immediate hand off but rather a gradual transition. It’s important that the PCP is aware of what to look for especially for the late recurrences, late potential side effects, probably more significantly than the early side effects, how to manage them when appropriate, and when to ask the patient to see our team more frequently in follow-up.

William Aronson. We have a number of patients who travel tremendous distances to see us, and I tend to think that many of our follow-up patients, once things are stabilized with regards to management of their side effects, really could see their primary care doctors if we can give them specific instructions on, for example, when to get a prostate-specific antigen (PSA) test and when to refer back to us.

Alison, can you think of some specific cases where you feel like we’ve successfully done that?

Alison Neymark, MS. For the most part we haven’t discharged people, either. What we have done is transitioned them over to a phone clinic. In our department, we have 4 nurse practitioners (NPs) who each have a half-day of phone clinic where they call patients with their test results. Some of those patients are prostate cancer patients that we have been following for years. We schedule them for a phone call, whether it’s every 3 months, every 6 months or every year, to review the updated PSA level and to just check in with them by phone. It’s a win-win because it’s a really quick phone call to reassure the veteran that the PSA level is being followed, and it frees up an in-person appointment slot for another veteran.

We still have patients that prefer face-to-face visits, even though they know we’re not doing anything except discussing a PSA level with them—they just want that security of seeing our face. Some patients are very nervous, and they don’t necessarily want to be discharged, so to speak, back to primary care. Also, for those patients that travel a long distance to clinic, we offer an appointment in the video chat clinic, with the community-based outpatient clinics in Bakersfield and Santa Maria, California.

PSA Levels

William Aronson. I probably see a patient about every 4 to 6 weeks who has a low PSA after about 10 years and has a long distance to travel and mobility and other problems that make it difficult to come in. 

The challenge that I have is, what is that specific guideline to give with regards to the rise in PSA? I think it all depends on the patients prostate cancer clinical features and comorbidities.

Nicholas Nickols. If a patient has been seen by me in follow-up a number of times and there’s really no active issues and there’s a low suspicion of recurrence, then I offer the patient the option of a phone follow-up as an alternative to face to face. Some of them accept that, but I ask that they agree to also see either urology or their PCP face to face. I will also remotely ensure that they’re getting the right laboratory tests, and if not, I’ll put those orders in.

With regard to when to refer a patient back for a suspected recurrence after definitive radiation therapy, there is an accepted definition of biochemical failure called the Phoenix definition, which is an absolute rise in 2 ng/mL of PSA over their posttreatment nadir. Often the posttreatment nadir, especially if they were on hormone therapy, will be close to 0. If the PSA gets to 2, that is a good trigger for a referral back to me and/or urology to discuss restaging and workup for a suspected recurrence.

For patients that are postsurgery and then subsequently get salvage radiation, it is not as clear when a restaging workup should be initiated. Currently, the imaging that is routine care is not very sensitive for detecting PSA in that setting until the PSA is around 0.8 ng/mL, and that’s with the most modern imaging available. Over time that may improve.

William Aronson. The other index patient to think about would be the patient who is on watchful waiting for their prostate cancer, which is to be distinguished from active surveillance. If someone’s on active surveillance, we’re regularly doing prostate biopsies and doing very close monitoring; but we also have patients who have multiple other medical problems, have a limited life expectancy, don’t have aggressive prostate cancer, and it’s extremely reasonable not to do a biopsy in those patients.

Again, those are patients where we do follow the PSA generally every 6 months. And I think there’s also scenarios there where it’s reasonable to refer back to primary care with specific instructions. These, again, are patients who had difficulty getting in to see us or have mobility issues, but it is also a way to limit patient visits if that’s their desire.

Peter Glassman, MBBS, MSc: I’m trained as both a general internist and board certified in hospice and palliative medicine. I currently provide primary care as well as palliative care. I view prostate cancer from the diagnosis through the treatment spectrum as a continuum. It starts with the PCP with an elevated PSA level or if the digital rectal exam has an abnormality, and then the role of the genitourinary (GU) practitioner becomes more significant during the active treatment and diagnostic phases.

Primary care doesn’t disappear, and I think there are 2 major issues that go along with that. First of all, we in primary care, because we take care of patients that often have other comorbidities, need to work with the patient on those comorbidities. Secondly, we need the information shared between the GU and primary care providers so that we can answer questions from our patients and have an understanding of what they’re going through and when.

As time goes on, we go through various phases: We may reach a cure, a quiescent period, active therapy, watchful waiting, or recurrence. Primary care gets involved as time goes on when the disease either becomes quiescent, is just being followed, or is considered cured. Clearly when you have watchful waiting, active treatment, or are in a recurrence, then GU takes the forefront.

I view it as a wave function. Primary care to GU with primary in smaller letters and then primary, if you will, in larger letters, GU becomes a lesser participant unless there is active therapy, watchful waiting or recurrence.

In doing a little bit of research, I found 2 very good and very helpful documents. One is the American Cancer Society (ACS) prostate cancer survivorship care guidelines (Box). And the other is a synopsis of the guidelines. What I liked was that the guidelines focused not only on what should be done for the initial period of prostate cancer, but also for many of the ancillary issues which we often don’t give voice to. The guidelines provide a structure, a foundation to work with our patients over time on their prostate cancer-related issues while, at the same time, being cognizant that we need to deal with their other comorbid conditions.

Modes of Communication

Alison Neymark. We find that including parameters for PSA monitoring in our Progress Notes in the electronic health record (EHR) the best way to communicate with other providers. We’ll say, “If PSA gets to this level, please refer back.” We try to make it clear because with the VA being a training facility, it could be a different resident/attending physician team that’s going to see the patient the next time he is in primary care.

Peter Glassman. Yes, we’re very lucky, as Bill talked about earlier and Alison just mentioned. We have the EHR, and Bill may remember this. Before the EHR, we were constantly fishing to find the most relevant notes. If a patient saw a GU practitioner the day before they saw me, I was often asking the patient what was said. Now we can just review the notes.

It’s a double-edged sword though because there are, of course, many notes in a medical record; and you have to look for the specific items. The EHR and documenting the medical record probably plays the primary role in getting information across. When you want to have an active handoff, or you need to communicate with each other, we have a variety of mechanisms, ranging from the phone to the Microsoft Skype Link (Redmond, WA) system that allows us to tap a message to a colleague.

And I’ve been here long enough that I’ve seen most permutations of how prostate cancer is diagnosed as well as shared among providers. Bill and I have shared patients. Alison and I have shared patients, not necessarily with prostate cancer, although that too. But we know how to communicate with each other. And of course, there’s paging if you need something more urgently.

William Aronson. We also use Microsoft Outlook e-mail, and encrypt the messages to keep them confidential and private. The other nice thing we have is there is a nationwide urology Outlook e-mail, so if any of us have any specific questions, through one e-mail we can send it around the country; and there’s usually multiple very useful responses. That’s another real strength of our system within the VA that helps patient care enormously.

Nicholas Nickols. Sometimes, if there’s a critical note that I absolutely want someone on the care team to read, I’ll add them as a cosigner; and that will pop up when they log in to the Computerized Patient Record System (CPRS) as something that they need to read.

If the patient lives particularly far or gets his care at another VA medical center and laboratory tests are needed, then I will reach out to their PCP via e-mail. If contact is not confirmed, I will reach out via phone or Skype.

Peter Glassman. The most helpful notes are those that are very specific as to what primary care is being asked to do and/or what urology is going to be doing. So, the more specific we get in the notes as to what is being addressed, I think that’s very helpful.

I have been here long enough that I’ve known both Alison and Bill; and if they have an issue, they will tap me a message. It wasn’t long ago that Bill sent a message to me, and we worked on a patient with prostate cancer who was going to be on long-term hormone therapy. We talked about osteoporosis management, and between us we worked out who was going to do what. Those are the kind of shared decision-making situations that are very, very helpful.
 

Alison Neymark. Also, GLAVAHCS has a home-based primary care team (HBPC), and a lot of the PCPs for that team are NPs. They know that they can contact me for their patients because a lot of those patients are on watchful waiting, and we do not necessarily need to see them face to face in clinic. Our urology team just needs to review updated lab results and how they are doing clinically. The HBPC NP who knows them best can contact me every 6 months or so, and we’ll discuss the case, which avoids making the patient come in, especially when they’re homebound. Those of us that have been working at the VA for many years have established good relationships. We feel very comfortable reaching out and talking to each other about these patients

Peter Glassman. Alison, I agree. When I can talk to my patients and say, “You know, we had that question about,” whatever the question might be, “and I contacted urology, and this is what they said.” It gives the patient confidence that we’re following up on the issues that they have and that we’re communicating with each other in a way that is to their benefit. And I think it’s very appreciated both by the provider as well as the patient.

William Aronson. Not infrequently I’ll have patients who have nonurologic issues, which I may first detect, or who have specific issues with their prostate cancer that can be comanaged. And I have found that when I send an encrypted e-mail to the PCP, it has been an extremely satisfying interaction; and we really get to the heart of the matter quickly for the sake of the veteran.

Veterans With Comorbidities

William Aronson. Posttraumatic stress disorder (PTSD) is a very significant and unique aspect of our patients, which is enormously important to recognize. For example, the side effects of prostate treatments can be very significant, whether radiation or surgery. Our patients understandably can be very fearful of the prostate cancer diagnosis and treatment side effects.

We know, for example, after a patient gets a diagnosis of prostate cancer, they’re at increased risk of cardiac death. That’s an especially important issue for our patients that there be an ongoing interaction between urology and primary care.

The ACS guidelines that Dr. Glassman referred to were enlightening. In many cases, primary care can look at the whole patient and their circumstances better than we can and may detect, for example, specific psychological issues that either they can manage or refer to other specialists.

Peter Glassman. One of the things that was highlighted in the ACS guideline is that in any population of men who have this disease, there’s going to be distress, anxiety, and full-fledged depression. Of course, there are psychosocial aspects of prostate cancer, such as sexual activity and intimacy with a partner that we often don’t explore but are probably playing an important role in the overall health of our patients. We need to be mindful of these psychosocial aspects and at least periodically ask them, “How are you doing with this? How are things at home?” And of course, we already use screeners for depression. As the article noted, distress and anxiety and other factors can make somebody’s life less optimal with poorer quality of life.

Dual Care Patients

Alison Neymark. Many patients whether they have Medicare, insurance through their spouse, or Kaiser Permanente through their job, choose to go to both places. The challenge is communicating with the non-VA providers because here at the VA we can communicate easily through Skype, Outlook e-mail, or CPRS, but for dual care patients who’s in charge? I encourage the veterans to choose whom they want to manage their care; we’re always here and happy to treat them, but they need to decide who’s in charge because I don’t want them to get into a situation where the differing opinions lead to a delay in care.

Nicholas Nickols. The communication when the patient is receiving care outside VA, either on a continuous basis or temporarily, is more of a challenge. We obviously can’t rely upon the messaging system, face-to-face contact is difficult, and they may not be able to use e-mail as well. So in those situations, usually a phone call is the best approach. I have found that the outside providers are happy to speak on the phone to coordinate care.

Peter Glassman. I agree, it does add a layer of complexity because we don’t readily have the notes, any information in front of us. That said, a lot of our patients can and do bring in information from outside specialists, and I’m hopeful that they share the information that we provide back to their outside doctors as well.

William Aronson. Some patient get nervous. They might decide they want care elsewhere, but they still want the VA available for them. I always let them know they should proceed in whatever way they prefer, but we’re always available and here for them. I try to empower them to make their own decisions and feel comfortable with them.

Nicholas Nickols. Notes from the outside, if they’re being referred for VA Choice or community care, do get uploaded into VistA Imaging and can be accessed, although it’s not instantaneous. Sometimes there’s a delay, but I have been able to access outside notes most of the time. If a patient goes through a clinic at the VA, the note is written in real time, and you can read it immediately.

Peter Glassman. That is true for patients that are within the VA system who receive contracted care either through Choice or through non-VA care that is contracted through VA. For somebody who is choosing to use 2 health care systems, that can provide more of a challenge because those notes don’t come to us. Over time, most of my patients have brought test results to me.

The thing with oncologic care, of course, is it’s a lot more complex. And it’s hard to know without reasonable documentation what’s been going on. At some level, you have to trust that the outside provider is doing whatever they need to do, or you have to take it upon yourself to do it within the system.

Alison Neymark. In my experience with the Choice Program, it really depends on the outside providers and how comfortable they are with the system that has been established to share records. Not all providers are going into that system and accessing it. I have had cases where I will see the non-VA provider’s note and it’ll say, “No documentation available for this consultation.” It just happens that they didn’t go into the system to review it. So it can be a challenge.

I’ve had good communication with the providers who use the system correctly. In some cases, just to make it easier, I will go ahead and communicate with them through encrypted e-mail, or I’ll talk to their care coordinators directly by phone. 

Peter Glassman. Many, if not most, PCPs are going to take care of these patients, certainly within the VA, with their GU colleagues. And most of us feel comfortable using the current documentation system in a way that allows us to share information or at least to gather information about these patients.

One of the things that I think came out for me in looking at this was that there are guidelines or there are ideas out there on how to take better care of these patients. And I for one learned a fair bit just by going through these documents, which I’m very appreciative of. But it does highlight to me that we can give good care and provide good shared care for prostate cancer survivors. I think that is something that perhaps this discussion will highlight that not only are people doing that, but there are resources they can utilize that will help them get a more comprehensive picture of taking care of prostate cancer survivors in the primary care clinic.

The beauty of the VA system as a system is that as these issues come up that might affect the overall health of the veteran with prostate cancer, for example, psychosocial issues, we have many people that can address this that are experts in their area. And one of the great beauties of having an all-encompassing healthcare system is being able to use resources within the system, whether that be for other medical problems or other social or other psychological issues, that we ourselves are not expert in. We can reach out to our other colleagues and ask them for assistance. We have that available to help the patients. It’s really holistic.

We even have integrated medicine where we can help patients, hopefully, get back into a healthy lifestyle, for example, whereas we may not have that expertise or knowledge. We often think of this as sort of a shared decision between GU and primary care. But, in fact, it’s really the responsibility of many, many people of the system at large. We are very lucky to have that.

The following is a lightly edited transcript of a teleconference recorded in July 2018. The teleconference brought together health care providers from the Greater Los Angeles VA Health Care System (GLAVAHCS) to discuss the real-world processes for managing the treatment of patients with prostate cancer as they move between primary and specialist care.

William J. Aronson, MD. We are fortunate in having a superb medical record system at the Department of Veterans Affairs (VA) where we can all communicate with each other through a number of methods. Let’s start our discussion by reviewing an index patient that we see in our practice who has been treated with either radical prostatectomy or radiation therapy. One question to address is: Is there a point when the Urology or Radiation Oncology service can transition the patient’s entire care back to the primary care team? And if so, what would be the optimal way to accomplish this?

Nick, is there some point at which you discharge the patient from the radiation oncology service and give specific directions to primary care, or is it primarily just back to urology in your case?

Nicholas G. Nickols, MD, PhD. I have not discharged any patient from my clinic after definitive prostate cancer treatment. During treatment, patients are seen every week. Subsequently, I see them 6 weeks posttreatment, and then every 4 months for the first year, then every 6 months for the next 4 years, and then yearly after that. Although I never formally discharged a patient from my clinic, you can see based on the frequency of visits, that the patient will see more often than their primary care provider (PCP) toward the beginning. And then, after some years, the patient sees their primary more than they me. So it’s not an immediate hand off but rather a gradual transition. It’s important that the PCP is aware of what to look for especially for the late recurrences, late potential side effects, probably more significantly than the early side effects, how to manage them when appropriate, and when to ask the patient to see our team more frequently in follow-up.

William Aronson. We have a number of patients who travel tremendous distances to see us, and I tend to think that many of our follow-up patients, once things are stabilized with regards to management of their side effects, really could see their primary care doctors if we can give them specific instructions on, for example, when to get a prostate-specific antigen (PSA) test and when to refer back to us.

Alison, can you think of some specific cases where you feel like we’ve successfully done that?

Alison Neymark, MS. For the most part we haven’t discharged people, either. What we have done is transitioned them over to a phone clinic. In our department, we have 4 nurse practitioners (NPs) who each have a half-day of phone clinic where they call patients with their test results. Some of those patients are prostate cancer patients that we have been following for years. We schedule them for a phone call, whether it’s every 3 months, every 6 months or every year, to review the updated PSA level and to just check in with them by phone. It’s a win-win because it’s a really quick phone call to reassure the veteran that the PSA level is being followed, and it frees up an in-person appointment slot for another veteran.

We still have patients that prefer face-to-face visits, even though they know we’re not doing anything except discussing a PSA level with them—they just want that security of seeing our face. Some patients are very nervous, and they don’t necessarily want to be discharged, so to speak, back to primary care. Also, for those patients that travel a long distance to clinic, we offer an appointment in the video chat clinic, with the community-based outpatient clinics in Bakersfield and Santa Maria, California.

PSA Levels

William Aronson. I probably see a patient about every 4 to 6 weeks who has a low PSA after about 10 years and has a long distance to travel and mobility and other problems that make it difficult to come in. 

The challenge that I have is, what is that specific guideline to give with regards to the rise in PSA? I think it all depends on the patients prostate cancer clinical features and comorbidities.

Nicholas Nickols. If a patient has been seen by me in follow-up a number of times and there’s really no active issues and there’s a low suspicion of recurrence, then I offer the patient the option of a phone follow-up as an alternative to face to face. Some of them accept that, but I ask that they agree to also see either urology or their PCP face to face. I will also remotely ensure that they’re getting the right laboratory tests, and if not, I’ll put those orders in.

With regard to when to refer a patient back for a suspected recurrence after definitive radiation therapy, there is an accepted definition of biochemical failure called the Phoenix definition, which is an absolute rise in 2 ng/mL of PSA over their posttreatment nadir. Often the posttreatment nadir, especially if they were on hormone therapy, will be close to 0. If the PSA gets to 2, that is a good trigger for a referral back to me and/or urology to discuss restaging and workup for a suspected recurrence.

For patients that are postsurgery and then subsequently get salvage radiation, it is not as clear when a restaging workup should be initiated. Currently, the imaging that is routine care is not very sensitive for detecting PSA in that setting until the PSA is around 0.8 ng/mL, and that’s with the most modern imaging available. Over time that may improve.

William Aronson. The other index patient to think about would be the patient who is on watchful waiting for their prostate cancer, which is to be distinguished from active surveillance. If someone’s on active surveillance, we’re regularly doing prostate biopsies and doing very close monitoring; but we also have patients who have multiple other medical problems, have a limited life expectancy, don’t have aggressive prostate cancer, and it’s extremely reasonable not to do a biopsy in those patients.

Again, those are patients where we do follow the PSA generally every 6 months. And I think there’s also scenarios there where it’s reasonable to refer back to primary care with specific instructions. These, again, are patients who had difficulty getting in to see us or have mobility issues, but it is also a way to limit patient visits if that’s their desire.

Peter Glassman, MBBS, MSc: I’m trained as both a general internist and board certified in hospice and palliative medicine. I currently provide primary care as well as palliative care. I view prostate cancer from the diagnosis through the treatment spectrum as a continuum. It starts with the PCP with an elevated PSA level or if the digital rectal exam has an abnormality, and then the role of the genitourinary (GU) practitioner becomes more significant during the active treatment and diagnostic phases.

Primary care doesn’t disappear, and I think there are 2 major issues that go along with that. First of all, we in primary care, because we take care of patients that often have other comorbidities, need to work with the patient on those comorbidities. Secondly, we need the information shared between the GU and primary care providers so that we can answer questions from our patients and have an understanding of what they’re going through and when.

As time goes on, we go through various phases: We may reach a cure, a quiescent period, active therapy, watchful waiting, or recurrence. Primary care gets involved as time goes on when the disease either becomes quiescent, is just being followed, or is considered cured. Clearly when you have watchful waiting, active treatment, or are in a recurrence, then GU takes the forefront.

I view it as a wave function. Primary care to GU with primary in smaller letters and then primary, if you will, in larger letters, GU becomes a lesser participant unless there is active therapy, watchful waiting or recurrence.

In doing a little bit of research, I found 2 very good and very helpful documents. One is the American Cancer Society (ACS) prostate cancer survivorship care guidelines (Box). And the other is a synopsis of the guidelines. What I liked was that the guidelines focused not only on what should be done for the initial period of prostate cancer, but also for many of the ancillary issues which we often don’t give voice to. The guidelines provide a structure, a foundation to work with our patients over time on their prostate cancer-related issues while, at the same time, being cognizant that we need to deal with their other comorbid conditions.

Modes of Communication

Alison Neymark. We find that including parameters for PSA monitoring in our Progress Notes in the electronic health record (EHR) the best way to communicate with other providers. We’ll say, “If PSA gets to this level, please refer back.” We try to make it clear because with the VA being a training facility, it could be a different resident/attending physician team that’s going to see the patient the next time he is in primary care.

Peter Glassman. Yes, we’re very lucky, as Bill talked about earlier and Alison just mentioned. We have the EHR, and Bill may remember this. Before the EHR, we were constantly fishing to find the most relevant notes. If a patient saw a GU practitioner the day before they saw me, I was often asking the patient what was said. Now we can just review the notes.

It’s a double-edged sword though because there are, of course, many notes in a medical record; and you have to look for the specific items. The EHR and documenting the medical record probably plays the primary role in getting information across. When you want to have an active handoff, or you need to communicate with each other, we have a variety of mechanisms, ranging from the phone to the Microsoft Skype Link (Redmond, WA) system that allows us to tap a message to a colleague.

And I’ve been here long enough that I’ve seen most permutations of how prostate cancer is diagnosed as well as shared among providers. Bill and I have shared patients. Alison and I have shared patients, not necessarily with prostate cancer, although that too. But we know how to communicate with each other. And of course, there’s paging if you need something more urgently.

William Aronson. We also use Microsoft Outlook e-mail, and encrypt the messages to keep them confidential and private. The other nice thing we have is there is a nationwide urology Outlook e-mail, so if any of us have any specific questions, through one e-mail we can send it around the country; and there’s usually multiple very useful responses. That’s another real strength of our system within the VA that helps patient care enormously.

Nicholas Nickols. Sometimes, if there’s a critical note that I absolutely want someone on the care team to read, I’ll add them as a cosigner; and that will pop up when they log in to the Computerized Patient Record System (CPRS) as something that they need to read.

If the patient lives particularly far or gets his care at another VA medical center and laboratory tests are needed, then I will reach out to their PCP via e-mail. If contact is not confirmed, I will reach out via phone or Skype.

Peter Glassman. The most helpful notes are those that are very specific as to what primary care is being asked to do and/or what urology is going to be doing. So, the more specific we get in the notes as to what is being addressed, I think that’s very helpful.

I have been here long enough that I’ve known both Alison and Bill; and if they have an issue, they will tap me a message. It wasn’t long ago that Bill sent a message to me, and we worked on a patient with prostate cancer who was going to be on long-term hormone therapy. We talked about osteoporosis management, and between us we worked out who was going to do what. Those are the kind of shared decision-making situations that are very, very helpful.
 

Alison Neymark. Also, GLAVAHCS has a home-based primary care team (HBPC), and a lot of the PCPs for that team are NPs. They know that they can contact me for their patients because a lot of those patients are on watchful waiting, and we do not necessarily need to see them face to face in clinic. Our urology team just needs to review updated lab results and how they are doing clinically. The HBPC NP who knows them best can contact me every 6 months or so, and we’ll discuss the case, which avoids making the patient come in, especially when they’re homebound. Those of us that have been working at the VA for many years have established good relationships. We feel very comfortable reaching out and talking to each other about these patients

Peter Glassman. Alison, I agree. When I can talk to my patients and say, “You know, we had that question about,” whatever the question might be, “and I contacted urology, and this is what they said.” It gives the patient confidence that we’re following up on the issues that they have and that we’re communicating with each other in a way that is to their benefit. And I think it’s very appreciated both by the provider as well as the patient.

William Aronson. Not infrequently I’ll have patients who have nonurologic issues, which I may first detect, or who have specific issues with their prostate cancer that can be comanaged. And I have found that when I send an encrypted e-mail to the PCP, it has been an extremely satisfying interaction; and we really get to the heart of the matter quickly for the sake of the veteran.

Veterans With Comorbidities

William Aronson. Posttraumatic stress disorder (PTSD) is a very significant and unique aspect of our patients, which is enormously important to recognize. For example, the side effects of prostate treatments can be very significant, whether radiation or surgery. Our patients understandably can be very fearful of the prostate cancer diagnosis and treatment side effects.

We know, for example, after a patient gets a diagnosis of prostate cancer, they’re at increased risk of cardiac death. That’s an especially important issue for our patients that there be an ongoing interaction between urology and primary care.

The ACS guidelines that Dr. Glassman referred to were enlightening. In many cases, primary care can look at the whole patient and their circumstances better than we can and may detect, for example, specific psychological issues that either they can manage or refer to other specialists.

Peter Glassman. One of the things that was highlighted in the ACS guideline is that in any population of men who have this disease, there’s going to be distress, anxiety, and full-fledged depression. Of course, there are psychosocial aspects of prostate cancer, such as sexual activity and intimacy with a partner that we often don’t explore but are probably playing an important role in the overall health of our patients. We need to be mindful of these psychosocial aspects and at least periodically ask them, “How are you doing with this? How are things at home?” And of course, we already use screeners for depression. As the article noted, distress and anxiety and other factors can make somebody’s life less optimal with poorer quality of life.

Dual Care Patients

Alison Neymark. Many patients whether they have Medicare, insurance through their spouse, or Kaiser Permanente through their job, choose to go to both places. The challenge is communicating with the non-VA providers because here at the VA we can communicate easily through Skype, Outlook e-mail, or CPRS, but for dual care patients who’s in charge? I encourage the veterans to choose whom they want to manage their care; we’re always here and happy to treat them, but they need to decide who’s in charge because I don’t want them to get into a situation where the differing opinions lead to a delay in care.

Nicholas Nickols. The communication when the patient is receiving care outside VA, either on a continuous basis or temporarily, is more of a challenge. We obviously can’t rely upon the messaging system, face-to-face contact is difficult, and they may not be able to use e-mail as well. So in those situations, usually a phone call is the best approach. I have found that the outside providers are happy to speak on the phone to coordinate care.

Peter Glassman. I agree, it does add a layer of complexity because we don’t readily have the notes, any information in front of us. That said, a lot of our patients can and do bring in information from outside specialists, and I’m hopeful that they share the information that we provide back to their outside doctors as well.

William Aronson. Some patient get nervous. They might decide they want care elsewhere, but they still want the VA available for them. I always let them know they should proceed in whatever way they prefer, but we’re always available and here for them. I try to empower them to make their own decisions and feel comfortable with them.

Nicholas Nickols. Notes from the outside, if they’re being referred for VA Choice or community care, do get uploaded into VistA Imaging and can be accessed, although it’s not instantaneous. Sometimes there’s a delay, but I have been able to access outside notes most of the time. If a patient goes through a clinic at the VA, the note is written in real time, and you can read it immediately.

Peter Glassman. That is true for patients that are within the VA system who receive contracted care either through Choice or through non-VA care that is contracted through VA. For somebody who is choosing to use 2 health care systems, that can provide more of a challenge because those notes don’t come to us. Over time, most of my patients have brought test results to me.

The thing with oncologic care, of course, is it’s a lot more complex. And it’s hard to know without reasonable documentation what’s been going on. At some level, you have to trust that the outside provider is doing whatever they need to do, or you have to take it upon yourself to do it within the system.

Alison Neymark. In my experience with the Choice Program, it really depends on the outside providers and how comfortable they are with the system that has been established to share records. Not all providers are going into that system and accessing it. I have had cases where I will see the non-VA provider’s note and it’ll say, “No documentation available for this consultation.” It just happens that they didn’t go into the system to review it. So it can be a challenge.

I’ve had good communication with the providers who use the system correctly. In some cases, just to make it easier, I will go ahead and communicate with them through encrypted e-mail, or I’ll talk to their care coordinators directly by phone. 

Peter Glassman. Many, if not most, PCPs are going to take care of these patients, certainly within the VA, with their GU colleagues. And most of us feel comfortable using the current documentation system in a way that allows us to share information or at least to gather information about these patients.

One of the things that I think came out for me in looking at this was that there are guidelines or there are ideas out there on how to take better care of these patients. And I for one learned a fair bit just by going through these documents, which I’m very appreciative of. But it does highlight to me that we can give good care and provide good shared care for prostate cancer survivors. I think that is something that perhaps this discussion will highlight that not only are people doing that, but there are resources they can utilize that will help them get a more comprehensive picture of taking care of prostate cancer survivors in the primary care clinic.

The beauty of the VA system as a system is that as these issues come up that might affect the overall health of the veteran with prostate cancer, for example, psychosocial issues, we have many people that can address this that are experts in their area. And one of the great beauties of having an all-encompassing healthcare system is being able to use resources within the system, whether that be for other medical problems or other social or other psychological issues, that we ourselves are not expert in. We can reach out to our other colleagues and ask them for assistance. We have that available to help the patients. It’s really holistic.

We even have integrated medicine where we can help patients, hopefully, get back into a healthy lifestyle, for example, whereas we may not have that expertise or knowledge. We often think of this as sort of a shared decision between GU and primary care. But, in fact, it’s really the responsibility of many, many people of the system at large. We are very lucky to have that.

The following is a lightly edited transcript of a teleconference recorded in July 2018. The teleconference brought together health care providers from the Greater Los Angeles VA Health Care System (GLAVAHCS) to discuss the real-world processes for managing the treatment of patients with prostate cancer as they move between primary and specialist care.

William J. Aronson, MD. We are fortunate in having a superb medical record system at the Department of Veterans Affairs (VA) where we can all communicate with each other through a number of methods. Let’s start our discussion by reviewing an index patient that we see in our practice who has been treated with either radical prostatectomy or radiation therapy. One question to address is: Is there a point when the Urology or Radiation Oncology service can transition the patient’s entire care back to the primary care team? And if so, what would be the optimal way to accomplish this?

Nick, is there some point at which you discharge the patient from the radiation oncology service and give specific directions to primary care, or is it primarily just back to urology in your case?

Nicholas G. Nickols, MD, PhD. I have not discharged any patient from my clinic after definitive prostate cancer treatment. During treatment, patients are seen every week. Subsequently, I see them 6 weeks posttreatment, and then every 4 months for the first year, then every 6 months for the next 4 years, and then yearly after that. Although I never formally discharged a patient from my clinic, you can see based on the frequency of visits, that the patient will see more often than their primary care provider (PCP) toward the beginning. And then, after some years, the patient sees their primary more than they me. So it’s not an immediate hand off but rather a gradual transition. It’s important that the PCP is aware of what to look for especially for the late recurrences, late potential side effects, probably more significantly than the early side effects, how to manage them when appropriate, and when to ask the patient to see our team more frequently in follow-up.

William Aronson. We have a number of patients who travel tremendous distances to see us, and I tend to think that many of our follow-up patients, once things are stabilized with regards to management of their side effects, really could see their primary care doctors if we can give them specific instructions on, for example, when to get a prostate-specific antigen (PSA) test and when to refer back to us.

Alison, can you think of some specific cases where you feel like we’ve successfully done that?

Alison Neymark, MS. For the most part we haven’t discharged people, either. What we have done is transitioned them over to a phone clinic. In our department, we have 4 nurse practitioners (NPs) who each have a half-day of phone clinic where they call patients with their test results. Some of those patients are prostate cancer patients that we have been following for years. We schedule them for a phone call, whether it’s every 3 months, every 6 months or every year, to review the updated PSA level and to just check in with them by phone. It’s a win-win because it’s a really quick phone call to reassure the veteran that the PSA level is being followed, and it frees up an in-person appointment slot for another veteran.

We still have patients that prefer face-to-face visits, even though they know we’re not doing anything except discussing a PSA level with them—they just want that security of seeing our face. Some patients are very nervous, and they don’t necessarily want to be discharged, so to speak, back to primary care. Also, for those patients that travel a long distance to clinic, we offer an appointment in the video chat clinic, with the community-based outpatient clinics in Bakersfield and Santa Maria, California.

PSA Levels

William Aronson. I probably see a patient about every 4 to 6 weeks who has a low PSA after about 10 years and has a long distance to travel and mobility and other problems that make it difficult to come in. 

The challenge that I have is, what is that specific guideline to give with regards to the rise in PSA? I think it all depends on the patients prostate cancer clinical features and comorbidities.

Nicholas Nickols. If a patient has been seen by me in follow-up a number of times and there’s really no active issues and there’s a low suspicion of recurrence, then I offer the patient the option of a phone follow-up as an alternative to face to face. Some of them accept that, but I ask that they agree to also see either urology or their PCP face to face. I will also remotely ensure that they’re getting the right laboratory tests, and if not, I’ll put those orders in.

With regard to when to refer a patient back for a suspected recurrence after definitive radiation therapy, there is an accepted definition of biochemical failure called the Phoenix definition, which is an absolute rise in 2 ng/mL of PSA over their posttreatment nadir. Often the posttreatment nadir, especially if they were on hormone therapy, will be close to 0. If the PSA gets to 2, that is a good trigger for a referral back to me and/or urology to discuss restaging and workup for a suspected recurrence.

For patients that are postsurgery and then subsequently get salvage radiation, it is not as clear when a restaging workup should be initiated. Currently, the imaging that is routine care is not very sensitive for detecting PSA in that setting until the PSA is around 0.8 ng/mL, and that’s with the most modern imaging available. Over time that may improve.

William Aronson. The other index patient to think about would be the patient who is on watchful waiting for their prostate cancer, which is to be distinguished from active surveillance. If someone’s on active surveillance, we’re regularly doing prostate biopsies and doing very close monitoring; but we also have patients who have multiple other medical problems, have a limited life expectancy, don’t have aggressive prostate cancer, and it’s extremely reasonable not to do a biopsy in those patients.

Again, those are patients where we do follow the PSA generally every 6 months. And I think there’s also scenarios there where it’s reasonable to refer back to primary care with specific instructions. These, again, are patients who had difficulty getting in to see us or have mobility issues, but it is also a way to limit patient visits if that’s their desire.

Peter Glassman, MBBS, MSc: I’m trained as both a general internist and board certified in hospice and palliative medicine. I currently provide primary care as well as palliative care. I view prostate cancer from the diagnosis through the treatment spectrum as a continuum. It starts with the PCP with an elevated PSA level or if the digital rectal exam has an abnormality, and then the role of the genitourinary (GU) practitioner becomes more significant during the active treatment and diagnostic phases.

Primary care doesn’t disappear, and I think there are 2 major issues that go along with that. First of all, we in primary care, because we take care of patients that often have other comorbidities, need to work with the patient on those comorbidities. Secondly, we need the information shared between the GU and primary care providers so that we can answer questions from our patients and have an understanding of what they’re going through and when.

As time goes on, we go through various phases: We may reach a cure, a quiescent period, active therapy, watchful waiting, or recurrence. Primary care gets involved as time goes on when the disease either becomes quiescent, is just being followed, or is considered cured. Clearly when you have watchful waiting, active treatment, or are in a recurrence, then GU takes the forefront.

I view it as a wave function. Primary care to GU with primary in smaller letters and then primary, if you will, in larger letters, GU becomes a lesser participant unless there is active therapy, watchful waiting or recurrence.

In doing a little bit of research, I found 2 very good and very helpful documents. One is the American Cancer Society (ACS) prostate cancer survivorship care guidelines (Box). And the other is a synopsis of the guidelines. What I liked was that the guidelines focused not only on what should be done for the initial period of prostate cancer, but also for many of the ancillary issues which we often don’t give voice to. The guidelines provide a structure, a foundation to work with our patients over time on their prostate cancer-related issues while, at the same time, being cognizant that we need to deal with their other comorbid conditions.

Modes of Communication

Alison Neymark. We find that including parameters for PSA monitoring in our Progress Notes in the electronic health record (EHR) the best way to communicate with other providers. We’ll say, “If PSA gets to this level, please refer back.” We try to make it clear because with the VA being a training facility, it could be a different resident/attending physician team that’s going to see the patient the next time he is in primary care.

Peter Glassman. Yes, we’re very lucky, as Bill talked about earlier and Alison just mentioned. We have the EHR, and Bill may remember this. Before the EHR, we were constantly fishing to find the most relevant notes. If a patient saw a GU practitioner the day before they saw me, I was often asking the patient what was said. Now we can just review the notes.

It’s a double-edged sword though because there are, of course, many notes in a medical record; and you have to look for the specific items. The EHR and documenting the medical record probably plays the primary role in getting information across. When you want to have an active handoff, or you need to communicate with each other, we have a variety of mechanisms, ranging from the phone to the Microsoft Skype Link (Redmond, WA) system that allows us to tap a message to a colleague.

And I’ve been here long enough that I’ve seen most permutations of how prostate cancer is diagnosed as well as shared among providers. Bill and I have shared patients. Alison and I have shared patients, not necessarily with prostate cancer, although that too. But we know how to communicate with each other. And of course, there’s paging if you need something more urgently.

William Aronson. We also use Microsoft Outlook e-mail, and encrypt the messages to keep them confidential and private. The other nice thing we have is there is a nationwide urology Outlook e-mail, so if any of us have any specific questions, through one e-mail we can send it around the country; and there’s usually multiple very useful responses. That’s another real strength of our system within the VA that helps patient care enormously.

Nicholas Nickols. Sometimes, if there’s a critical note that I absolutely want someone on the care team to read, I’ll add them as a cosigner; and that will pop up when they log in to the Computerized Patient Record System (CPRS) as something that they need to read.

If the patient lives particularly far or gets his care at another VA medical center and laboratory tests are needed, then I will reach out to their PCP via e-mail. If contact is not confirmed, I will reach out via phone or Skype.

Peter Glassman. The most helpful notes are those that are very specific as to what primary care is being asked to do and/or what urology is going to be doing. So, the more specific we get in the notes as to what is being addressed, I think that’s very helpful.

I have been here long enough that I’ve known both Alison and Bill; and if they have an issue, they will tap me a message. It wasn’t long ago that Bill sent a message to me, and we worked on a patient with prostate cancer who was going to be on long-term hormone therapy. We talked about osteoporosis management, and between us we worked out who was going to do what. Those are the kind of shared decision-making situations that are very, very helpful.
 

Alison Neymark. Also, GLAVAHCS has a home-based primary care team (HBPC), and a lot of the PCPs for that team are NPs. They know that they can contact me for their patients because a lot of those patients are on watchful waiting, and we do not necessarily need to see them face to face in clinic. Our urology team just needs to review updated lab results and how they are doing clinically. The HBPC NP who knows them best can contact me every 6 months or so, and we’ll discuss the case, which avoids making the patient come in, especially when they’re homebound. Those of us that have been working at the VA for many years have established good relationships. We feel very comfortable reaching out and talking to each other about these patients

Peter Glassman. Alison, I agree. When I can talk to my patients and say, “You know, we had that question about,” whatever the question might be, “and I contacted urology, and this is what they said.” It gives the patient confidence that we’re following up on the issues that they have and that we’re communicating with each other in a way that is to their benefit. And I think it’s very appreciated both by the provider as well as the patient.

William Aronson. Not infrequently I’ll have patients who have nonurologic issues, which I may first detect, or who have specific issues with their prostate cancer that can be comanaged. And I have found that when I send an encrypted e-mail to the PCP, it has been an extremely satisfying interaction; and we really get to the heart of the matter quickly for the sake of the veteran.

Veterans With Comorbidities

William Aronson. Posttraumatic stress disorder (PTSD) is a very significant and unique aspect of our patients, which is enormously important to recognize. For example, the side effects of prostate treatments can be very significant, whether radiation or surgery. Our patients understandably can be very fearful of the prostate cancer diagnosis and treatment side effects.

We know, for example, after a patient gets a diagnosis of prostate cancer, they’re at increased risk of cardiac death. That’s an especially important issue for our patients that there be an ongoing interaction between urology and primary care.

The ACS guidelines that Dr. Glassman referred to were enlightening. In many cases, primary care can look at the whole patient and their circumstances better than we can and may detect, for example, specific psychological issues that either they can manage or refer to other specialists.

Peter Glassman. One of the things that was highlighted in the ACS guideline is that in any population of men who have this disease, there’s going to be distress, anxiety, and full-fledged depression. Of course, there are psychosocial aspects of prostate cancer, such as sexual activity and intimacy with a partner that we often don’t explore but are probably playing an important role in the overall health of our patients. We need to be mindful of these psychosocial aspects and at least periodically ask them, “How are you doing with this? How are things at home?” And of course, we already use screeners for depression. As the article noted, distress and anxiety and other factors can make somebody’s life less optimal with poorer quality of life.

Dual Care Patients

Alison Neymark. Many patients whether they have Medicare, insurance through their spouse, or Kaiser Permanente through their job, choose to go to both places. The challenge is communicating with the non-VA providers because here at the VA we can communicate easily through Skype, Outlook e-mail, or CPRS, but for dual care patients who’s in charge? I encourage the veterans to choose whom they want to manage their care; we’re always here and happy to treat them, but they need to decide who’s in charge because I don’t want them to get into a situation where the differing opinions lead to a delay in care.

Nicholas Nickols. The communication when the patient is receiving care outside VA, either on a continuous basis or temporarily, is more of a challenge. We obviously can’t rely upon the messaging system, face-to-face contact is difficult, and they may not be able to use e-mail as well. So in those situations, usually a phone call is the best approach. I have found that the outside providers are happy to speak on the phone to coordinate care.

Peter Glassman. I agree, it does add a layer of complexity because we don’t readily have the notes, any information in front of us. That said, a lot of our patients can and do bring in information from outside specialists, and I’m hopeful that they share the information that we provide back to their outside doctors as well.

William Aronson. Some patient get nervous. They might decide they want care elsewhere, but they still want the VA available for them. I always let them know they should proceed in whatever way they prefer, but we’re always available and here for them. I try to empower them to make their own decisions and feel comfortable with them.

Nicholas Nickols. Notes from the outside, if they’re being referred for VA Choice or community care, do get uploaded into VistA Imaging and can be accessed, although it’s not instantaneous. Sometimes there’s a delay, but I have been able to access outside notes most of the time. If a patient goes through a clinic at the VA, the note is written in real time, and you can read it immediately.

Peter Glassman. That is true for patients that are within the VA system who receive contracted care either through Choice or through non-VA care that is contracted through VA. For somebody who is choosing to use 2 health care systems, that can provide more of a challenge because those notes don’t come to us. Over time, most of my patients have brought test results to me.

The thing with oncologic care, of course, is it’s a lot more complex. And it’s hard to know without reasonable documentation what’s been going on. At some level, you have to trust that the outside provider is doing whatever they need to do, or you have to take it upon yourself to do it within the system.

Alison Neymark. In my experience with the Choice Program, it really depends on the outside providers and how comfortable they are with the system that has been established to share records. Not all providers are going into that system and accessing it. I have had cases where I will see the non-VA provider’s note and it’ll say, “No documentation available for this consultation.” It just happens that they didn’t go into the system to review it. So it can be a challenge.

I’ve had good communication with the providers who use the system correctly. In some cases, just to make it easier, I will go ahead and communicate with them through encrypted e-mail, or I’ll talk to their care coordinators directly by phone. 

Peter Glassman. Many, if not most, PCPs are going to take care of these patients, certainly within the VA, with their GU colleagues. And most of us feel comfortable using the current documentation system in a way that allows us to share information or at least to gather information about these patients.

One of the things that I think came out for me in looking at this was that there are guidelines or there are ideas out there on how to take better care of these patients. And I for one learned a fair bit just by going through these documents, which I’m very appreciative of. But it does highlight to me that we can give good care and provide good shared care for prostate cancer survivors. I think that is something that perhaps this discussion will highlight that not only are people doing that, but there are resources they can utilize that will help them get a more comprehensive picture of taking care of prostate cancer survivors in the primary care clinic.

The beauty of the VA system as a system is that as these issues come up that might affect the overall health of the veteran with prostate cancer, for example, psychosocial issues, we have many people that can address this that are experts in their area. And one of the great beauties of having an all-encompassing healthcare system is being able to use resources within the system, whether that be for other medical problems or other social or other psychological issues, that we ourselves are not expert in. We can reach out to our other colleagues and ask them for assistance. We have that available to help the patients. It’s really holistic.

We even have integrated medicine where we can help patients, hopefully, get back into a healthy lifestyle, for example, whereas we may not have that expertise or knowledge. We often think of this as sort of a shared decision between GU and primary care. But, in fact, it’s really the responsibility of many, many people of the system at large. We are very lucky to have that.

An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.^1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.

Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.³ This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.³

Immune Biology

CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.⁴

Immunotherapy Treatments in Cisplatin-Ineligible Patients

Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).

In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.⁵At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.⁵ The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.⁵

Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.⁶ Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.³

Immunotherapy Treatments After Progression With Cisplatin

Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.⁷ Immunotherapy provides an effective and a much-needed option in this scenario.

Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).³ In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).⁷ Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).⁷ In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.⁸ The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.⁸

It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.⁹ In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.^10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.¹²

Future Directions

Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.

Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.

Conclusion

Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.

An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.^1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.

Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.³ This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.³

Immune Biology

CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.⁴

Immunotherapy Treatments in Cisplatin-Ineligible Patients

Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).

In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.⁵At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.⁵ The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.⁵

Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.⁶ Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.³

Immunotherapy Treatments After Progression With Cisplatin

Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.⁷ Immunotherapy provides an effective and a much-needed option in this scenario.

Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).³ In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).⁷ Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).⁷ In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.⁸ The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.⁸

It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.⁹ In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.^10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.¹²

Future Directions

Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.

Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.

Conclusion

Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.

An essential feature of cancer is its ability to evade the immune system. Multiple mechanisms are used for this purpose, including the disruption of antigen presentation and suppression of the immune response. The latter mechanism involves the activation of T-cell inhibition by recruiting regulatory T cells that weaken this response. Recent progress in understanding the ability of cancer to evade the immune system has paved the way to develop strategies to reverse this process and reactivate the immune system. Particularly, immune checkpoint signaling between T cells and tumor cells has been targeted with a new class of drug, immune checkpoint inhibitors. Immunotherapy has been an established and effective treatment in bladder cancer since 1976 when Morales and colleagues demonstrated that intravesical treatments with bacillus Calmette-Guérin can treat carcinoma in situ and prevent nonmuscle invasive urothelial cancer recurrence.^1,2 This treatment elicits a cytotoxic response via antigenic presentation by bladder tumor cells.

Cytotoxic T-lymphocyte-associated protein (CTLA)-4, programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) are molecules that downregulate the immune response and are targets of therapeutic antibodies that have demonstrated clinical efficacy across a wide range of malignancies. Five such agents—pembrolizumab, atezolizumab, nivolumab, avelumab and durvalumab—were recently approved by the US Food and Drug Administration (FDA) for clinical use in patients with advanced urothelial cancers.³ This class of agents also has been approved for several other malignancies, most notably in melanoma, non-small cell lung cancer, and renal cell carcinoma.³

Immune Biology

CTLA-4 is expressed on activated CD4 and CD8 T cells and competes with CD28 on T cells to interact with the costimulatory B7 proteins on antigen presenting cells. The CD28/B7 interaction promotes T-cell activation and effector functions, and the CTLA-4/B7 interaction inhibits them. In addition, PD-1 is a receptor expressed on CD4 and CD8 T cells, T regulatory (Treg) cells, B cells and natural killer (NK) cells that interacts with its ligand PD-L1 to suppress the immune response. Urothelial cancer possesses features that make it an adequate target for immunotherapeutic agents. Primarily, it is characterized by a high-mutation load, which lends itself to an increased expression of immunogenic antigens on tumor cells.⁴

Immunotherapy Treatments in Cisplatin-Ineligible Patients

Cisplatin-based chemotherapy is the first-line treatment and standard of care in unresectable or metastatic urothelial cancer. However, many patients are unable to receive cisplatin secondary to renal dysfunction, poor performance status, or other comorbidities. Alternative cytotoxic therapies in the first-line setting such as carboplatin-based regimens are associated with inferior outcomes and poor tolerability. There is, therefore, a need for effective and well-tolerated therapies in cisplatin-ineligible patients (Table).

In the phase 2 Keynote-052 trial, 370 cisplatin-ineligible patients were treated with the anti-PD-1 antibody pembrolizumab 200 mg every 3 weeks for up to 2 years.⁵At a median follow-up of 9.5 months, the objective response rate (+ORR) was 29% for the entire cohort, with a 7% complete response (CR) rate, and a 22% partial response (PR) rate.⁵ The median duration of response had not been reached at the time of analysis. Responses were seen regardless of PD-L1 expression, although high response rates were noted in patients whose tumors had PD-L1 expression > 10%. Pembrolizumab had an acceptable tolerability profile in this population. The most common grade 3 or 4 treatment-related adverse event (AE) was fatigue at 2%; 5% of patients discontinued therapy due to treatment related AEs, whereas 17% of patients had immune-mediated AEs.⁵

Similarly, in a single-arm phase 2 trial, atezolizumab, an anti-PD-L1 antibody, dosed at 1,200 mg every 3 weeks was used as first-line therapy in 119 patients with advanced urothelial cancer who were cisplatin ineligible. At a median follow-up of 17 months, the ORR was 23%, with a 9% CR rate. The median duration of response had not been reached. Median progression free survival (PFS) was 2.7 months, whereas overall survival (OS) was 16 months. Eight percent of patients had an AE leading to treatment discontinuation, and 17% had immune-mediated AEs.⁶ Both pembrolizumab and atezolizumab were granted FDA approval in 2017 for patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-based chemotherapy.³

Immunotherapy Treatments After Progression With Cisplatin

Cytotoxic chemotherapy in the second-line setting with disease progression following platinum-based treatment has shown dismal responses, with a median OS of about 6 to 7 months.⁷ Immunotherapy provides an effective and a much-needed option in this scenario.

Five antibodies targeting the PD-1/PD-L1 pathway, pembrolizumab, nivolumab, atezolizumab, avelumab and durvalumab, have been granted FDA approval for patients who have progressed during or after platinum-based therapy (Table).³ In the phase 3 Keynote-045 trial, 542 patients were randomly assigned to receive either pembrolizumab 200 mg administered every 3 weeks or investigator’s choice chemotherapy (paclitaxel, docetaxel, or vinflunine).⁷ Median OS was 10.3 months in the pembrolizumab group and 7.4 months in the chemotherapy group (hazard ratio for death, 0.73; P = .002). Serious (grade 3 or above) treatment-related AEs were significantly less frequent with pembrolizumab (15% vs 49.4%).⁷ In a phase 2 trial, 270 patients were treated with nivolumab, a PD-1 inhibitor, at a dose of 3 mg/kg given every 2 weeks.⁸ The ORR was 19.6%, while the median OS for the entire cohort was 7 months. Responses were seen at all levels of PD-L1 expression, although in patients whose tumor expressed PD-L1 ≥1%, median OS was 11.3 months.⁸

It should be noted that in a large phase 3 trial comparing atezolizumab with chemotherapy in the second-line setting, ORR and OS were not statistically different between the 2 groups, although the duration of response was longer with atezolizumab.⁹ In early phase trials, avelumab and durvalumab, both PD-L1 inhibitors showed an ORR of about 17%, with higher ORR seen in patients with tumors positive for PD-L1 expression.^10,11 The AE profile of immune checkpoint inhibitors is relatively favorable in clinical trials. The American Society of Clinical Oncology and National Comprehensive Cancer Network have jointly published evidence-based guidelines for the management of their immune related AEs.¹²

Future Directions

Several challenges have emerged with immunotherapy treatments. One issue is the relatively low ORRs for immune checkpoint inhibitors, ranging from 13.4% to 24% depending on the trial. Therefore, there is a need to identify reliable biomarkers and selection criteria to predict their efficacy and improve patient selection. Although tumor PD-L1 expression has shown some usefulness in this setting, responses have been noted in patients whose tumors have low or no expression of PD-L1. This low predictive accuracy is caused by several factors, including PD-L1 intratumor expression heterogeneity, primary vs metastatic site PD-L1 expression heterogeneity, lack of consensus on which PD-L1 assays and which value cutoffs to use, and the differences seen in marker expression depending on the freshness of the tissue specimen.

Other predictive biomarkers with potential include tumor gene expression profiles/tumor mutational load, T-cell and B-cell signatures. The optimal imaging modality and timing of this imaging for response assessment also is uncertain. So-called tumor pseudo-progression seen on imaging after treatment with these agents as a result of the immune/inflammatory response to the tumor is now a well-recognized phenomenon, but it can be challenging to differentiate from true disease progression. Other challenges include deciding on which immune checkpoint inhibitor to use given a lack of head-to-head comparisons of these immunotherapeutic agents, finding the proper drug doses to maximize efficacy, as well as determining the optimal duration of treatment in patients with continued response to immunotherapy. Many oncologists continue these treatments for up to 2 years in the setting of a significant or complete response.

Conclusion

Immune checkpoint inhibitors have emerged as pivotal treatments for patients with advanced urothelial cancer who are unfit to receive cisplatin in the first-line setting or who experience disease progression after cisplatin-based chemotherapy. This field continues to expand at a rapid pace due to multiple ongoing clinical trials assessing these agents, whether alone, in combination with cytotoxic, targeted, radiation therapies, or with other immune checkpoint inhibitors, both in the advanced as well as the neoadjuvant/adjuvant settings.

Lung cancer is the leading cause of cancer death in the US, with 154 050 deaths in 2018.¹ There have been many attempts to reduce mortality of the disease through early diagnosis with use of computed tomography (CT). The National Lung Cancer Screening trial showed that screening high-risk populations with low-dose CT (LDCT) can reduce mortality.² However, implementing LDCT screening in the clinical setting has proven challenging, as illustrated by the VA Lung Cancer Screening Demonstration Project (LCSDP).³ A lung cancer diagnosis typically comprises several steps that require different medical specialties; this can lead to delays. In the LCSDP, the mean time to diagnosis was 137 days.³ There are no federal standards for timeliness of lung cancer diagnosis.

The nonprofit RAND Corporation is the only American research organization that has published guidelines specifying acceptable intervals for the diagnosis and treatment of lung cancer. In Quality of Care for Oncologic Conditions and HIV, RAND Corporation researchers propose management quality indicators: lung cancer diagnosis within 2 months of an abnormal radiologic study and treatment within 6 weeks of diagnosis.⁴ The Swedish Lung Cancer Study⁵ and the Canadian Strategy for Cancer Control⁶ both recommended a standard of about 30 days—half the time recommended by the RAND Corporation.

Bukhari and colleagues at the Dayton US Department of Veterans Affairs (VA) Medical Center (VAMC) conducted a quality improvement study that examined lung cancer diagnosis and management.7 They found the time (SD) from abnormal chest imaging to diagnosis was 35.5 (31.6) days. Of those veterans who received a lung cancer diagnosis, 89.2% had the diagnosis made within the 60 days recommended by the RAND Corporation. Although these results surpass those of the LCSDP, they can be exceeded.

Beyond the potential emotional distress of awaiting the final diagnosis of a lung lesion, a delay in diagnosis and treatment may adversely affect outcomes. LDCT screening has been shown to reduce mortality, which implies a link between survival and time to intervention. There is no published evidence that time to diagnosis in advanced stage lung cancer affects outcome. The National Cancer Database (NCDB) contains informtion on about 70% of the cancers diagnosed each year in the US.8 An analysis of 4984 patients with stage IA squamous cell lung cancer undergoing lobectomy from NCDB showed that earlier surgery was associated with an absolute decrease in 5-year mortality of 5% to 8%. 9 Hence, at least in early-stage disease, reduced time from initial suspect imaging to definitive treatment may improve survival.

A system that coordinates the requisite diagnostic steps and avoids delays should provide a significant improvement in patient care. The results of such an approach that utilized nurse navigators has been previously published. 10 Here, we present the results of a dedicated VA referral clinic with priority access to pulmonary consultation and procedures in place that are designed to expedite the diagnosis of potential lung cancer.

Methods

The John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas institutional review board approved this study, which was performed in accordance with the Declaration of Helsinki. Requirement for informed consent was waived, and patient confidentiality was maintained throughout.

We have developed a plan of care specifically to facilitate diagnosis and treatment of the large number of veterans referred to the JLMMVH Diagnostic Clinic for abnormal results of chest imaging. The clinic has priority access to same-day imaging and subspecialty consultation services. In the clinic, medical students and residents perform evaluations and a registered nurse (RN) manager coordinates care.

A Diagnostic Clinic consult for abnormal thoracic imaging immediately triggers an e-consult to an interventional pulmonologist (Figure). The RN manager and pulmonologist perform a joint review of records/imaging prior to scheduling, and the pulmonologist triages the patient. Triage options include follow-up imaging, bronchoscopy with endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and CT-guided biopsy.

The RN manager then schedules a clinic visit that includes a medical evaluation by clinic staff and any indicated procedures on the same day. The interventional pulmonologist performs EBUS, EUS with the convex curvilinear bronchoscope, or both combined as indicated for diagnosis and staging. All procedures are performed in the JLMMVH bronchoscopy suite with standard conscious sedation using midazolam and fentanyl. Any other relevant procedures, such as pleural tap, also are performed at time of procedure. The pulmonologist and an attending pathologist interpret biopsies obtained in the bronchoscopy suite.

We performed a retrospective chart review of patients diagnosed with primary lung cancer through referral to the JLMMVH Diagnostic Clinic. The primary outcome was time from initial suspect chest imaging to cancer diagnosis. The study population consisted of patients referred for abnormal thoracic imaging between January 1, 2013 and December 31, 2016 and subsequently diagnosed with a primary lung cancer.

Subjects were excluded if (1) the patient was referred from outside our care network and a delay of > 10 days occurred between initial lesion imaging and referral; (2) the patient did not show up for appointments or chose to delay evaluation following referral; (3) biopsy demonstrated a nonlung primary cancer; and (4) serious intercurrent illness interrupted the diagnostic plan. In some cases, the radiologist or consulting pulmonologist had judged the lung lesion too small for immediate biopsy and recommended repeat imaging at a later date.

Patients were included in the study if the follow- up imaging led to a lung cancer diagnosis. However, because the interval between the initial imaging and the follow-up imaging in these patients did not represent a systems delay problem, the date of the scheduled follow-up abnormal imaging, which resulted in initiation of a potential cancer evaluation, served as the index suspect imaging date for this study.

Patient electronic medical records were reviewed and the following data were abstracted: date of the abnormal imaging that led to referral and time from abnormal chest X-ray to chest CT scan if applicable; date of referral and date of clinic visit; date of biopsy; date of lung cancer diagnosis; method of obtaining diagnostic specimen; lung cancer type and stage; type and date of treatment initiation or decision for supportive care only; and decision to seek further evaluation or care outside of our system.

All patients diagnosed with lung cancer during the study period were reviewed for inclusion, hence no required sample-size estimate was calculated. All outcomes were assessed as calendar days. The primary outcome was the time from the index suspect chest imaging study to the date of diagnosis of lung cancer. Prior to the initiation of our study, we chose this more stringent 30-day recommendation of the Canadian6 and Swedish5 studies as the comparator for our primary outcome, although data with respect to the 60-day Rand Corporation guidelines also are reported.⁴

Statistical Methods

The mean time to lung cancer diagnosis in our cohort was compared with this 30-day standard using a 2-sided Mann–Whitney U test. Normality of data distribution was determined using the Kolmogorov–Smirnov test. For statistical significance testing a P value of .05 was used. Statistical calculations were performed using R statistical software version 3.2.4. Secondary outcomes consisted of time from diagnosis to treatment; proportion of subjects diagnosed within 60 days; time from initial clinic visit to biopsy; and time from biopsy to diagnosis.

Results

Overall, 222 patients were diagnosed with a malignant lung lesion, of which 63 were excluded from analysis: 22 cancelled or did not appear for appointments, declined further evaluation, or completed evaluation outside of our network; 13 had the diagnosis made prior to Diagnostic Clinic visit; 13 proved to have a nonlung primary tumor presenting in the lung or mediastinal nodes; 12 were delayed > 10 days in referral from an outside network; and 3 had an intervening serious acute medical problem forcing delay in the diagnostic process.

Of the 159 included subjects, 154 (96.9%) were male, and the mean (SD) age was 67.6 (8.1) years. For 76 subjects, the abnormal chest X-ray and subsequent chest CT scan were performed the same day or the lung lesion had initially been noted on a CT scan. For 54 subjects, there was a delay of ≥ 1 week in obtaining a chest CT scan. The mean (SD) time from placement of the Diagnostic Clinic consultation by the primary care provider (PCP) or other provider and the initial Diagnostic Clinic visit was 6.3 (4.4) days. The mean (SD) time from suspect imaging to diagnosis (primary outcome) was 22.6(16.6) days.

The distribution of this outcome was nonnormal (Kolmogorov-Smirnov test P < .01). When compared with the standard of 30 days, the primary outcome of 22.6 days was significantly shorter (2-sided Mann–Whitney U test P < .01). Three-quarters (76.1%) of subjects were diagnosed within 30 days and 95.0% of subjects were diagnosed within 60 days of the initial imaging. For the 8 subjects diagnosed after 60 days, contributing factors included PCP delay in Diagnostic Clinic consultation, initial negative biopsy, delay in performance of chest CT scan prior to consultation, and outsourcing of positron emission tomography (PET) scans.

Overall, 57 (35.8%) of the subjects underwent biopsy on the day of their Diagnostic Clinic visit: 14 underwent CT-guided biopsy and 43 underwent EBUS/EUS. Within 2 days of the initial visit 106 subjects (66.7%) had undergone biopsy. The mean (SD) time from initial Diagnostic Clinic visit to biopsy was 6.3 (9.5) days. The mean (SD) interval was 1.8 (3.0) days for EBUS/ EUS and 11.3 (11.7) days for CT-guided biopsy. The mean (SD) interval from biopsy to diagnosis was 3.2 (6.2) days with 64 cases (40.3%) diagnosed the day of biopsy.

Excluding subjects whose treatment was delayed by patient choice or intercurrent illness, and those who left the VA system to seek treatment elsewhere (n = 21), 24 opted for palliative care, 5 died before treatment could be initiated, and 109 underwent treatment for their tumors (Table). The mean times (SD) from diagnosis to treatment were: chemotherapy alone 34.7 (25.3) days; chemoradiation 37.0 (22.8) days; surgery 44.3 (24.4) days; radiation therapy alone 47.9 (26.0) days. With respect to the RAND Corporation recommended diagnosis to treatment time, 60.9% of chemotherapy alone, 61.5% of chemoradiation, 66.7% of surgery, and 45.0% of radiation therapy alone treatments were initiated within the 6-week window.

Discussion

This retrospective case study demonstrates the effectiveness of a dedicated diagnostic clinic with priority EBUS/EUS access in diagnosing lung cancer within the VA system. Although there is no universally accepted quality standard for comparison, the RAND Corporation recommendation of 60 days from abnormal imaging to diagnosis and the Dayton VAMC published mean of 35.5 days are guideposts; however, the results from the Dayton VAMC may have been affected negatively by some subjects undergoing serial imaging for asymptomatic nodules. We chose a more stringent standard of 30 days as recommended by Swedish and Canadian task forces.

When diagnosing lung cancer, the overriding purpose of the Diagnostic Clinic is to minimize system delays. The method is to have as simple a task as possible for the PCP or other provider who identifies a lung nodule or mass and submits a single consultation request to the Diagnostic Clinic. Once this consultation is placed, the clinic RN manager oversees all further steps required for diagnosis and referral for treatment. The key factor in achieving a mean diagnosis time of 22.6 days is the cooperation between the RN manager and the interventional pulmonologist. When a consultation is received, the RN manager and pulmonologist review the data together and schedule the initial clinic visit; the goal is same-day biopsy, which is achieved in more than one-third of cases. Not all patients with a chest image suspected for lung cancer had it ordered by their PCP. For this reason, a Diagnostic Clinic consultation is available to all health care providers in our system. Many patients reach the clinic after the discovery of a suspect chest X-ray during an emergency department visit, a regularly scheduled subspecialty appointment, or during a preoperative evaluation.

The mean time from initial visit to biopsy was 1.8 days for EBUS/EUS compared with an interval of 11.3 days for CT-guided biopsy. This difference reflects the pulmonologist’s involvement in initial scheduling of Diagnostic Clinic patients. The ability of the pulmonologist to provide an accurate assessment of sample adequacy and a preliminary diagnosis at bedside, with concurrent confirmation by a staff pathologist, permitted the Diagnostic Clinic to inform 40.3% of patients of the finding of malignancy on the day of biopsy. A published comparison of the onsite review of biopsy material showed our pulmonologist and staff pathologists to be equally accurate in their interpretations.¹¹

Sources of Delays

While this study documents the shortest intervals from suspect imaging to diagnosis reported to date, it also identifies sources of system delay in diagnosing lung cancer that JLMMVH could further optimize. The first is the time from initial abnormal chest X-ray imaging to performance of the chest CT scan. On occasion, the index lung lesion is identified unexpectedly on an outpatient or emergency department chest CT scan. With greater use of LDCT lung cancer screening, the initial detection of suspect lesions by CT scanning will increase in the future. However, the PCP most often investigates a patient complaint with a standard chest X-ray that reveals a suspect nodule or mass. When ordered by the PCP as an outpatient test, scheduling of the follow-up chest CT scan is not given priority. More than a third of subjects experienced a delay ≥ 1 week in obtaining a chest CT scan ordered by the PCP; for 29 subjects the delay was ≥ 3weeks. At JLMMVH, the Diagnostic Clinic is given priority in scheduling CT scans. Hence, for suspect lung lesions, the chest CT scan, if not already obtained, is generally performed on the morning of the clinic visit. Educating the PCP to refer the patient immediately to the Diagnostic Clinic rather than waiting to obtain an outpatient chest CT scan may remove this source of unnecessary delay.

Scheduling a CT-guided fine needle aspiration of a lung lesion is another source of system delay. When the chest CT scan is available at the time of the Diagnostic Clinic referral, the clinic visit is scheduled for the earliest day a required CT-guided biopsy can be performed. However, the mean time of 11.3 days from initial Diagnostic Clinic visit to CT-guided biopsy is indicative of the backlog faced by the interventional radiologists.

Although infrequent, PET scans that are required before biopsy can lead to substantial delays. PET scans are performed at our university affiliate, and the joint VA-university lung tumor board sometimes generates requests for such scans prior to tissue diagnosis, yet another source of delay.

The time from referral receipt to the Diagnostic Clinic visit averaged 6.3 days. This delay usually was determined by the availability of the CT-guided biopsy or the dedicated interventional pulmonologist. Although other interventional pulmonologists at JLMMVH may perform the requisite diagnostic procedures, they are not always available for immediate review of imaging studies of referred patients nor can their schedules flexibly accommodate the number of patients seen in our clinic for evaluation.

Lung Cancer Diagnosis

Prompt diagnosis in the setting of a worrisome chest X-ray may help decrease patient anxiety, but does the clinic improve lung cancer treatment outcomes? Such improvement has been demonstrated only in stage IA squamous cell lung cancer.⁹ Of our study population, 37.7% had squamous cell carcinoma, and 85.5% had non-small cell lung cancer. Of those with non-small cell lung cancer, 28.9% had a clinical stage I tumor. Stage I squamous cell carcinoma, the type of tumor most likely to benefit from early diagnosis and treatment, was diagnosed in 11.3% of patients. With the increased application of LDCT screening, the proportion of veterans identified with early stage lung cancer may rise. The Providence VAMC in Rhode Island reported its results from instituting LDCT screening.¹² Prior to screening, 28% of patients diagnosed with lung cancer had a stage I tumor. Following the introduction of LDCT screening, 49% diagnosed by LDCT screening had a stage I tumor. Nearly a third of their patients diagnosed with lung cancer through LDCT screening had squamous cell tumor histology. Thus, we can anticipate an increasing number of veterans with early stage lung cancer who would benefit from timely diagnosis.

The JLMMVH is a referral center for the entire state of Arkansas. Quite a few of its referred patients come from a long distance, which may require overnight housing and other related travel expenses. Apart from any potential outcome benefit, the efficiencies of the system described herein include the minimization of extra trips, an inconvenience and cost to both patient and JLMMVH.

Although the primary task of the clinic is diagnosis, we also seek to facilitate timely treatment. Our lack of an on-site PET scanner and radiation therapy, resources present on-site at the Dayton VAMC, contribute to longer therapy wait times. The shortest mean wait time at JLMMVH is for chemotherapy alone (34.7 days), in part because the JLMMVH oncologists, performing initial consultations 2 to 3 times weekly in the Diagnostic Clinic, are more readily available than are our thoracic surgeons or radiation therapists. Yet overall, JLMMVH patients often face delay from the time of lung cancer diagnosis to initiation of treatment.

The Connecticut Veterans Affairs Healthcare System has published the results of changes in lung cancer management associated with a nurse navigator system.10 Prior to creating the position of cancer care coordinator, filled by an advanced practice RNs, the mean time from clinical suspicion of lung cancer to treatment was 117 days. After 4 years of such care navigation, this waiting time had decreased to 52.4 days. Associated with this dramatic improvement in overall waiting time were decreases in the turnaround time required for performance of CT and PET scans. With respect to this big picture view of lung cancer care, our Diagnostic Clinic serves as a model for the initial step of diagnosis. Coordination and streamlining of the various steps from diagnosis to definitive therapy shall require a more system-wide effort involving all the key players in cancer care.

Conclusion

We have developed a care pathway based in a dedicated diagnostic clinic and have been able to document the shortest interval from abnormality to diagnosis of lung cancer reported in the literature to date. Efficient functioning of this clinic is dependent upon the close cooperation between a full-time RN clinic manager and an interventional pulmonologist experienced in lung cancer management and able to interpret cytologic samples at the time of biopsy. Shortening the delay between diagnosis and definitive therapy remains a challenge and may benefit from the oncology nurse navigator model previously described within the VA system. ¹⁰

Lung cancer is the leading cause of cancer death in the US, with 154 050 deaths in 2018.¹ There have been many attempts to reduce mortality of the disease through early diagnosis with use of computed tomography (CT). The National Lung Cancer Screening trial showed that screening high-risk populations with low-dose CT (LDCT) can reduce mortality.² However, implementing LDCT screening in the clinical setting has proven challenging, as illustrated by the VA Lung Cancer Screening Demonstration Project (LCSDP).³ A lung cancer diagnosis typically comprises several steps that require different medical specialties; this can lead to delays. In the LCSDP, the mean time to diagnosis was 137 days.³ There are no federal standards for timeliness of lung cancer diagnosis.

The nonprofit RAND Corporation is the only American research organization that has published guidelines specifying acceptable intervals for the diagnosis and treatment of lung cancer. In Quality of Care for Oncologic Conditions and HIV, RAND Corporation researchers propose management quality indicators: lung cancer diagnosis within 2 months of an abnormal radiologic study and treatment within 6 weeks of diagnosis.⁴ The Swedish Lung Cancer Study⁵ and the Canadian Strategy for Cancer Control⁶ both recommended a standard of about 30 days—half the time recommended by the RAND Corporation.

Bukhari and colleagues at the Dayton US Department of Veterans Affairs (VA) Medical Center (VAMC) conducted a quality improvement study that examined lung cancer diagnosis and management.7 They found the time (SD) from abnormal chest imaging to diagnosis was 35.5 (31.6) days. Of those veterans who received a lung cancer diagnosis, 89.2% had the diagnosis made within the 60 days recommended by the RAND Corporation. Although these results surpass those of the LCSDP, they can be exceeded.

Beyond the potential emotional distress of awaiting the final diagnosis of a lung lesion, a delay in diagnosis and treatment may adversely affect outcomes. LDCT screening has been shown to reduce mortality, which implies a link between survival and time to intervention. There is no published evidence that time to diagnosis in advanced stage lung cancer affects outcome. The National Cancer Database (NCDB) contains informtion on about 70% of the cancers diagnosed each year in the US.8 An analysis of 4984 patients with stage IA squamous cell lung cancer undergoing lobectomy from NCDB showed that earlier surgery was associated with an absolute decrease in 5-year mortality of 5% to 8%. 9 Hence, at least in early-stage disease, reduced time from initial suspect imaging to definitive treatment may improve survival.

A system that coordinates the requisite diagnostic steps and avoids delays should provide a significant improvement in patient care. The results of such an approach that utilized nurse navigators has been previously published. 10 Here, we present the results of a dedicated VA referral clinic with priority access to pulmonary consultation and procedures in place that are designed to expedite the diagnosis of potential lung cancer.

Methods

The John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas institutional review board approved this study, which was performed in accordance with the Declaration of Helsinki. Requirement for informed consent was waived, and patient confidentiality was maintained throughout.

We have developed a plan of care specifically to facilitate diagnosis and treatment of the large number of veterans referred to the JLMMVH Diagnostic Clinic for abnormal results of chest imaging. The clinic has priority access to same-day imaging and subspecialty consultation services. In the clinic, medical students and residents perform evaluations and a registered nurse (RN) manager coordinates care.

A Diagnostic Clinic consult for abnormal thoracic imaging immediately triggers an e-consult to an interventional pulmonologist (Figure). The RN manager and pulmonologist perform a joint review of records/imaging prior to scheduling, and the pulmonologist triages the patient. Triage options include follow-up imaging, bronchoscopy with endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and CT-guided biopsy.

The RN manager then schedules a clinic visit that includes a medical evaluation by clinic staff and any indicated procedures on the same day. The interventional pulmonologist performs EBUS, EUS with the convex curvilinear bronchoscope, or both combined as indicated for diagnosis and staging. All procedures are performed in the JLMMVH bronchoscopy suite with standard conscious sedation using midazolam and fentanyl. Any other relevant procedures, such as pleural tap, also are performed at time of procedure. The pulmonologist and an attending pathologist interpret biopsies obtained in the bronchoscopy suite.

We performed a retrospective chart review of patients diagnosed with primary lung cancer through referral to the JLMMVH Diagnostic Clinic. The primary outcome was time from initial suspect chest imaging to cancer diagnosis. The study population consisted of patients referred for abnormal thoracic imaging between January 1, 2013 and December 31, 2016 and subsequently diagnosed with a primary lung cancer.

Subjects were excluded if (1) the patient was referred from outside our care network and a delay of > 10 days occurred between initial lesion imaging and referral; (2) the patient did not show up for appointments or chose to delay evaluation following referral; (3) biopsy demonstrated a nonlung primary cancer; and (4) serious intercurrent illness interrupted the diagnostic plan. In some cases, the radiologist or consulting pulmonologist had judged the lung lesion too small for immediate biopsy and recommended repeat imaging at a later date.

Patients were included in the study if the follow- up imaging led to a lung cancer diagnosis. However, because the interval between the initial imaging and the follow-up imaging in these patients did not represent a systems delay problem, the date of the scheduled follow-up abnormal imaging, which resulted in initiation of a potential cancer evaluation, served as the index suspect imaging date for this study.

Patient electronic medical records were reviewed and the following data were abstracted: date of the abnormal imaging that led to referral and time from abnormal chest X-ray to chest CT scan if applicable; date of referral and date of clinic visit; date of biopsy; date of lung cancer diagnosis; method of obtaining diagnostic specimen; lung cancer type and stage; type and date of treatment initiation or decision for supportive care only; and decision to seek further evaluation or care outside of our system.

All patients diagnosed with lung cancer during the study period were reviewed for inclusion, hence no required sample-size estimate was calculated. All outcomes were assessed as calendar days. The primary outcome was the time from the index suspect chest imaging study to the date of diagnosis of lung cancer. Prior to the initiation of our study, we chose this more stringent 30-day recommendation of the Canadian6 and Swedish5 studies as the comparator for our primary outcome, although data with respect to the 60-day Rand Corporation guidelines also are reported.⁴

Statistical Methods

The mean time to lung cancer diagnosis in our cohort was compared with this 30-day standard using a 2-sided Mann–Whitney U test. Normality of data distribution was determined using the Kolmogorov–Smirnov test. For statistical significance testing a P value of .05 was used. Statistical calculations were performed using R statistical software version 3.2.4. Secondary outcomes consisted of time from diagnosis to treatment; proportion of subjects diagnosed within 60 days; time from initial clinic visit to biopsy; and time from biopsy to diagnosis.

Results

Overall, 222 patients were diagnosed with a malignant lung lesion, of which 63 were excluded from analysis: 22 cancelled or did not appear for appointments, declined further evaluation, or completed evaluation outside of our network; 13 had the diagnosis made prior to Diagnostic Clinic visit; 13 proved to have a nonlung primary tumor presenting in the lung or mediastinal nodes; 12 were delayed > 10 days in referral from an outside network; and 3 had an intervening serious acute medical problem forcing delay in the diagnostic process.

Of the 159 included subjects, 154 (96.9%) were male, and the mean (SD) age was 67.6 (8.1) years. For 76 subjects, the abnormal chest X-ray and subsequent chest CT scan were performed the same day or the lung lesion had initially been noted on a CT scan. For 54 subjects, there was a delay of ≥ 1 week in obtaining a chest CT scan. The mean (SD) time from placement of the Diagnostic Clinic consultation by the primary care provider (PCP) or other provider and the initial Diagnostic Clinic visit was 6.3 (4.4) days. The mean (SD) time from suspect imaging to diagnosis (primary outcome) was 22.6(16.6) days.

The distribution of this outcome was nonnormal (Kolmogorov-Smirnov test P < .01). When compared with the standard of 30 days, the primary outcome of 22.6 days was significantly shorter (2-sided Mann–Whitney U test P < .01). Three-quarters (76.1%) of subjects were diagnosed within 30 days and 95.0% of subjects were diagnosed within 60 days of the initial imaging. For the 8 subjects diagnosed after 60 days, contributing factors included PCP delay in Diagnostic Clinic consultation, initial negative biopsy, delay in performance of chest CT scan prior to consultation, and outsourcing of positron emission tomography (PET) scans.

Overall, 57 (35.8%) of the subjects underwent biopsy on the day of their Diagnostic Clinic visit: 14 underwent CT-guided biopsy and 43 underwent EBUS/EUS. Within 2 days of the initial visit 106 subjects (66.7%) had undergone biopsy. The mean (SD) time from initial Diagnostic Clinic visit to biopsy was 6.3 (9.5) days. The mean (SD) interval was 1.8 (3.0) days for EBUS/ EUS and 11.3 (11.7) days for CT-guided biopsy. The mean (SD) interval from biopsy to diagnosis was 3.2 (6.2) days with 64 cases (40.3%) diagnosed the day of biopsy.

Excluding subjects whose treatment was delayed by patient choice or intercurrent illness, and those who left the VA system to seek treatment elsewhere (n = 21), 24 opted for palliative care, 5 died before treatment could be initiated, and 109 underwent treatment for their tumors (Table). The mean times (SD) from diagnosis to treatment were: chemotherapy alone 34.7 (25.3) days; chemoradiation 37.0 (22.8) days; surgery 44.3 (24.4) days; radiation therapy alone 47.9 (26.0) days. With respect to the RAND Corporation recommended diagnosis to treatment time, 60.9% of chemotherapy alone, 61.5% of chemoradiation, 66.7% of surgery, and 45.0% of radiation therapy alone treatments were initiated within the 6-week window.

Discussion

This retrospective case study demonstrates the effectiveness of a dedicated diagnostic clinic with priority EBUS/EUS access in diagnosing lung cancer within the VA system. Although there is no universally accepted quality standard for comparison, the RAND Corporation recommendation of 60 days from abnormal imaging to diagnosis and the Dayton VAMC published mean of 35.5 days are guideposts; however, the results from the Dayton VAMC may have been affected negatively by some subjects undergoing serial imaging for asymptomatic nodules. We chose a more stringent standard of 30 days as recommended by Swedish and Canadian task forces.

When diagnosing lung cancer, the overriding purpose of the Diagnostic Clinic is to minimize system delays. The method is to have as simple a task as possible for the PCP or other provider who identifies a lung nodule or mass and submits a single consultation request to the Diagnostic Clinic. Once this consultation is placed, the clinic RN manager oversees all further steps required for diagnosis and referral for treatment. The key factor in achieving a mean diagnosis time of 22.6 days is the cooperation between the RN manager and the interventional pulmonologist. When a consultation is received, the RN manager and pulmonologist review the data together and schedule the initial clinic visit; the goal is same-day biopsy, which is achieved in more than one-third of cases. Not all patients with a chest image suspected for lung cancer had it ordered by their PCP. For this reason, a Diagnostic Clinic consultation is available to all health care providers in our system. Many patients reach the clinic after the discovery of a suspect chest X-ray during an emergency department visit, a regularly scheduled subspecialty appointment, or during a preoperative evaluation.

The mean time from initial visit to biopsy was 1.8 days for EBUS/EUS compared with an interval of 11.3 days for CT-guided biopsy. This difference reflects the pulmonologist’s involvement in initial scheduling of Diagnostic Clinic patients. The ability of the pulmonologist to provide an accurate assessment of sample adequacy and a preliminary diagnosis at bedside, with concurrent confirmation by a staff pathologist, permitted the Diagnostic Clinic to inform 40.3% of patients of the finding of malignancy on the day of biopsy. A published comparison of the onsite review of biopsy material showed our pulmonologist and staff pathologists to be equally accurate in their interpretations.¹¹

Sources of Delays

While this study documents the shortest intervals from suspect imaging to diagnosis reported to date, it also identifies sources of system delay in diagnosing lung cancer that JLMMVH could further optimize. The first is the time from initial abnormal chest X-ray imaging to performance of the chest CT scan. On occasion, the index lung lesion is identified unexpectedly on an outpatient or emergency department chest CT scan. With greater use of LDCT lung cancer screening, the initial detection of suspect lesions by CT scanning will increase in the future. However, the PCP most often investigates a patient complaint with a standard chest X-ray that reveals a suspect nodule or mass. When ordered by the PCP as an outpatient test, scheduling of the follow-up chest CT scan is not given priority. More than a third of subjects experienced a delay ≥ 1 week in obtaining a chest CT scan ordered by the PCP; for 29 subjects the delay was ≥ 3weeks. At JLMMVH, the Diagnostic Clinic is given priority in scheduling CT scans. Hence, for suspect lung lesions, the chest CT scan, if not already obtained, is generally performed on the morning of the clinic visit. Educating the PCP to refer the patient immediately to the Diagnostic Clinic rather than waiting to obtain an outpatient chest CT scan may remove this source of unnecessary delay.

Scheduling a CT-guided fine needle aspiration of a lung lesion is another source of system delay. When the chest CT scan is available at the time of the Diagnostic Clinic referral, the clinic visit is scheduled for the earliest day a required CT-guided biopsy can be performed. However, the mean time of 11.3 days from initial Diagnostic Clinic visit to CT-guided biopsy is indicative of the backlog faced by the interventional radiologists.

Although infrequent, PET scans that are required before biopsy can lead to substantial delays. PET scans are performed at our university affiliate, and the joint VA-university lung tumor board sometimes generates requests for such scans prior to tissue diagnosis, yet another source of delay.

The time from referral receipt to the Diagnostic Clinic visit averaged 6.3 days. This delay usually was determined by the availability of the CT-guided biopsy or the dedicated interventional pulmonologist. Although other interventional pulmonologists at JLMMVH may perform the requisite diagnostic procedures, they are not always available for immediate review of imaging studies of referred patients nor can their schedules flexibly accommodate the number of patients seen in our clinic for evaluation.

Lung Cancer Diagnosis

Prompt diagnosis in the setting of a worrisome chest X-ray may help decrease patient anxiety, but does the clinic improve lung cancer treatment outcomes? Such improvement has been demonstrated only in stage IA squamous cell lung cancer.⁹ Of our study population, 37.7% had squamous cell carcinoma, and 85.5% had non-small cell lung cancer. Of those with non-small cell lung cancer, 28.9% had a clinical stage I tumor. Stage I squamous cell carcinoma, the type of tumor most likely to benefit from early diagnosis and treatment, was diagnosed in 11.3% of patients. With the increased application of LDCT screening, the proportion of veterans identified with early stage lung cancer may rise. The Providence VAMC in Rhode Island reported its results from instituting LDCT screening.¹² Prior to screening, 28% of patients diagnosed with lung cancer had a stage I tumor. Following the introduction of LDCT screening, 49% diagnosed by LDCT screening had a stage I tumor. Nearly a third of their patients diagnosed with lung cancer through LDCT screening had squamous cell tumor histology. Thus, we can anticipate an increasing number of veterans with early stage lung cancer who would benefit from timely diagnosis.

The JLMMVH is a referral center for the entire state of Arkansas. Quite a few of its referred patients come from a long distance, which may require overnight housing and other related travel expenses. Apart from any potential outcome benefit, the efficiencies of the system described herein include the minimization of extra trips, an inconvenience and cost to both patient and JLMMVH.

Although the primary task of the clinic is diagnosis, we also seek to facilitate timely treatment. Our lack of an on-site PET scanner and radiation therapy, resources present on-site at the Dayton VAMC, contribute to longer therapy wait times. The shortest mean wait time at JLMMVH is for chemotherapy alone (34.7 days), in part because the JLMMVH oncologists, performing initial consultations 2 to 3 times weekly in the Diagnostic Clinic, are more readily available than are our thoracic surgeons or radiation therapists. Yet overall, JLMMVH patients often face delay from the time of lung cancer diagnosis to initiation of treatment.

The Connecticut Veterans Affairs Healthcare System has published the results of changes in lung cancer management associated with a nurse navigator system.10 Prior to creating the position of cancer care coordinator, filled by an advanced practice RNs, the mean time from clinical suspicion of lung cancer to treatment was 117 days. After 4 years of such care navigation, this waiting time had decreased to 52.4 days. Associated with this dramatic improvement in overall waiting time were decreases in the turnaround time required for performance of CT and PET scans. With respect to this big picture view of lung cancer care, our Diagnostic Clinic serves as a model for the initial step of diagnosis. Coordination and streamlining of the various steps from diagnosis to definitive therapy shall require a more system-wide effort involving all the key players in cancer care.

Conclusion

We have developed a care pathway based in a dedicated diagnostic clinic and have been able to document the shortest interval from abnormality to diagnosis of lung cancer reported in the literature to date. Efficient functioning of this clinic is dependent upon the close cooperation between a full-time RN clinic manager and an interventional pulmonologist experienced in lung cancer management and able to interpret cytologic samples at the time of biopsy. Shortening the delay between diagnosis and definitive therapy remains a challenge and may benefit from the oncology nurse navigator model previously described within the VA system. ¹⁰

Lung cancer is the leading cause of cancer death in the US, with 154 050 deaths in 2018.¹ There have been many attempts to reduce mortality of the disease through early diagnosis with use of computed tomography (CT). The National Lung Cancer Screening trial showed that screening high-risk populations with low-dose CT (LDCT) can reduce mortality.² However, implementing LDCT screening in the clinical setting has proven challenging, as illustrated by the VA Lung Cancer Screening Demonstration Project (LCSDP).³ A lung cancer diagnosis typically comprises several steps that require different medical specialties; this can lead to delays. In the LCSDP, the mean time to diagnosis was 137 days.³ There are no federal standards for timeliness of lung cancer diagnosis.

The nonprofit RAND Corporation is the only American research organization that has published guidelines specifying acceptable intervals for the diagnosis and treatment of lung cancer. In Quality of Care for Oncologic Conditions and HIV, RAND Corporation researchers propose management quality indicators: lung cancer diagnosis within 2 months of an abnormal radiologic study and treatment within 6 weeks of diagnosis.⁴ The Swedish Lung Cancer Study⁵ and the Canadian Strategy for Cancer Control⁶ both recommended a standard of about 30 days—half the time recommended by the RAND Corporation.

Bukhari and colleagues at the Dayton US Department of Veterans Affairs (VA) Medical Center (VAMC) conducted a quality improvement study that examined lung cancer diagnosis and management.7 They found the time (SD) from abnormal chest imaging to diagnosis was 35.5 (31.6) days. Of those veterans who received a lung cancer diagnosis, 89.2% had the diagnosis made within the 60 days recommended by the RAND Corporation. Although these results surpass those of the LCSDP, they can be exceeded.

Beyond the potential emotional distress of awaiting the final diagnosis of a lung lesion, a delay in diagnosis and treatment may adversely affect outcomes. LDCT screening has been shown to reduce mortality, which implies a link between survival and time to intervention. There is no published evidence that time to diagnosis in advanced stage lung cancer affects outcome. The National Cancer Database (NCDB) contains informtion on about 70% of the cancers diagnosed each year in the US.8 An analysis of 4984 patients with stage IA squamous cell lung cancer undergoing lobectomy from NCDB showed that earlier surgery was associated with an absolute decrease in 5-year mortality of 5% to 8%. 9 Hence, at least in early-stage disease, reduced time from initial suspect imaging to definitive treatment may improve survival.

A system that coordinates the requisite diagnostic steps and avoids delays should provide a significant improvement in patient care. The results of such an approach that utilized nurse navigators has been previously published. 10 Here, we present the results of a dedicated VA referral clinic with priority access to pulmonary consultation and procedures in place that are designed to expedite the diagnosis of potential lung cancer.

Methods

The John L. McClellan Memorial Veterans Hospital (JLMMVH) in Little Rock, Arkansas institutional review board approved this study, which was performed in accordance with the Declaration of Helsinki. Requirement for informed consent was waived, and patient confidentiality was maintained throughout.

We have developed a plan of care specifically to facilitate diagnosis and treatment of the large number of veterans referred to the JLMMVH Diagnostic Clinic for abnormal results of chest imaging. The clinic has priority access to same-day imaging and subspecialty consultation services. In the clinic, medical students and residents perform evaluations and a registered nurse (RN) manager coordinates care.

A Diagnostic Clinic consult for abnormal thoracic imaging immediately triggers an e-consult to an interventional pulmonologist (Figure). The RN manager and pulmonologist perform a joint review of records/imaging prior to scheduling, and the pulmonologist triages the patient. Triage options include follow-up imaging, bronchoscopy with endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), and CT-guided biopsy.

The RN manager then schedules a clinic visit that includes a medical evaluation by clinic staff and any indicated procedures on the same day. The interventional pulmonologist performs EBUS, EUS with the convex curvilinear bronchoscope, or both combined as indicated for diagnosis and staging. All procedures are performed in the JLMMVH bronchoscopy suite with standard conscious sedation using midazolam and fentanyl. Any other relevant procedures, such as pleural tap, also are performed at time of procedure. The pulmonologist and an attending pathologist interpret biopsies obtained in the bronchoscopy suite.

We performed a retrospective chart review of patients diagnosed with primary lung cancer through referral to the JLMMVH Diagnostic Clinic. The primary outcome was time from initial suspect chest imaging to cancer diagnosis. The study population consisted of patients referred for abnormal thoracic imaging between January 1, 2013 and December 31, 2016 and subsequently diagnosed with a primary lung cancer.

Subjects were excluded if (1) the patient was referred from outside our care network and a delay of > 10 days occurred between initial lesion imaging and referral; (2) the patient did not show up for appointments or chose to delay evaluation following referral; (3) biopsy demonstrated a nonlung primary cancer; and (4) serious intercurrent illness interrupted the diagnostic plan. In some cases, the radiologist or consulting pulmonologist had judged the lung lesion too small for immediate biopsy and recommended repeat imaging at a later date.

Patients were included in the study if the follow- up imaging led to a lung cancer diagnosis. However, because the interval between the initial imaging and the follow-up imaging in these patients did not represent a systems delay problem, the date of the scheduled follow-up abnormal imaging, which resulted in initiation of a potential cancer evaluation, served as the index suspect imaging date for this study.

Patient electronic medical records were reviewed and the following data were abstracted: date of the abnormal imaging that led to referral and time from abnormal chest X-ray to chest CT scan if applicable; date of referral and date of clinic visit; date of biopsy; date of lung cancer diagnosis; method of obtaining diagnostic specimen; lung cancer type and stage; type and date of treatment initiation or decision for supportive care only; and decision to seek further evaluation or care outside of our system.

All patients diagnosed with lung cancer during the study period were reviewed for inclusion, hence no required sample-size estimate was calculated. All outcomes were assessed as calendar days. The primary outcome was the time from the index suspect chest imaging study to the date of diagnosis of lung cancer. Prior to the initiation of our study, we chose this more stringent 30-day recommendation of the Canadian6 and Swedish5 studies as the comparator for our primary outcome, although data with respect to the 60-day Rand Corporation guidelines also are reported.⁴

Statistical Methods

The mean time to lung cancer diagnosis in our cohort was compared with this 30-day standard using a 2-sided Mann–Whitney U test. Normality of data distribution was determined using the Kolmogorov–Smirnov test. For statistical significance testing a P value of .05 was used. Statistical calculations were performed using R statistical software version 3.2.4. Secondary outcomes consisted of time from diagnosis to treatment; proportion of subjects diagnosed within 60 days; time from initial clinic visit to biopsy; and time from biopsy to diagnosis.

Results

Overall, 222 patients were diagnosed with a malignant lung lesion, of which 63 were excluded from analysis: 22 cancelled or did not appear for appointments, declined further evaluation, or completed evaluation outside of our network; 13 had the diagnosis made prior to Diagnostic Clinic visit; 13 proved to have a nonlung primary tumor presenting in the lung or mediastinal nodes; 12 were delayed > 10 days in referral from an outside network; and 3 had an intervening serious acute medical problem forcing delay in the diagnostic process.

Of the 159 included subjects, 154 (96.9%) were male, and the mean (SD) age was 67.6 (8.1) years. For 76 subjects, the abnormal chest X-ray and subsequent chest CT scan were performed the same day or the lung lesion had initially been noted on a CT scan. For 54 subjects, there was a delay of ≥ 1 week in obtaining a chest CT scan. The mean (SD) time from placement of the Diagnostic Clinic consultation by the primary care provider (PCP) or other provider and the initial Diagnostic Clinic visit was 6.3 (4.4) days. The mean (SD) time from suspect imaging to diagnosis (primary outcome) was 22.6(16.6) days.

The distribution of this outcome was nonnormal (Kolmogorov-Smirnov test P < .01). When compared with the standard of 30 days, the primary outcome of 22.6 days was significantly shorter (2-sided Mann–Whitney U test P < .01). Three-quarters (76.1%) of subjects were diagnosed within 30 days and 95.0% of subjects were diagnosed within 60 days of the initial imaging. For the 8 subjects diagnosed after 60 days, contributing factors included PCP delay in Diagnostic Clinic consultation, initial negative biopsy, delay in performance of chest CT scan prior to consultation, and outsourcing of positron emission tomography (PET) scans.

Overall, 57 (35.8%) of the subjects underwent biopsy on the day of their Diagnostic Clinic visit: 14 underwent CT-guided biopsy and 43 underwent EBUS/EUS. Within 2 days of the initial visit 106 subjects (66.7%) had undergone biopsy. The mean (SD) time from initial Diagnostic Clinic visit to biopsy was 6.3 (9.5) days. The mean (SD) interval was 1.8 (3.0) days for EBUS/ EUS and 11.3 (11.7) days for CT-guided biopsy. The mean (SD) interval from biopsy to diagnosis was 3.2 (6.2) days with 64 cases (40.3%) diagnosed the day of biopsy.

Excluding subjects whose treatment was delayed by patient choice or intercurrent illness, and those who left the VA system to seek treatment elsewhere (n = 21), 24 opted for palliative care, 5 died before treatment could be initiated, and 109 underwent treatment for their tumors (Table). The mean times (SD) from diagnosis to treatment were: chemotherapy alone 34.7 (25.3) days; chemoradiation 37.0 (22.8) days; surgery 44.3 (24.4) days; radiation therapy alone 47.9 (26.0) days. With respect to the RAND Corporation recommended diagnosis to treatment time, 60.9% of chemotherapy alone, 61.5% of chemoradiation, 66.7% of surgery, and 45.0% of radiation therapy alone treatments were initiated within the 6-week window.

Discussion

This retrospective case study demonstrates the effectiveness of a dedicated diagnostic clinic with priority EBUS/EUS access in diagnosing lung cancer within the VA system. Although there is no universally accepted quality standard for comparison, the RAND Corporation recommendation of 60 days from abnormal imaging to diagnosis and the Dayton VAMC published mean of 35.5 days are guideposts; however, the results from the Dayton VAMC may have been affected negatively by some subjects undergoing serial imaging for asymptomatic nodules. We chose a more stringent standard of 30 days as recommended by Swedish and Canadian task forces.

When diagnosing lung cancer, the overriding purpose of the Diagnostic Clinic is to minimize system delays. The method is to have as simple a task as possible for the PCP or other provider who identifies a lung nodule or mass and submits a single consultation request to the Diagnostic Clinic. Once this consultation is placed, the clinic RN manager oversees all further steps required for diagnosis and referral for treatment. The key factor in achieving a mean diagnosis time of 22.6 days is the cooperation between the RN manager and the interventional pulmonologist. When a consultation is received, the RN manager and pulmonologist review the data together and schedule the initial clinic visit; the goal is same-day biopsy, which is achieved in more than one-third of cases. Not all patients with a chest image suspected for lung cancer had it ordered by their PCP. For this reason, a Diagnostic Clinic consultation is available to all health care providers in our system. Many patients reach the clinic after the discovery of a suspect chest X-ray during an emergency department visit, a regularly scheduled subspecialty appointment, or during a preoperative evaluation.

The mean time from initial visit to biopsy was 1.8 days for EBUS/EUS compared with an interval of 11.3 days for CT-guided biopsy. This difference reflects the pulmonologist’s involvement in initial scheduling of Diagnostic Clinic patients. The ability of the pulmonologist to provide an accurate assessment of sample adequacy and a preliminary diagnosis at bedside, with concurrent confirmation by a staff pathologist, permitted the Diagnostic Clinic to inform 40.3% of patients of the finding of malignancy on the day of biopsy. A published comparison of the onsite review of biopsy material showed our pulmonologist and staff pathologists to be equally accurate in their interpretations.¹¹

Sources of Delays

While this study documents the shortest intervals from suspect imaging to diagnosis reported to date, it also identifies sources of system delay in diagnosing lung cancer that JLMMVH could further optimize. The first is the time from initial abnormal chest X-ray imaging to performance of the chest CT scan. On occasion, the index lung lesion is identified unexpectedly on an outpatient or emergency department chest CT scan. With greater use of LDCT lung cancer screening, the initial detection of suspect lesions by CT scanning will increase in the future. However, the PCP most often investigates a patient complaint with a standard chest X-ray that reveals a suspect nodule or mass. When ordered by the PCP as an outpatient test, scheduling of the follow-up chest CT scan is not given priority. More than a third of subjects experienced a delay ≥ 1 week in obtaining a chest CT scan ordered by the PCP; for 29 subjects the delay was ≥ 3weeks. At JLMMVH, the Diagnostic Clinic is given priority in scheduling CT scans. Hence, for suspect lung lesions, the chest CT scan, if not already obtained, is generally performed on the morning of the clinic visit. Educating the PCP to refer the patient immediately to the Diagnostic Clinic rather than waiting to obtain an outpatient chest CT scan may remove this source of unnecessary delay.

Scheduling a CT-guided fine needle aspiration of a lung lesion is another source of system delay. When the chest CT scan is available at the time of the Diagnostic Clinic referral, the clinic visit is scheduled for the earliest day a required CT-guided biopsy can be performed. However, the mean time of 11.3 days from initial Diagnostic Clinic visit to CT-guided biopsy is indicative of the backlog faced by the interventional radiologists.

Although infrequent, PET scans that are required before biopsy can lead to substantial delays. PET scans are performed at our university affiliate, and the joint VA-university lung tumor board sometimes generates requests for such scans prior to tissue diagnosis, yet another source of delay.

The time from referral receipt to the Diagnostic Clinic visit averaged 6.3 days. This delay usually was determined by the availability of the CT-guided biopsy or the dedicated interventional pulmonologist. Although other interventional pulmonologists at JLMMVH may perform the requisite diagnostic procedures, they are not always available for immediate review of imaging studies of referred patients nor can their schedules flexibly accommodate the number of patients seen in our clinic for evaluation.

Lung Cancer Diagnosis

Prompt diagnosis in the setting of a worrisome chest X-ray may help decrease patient anxiety, but does the clinic improve lung cancer treatment outcomes? Such improvement has been demonstrated only in stage IA squamous cell lung cancer.⁹ Of our study population, 37.7% had squamous cell carcinoma, and 85.5% had non-small cell lung cancer. Of those with non-small cell lung cancer, 28.9% had a clinical stage I tumor. Stage I squamous cell carcinoma, the type of tumor most likely to benefit from early diagnosis and treatment, was diagnosed in 11.3% of patients. With the increased application of LDCT screening, the proportion of veterans identified with early stage lung cancer may rise. The Providence VAMC in Rhode Island reported its results from instituting LDCT screening.¹² Prior to screening, 28% of patients diagnosed with lung cancer had a stage I tumor. Following the introduction of LDCT screening, 49% diagnosed by LDCT screening had a stage I tumor. Nearly a third of their patients diagnosed with lung cancer through LDCT screening had squamous cell tumor histology. Thus, we can anticipate an increasing number of veterans with early stage lung cancer who would benefit from timely diagnosis.

The JLMMVH is a referral center for the entire state of Arkansas. Quite a few of its referred patients come from a long distance, which may require overnight housing and other related travel expenses. Apart from any potential outcome benefit, the efficiencies of the system described herein include the minimization of extra trips, an inconvenience and cost to both patient and JLMMVH.

Although the primary task of the clinic is diagnosis, we also seek to facilitate timely treatment. Our lack of an on-site PET scanner and radiation therapy, resources present on-site at the Dayton VAMC, contribute to longer therapy wait times. The shortest mean wait time at JLMMVH is for chemotherapy alone (34.7 days), in part because the JLMMVH oncologists, performing initial consultations 2 to 3 times weekly in the Diagnostic Clinic, are more readily available than are our thoracic surgeons or radiation therapists. Yet overall, JLMMVH patients often face delay from the time of lung cancer diagnosis to initiation of treatment.

The Connecticut Veterans Affairs Healthcare System has published the results of changes in lung cancer management associated with a nurse navigator system.10 Prior to creating the position of cancer care coordinator, filled by an advanced practice RNs, the mean time from clinical suspicion of lung cancer to treatment was 117 days. After 4 years of such care navigation, this waiting time had decreased to 52.4 days. Associated with this dramatic improvement in overall waiting time were decreases in the turnaround time required for performance of CT and PET scans. With respect to this big picture view of lung cancer care, our Diagnostic Clinic serves as a model for the initial step of diagnosis. Coordination and streamlining of the various steps from diagnosis to definitive therapy shall require a more system-wide effort involving all the key players in cancer care.

Conclusion

We have developed a care pathway based in a dedicated diagnostic clinic and have been able to document the shortest interval from abnormality to diagnosis of lung cancer reported in the literature to date. Efficient functioning of this clinic is dependent upon the close cooperation between a full-time RN clinic manager and an interventional pulmonologist experienced in lung cancer management and able to interpret cytologic samples at the time of biopsy. Shortening the delay between diagnosis and definitive therapy remains a challenge and may benefit from the oncology nurse navigator model previously described within the VA system. ¹⁰