With the number of aging Americans projected to grow dramatically in the next several years, the need for primary palliative care and advance care planning (ACP) is more important than ever. Patients and their families want and expect palliative care when needed, but initial conversations about ACP can be difficult for them. Appropriate timing in raising this subject and clear communication can give patients the opportunity, while they are still independent, to set their goals for medical care.

For the past several decades, political decisions and judicial cases have shaped palliative care as we know it today. And its shape is still evolving. In support of ACP, advocacy groups at a national level are developing models that practitioners can use to engage patients in setting goals. And Medicare is now reimbursing primary care providers for this work that they have been doing for years (although many still may not be billing for the service).

Finally, the busy primary care office may have its own set of challenges in addressing ACP. Our aim in this review is to identify the barriers we face and the solutions we can implement to make a difference in our patients’ end-of-life care planning.

LANDMARK EVENTS HAVE DEFINED ACP TODAY

In 1969, Luis Kutner, an Illinois attorney, proposed the idea of a “living will,” envisioned as a document specifying the types of treatment a person would be willing to receive were he or she unable at a later time to participate in making a decision.¹ In 1976, California became the first state to give living wills the power of the law through the Natural Death Act.²

Throughout the 1970s and ‘80s, several high-profile court cases brought this idea into the national spotlight. In 1975, the New Jersey Supreme Court granted the parents of 21-year-old Karen Ann Quinlan the right to discontinue the treatment sustaining her in a persistent vegetative state. Ms. Quinlan was removed from the ventilator and lived nine more months before dying in a nursing home.

In 1983, age 25, Nancy Cruzan was involved in a motor vehicle accident that left her in a persistent vegetative state. She remained so until 1988, when her parents asked that her feeding tube be removed. The hospital refused, indicating that it would lead to her death. The family sued, and the case eventually went to the US Supreme Court in 1989.

In a 5-to-4 decision, the Supreme Court ruled that a state was legally able to require “clear and convincing evidence” of a patient’s wish for removal of life-sustaining therapies. Cruzan’s family was able to provide such evidence, and her artificial nutrition was withheld. She died 12 days later.

The Cruzan case was instrumental in furthering ACP, leading to the passage of the Patient Self Determination Act by ­Congress in 1990. All federally funded health care facilities were now required to educate ­patients of their rights in determining their medical care and to ask about advance directives.³ The ACP movement gained ad­ditional momentum from the landmark SUPPORT study that documented short­comings in communication between phys­icians and patients/families about treat­ment preferences and end-of-life care in US hospitals.⁴

In the Terri Schiavo case, the patient’s husband disagreed with the life-sustaining decisions of his wife’s parents, given her persistent vegetative state and the fact that she had no chance of meaningful recovery. After a prolonged national debate, it was ultimately decided that the husband could elect to withhold artificial nutrition. (She died in 2005.) The Schiavo case, as well as the Institute of Medicine’s report on Dying in America, influenced Congress in 2016 to pass legislation funding ACP conversations.⁵

THE DEMONSTRATED BENEFITS OF ACP

When done comprehensively, ACP yields many benefits for patients and families and for the health care system. A systematic review demonstrated that, despite the few studies examining the economic cost of ACP, the process may lead to decreased health care costs in certain populations (nursing home residents, community-dwelling adults with dementia, and those living in high health care–spending regions) and at the very least does not increase health care costs.⁶ ACP has increased the number of do-not-resuscitate orders and has decreased hospitalizations, admissions to intensive care units, and rates of cardiopulmonary resuscitation, mechanical ventilation, and use of tube feeding.^6-8

More noteworthy than the decrease in resource utilization and potential cost savings is the impact that ACP can have on a patient’s quality of life. Patients who receive aggressive care at the end of life tend to experience decreased quality of life compared with those receiving hospice care.⁷ Quality-of-life scores for patients in hospice improved with the length of enrollment in that care.⁷ When ACP discussions have taken place, the care patients receive at the end of life tends to conform more closely to their wishes and to increase family satis­faction.^9-11

One reason that practitioners often give for not completing ACP is the fear of increasing patient or family anxiety or post-traumatic stress disorder (PTSD). However, studies have shown this concern to be unfounded.^7,12 While ACP studies have not shown a decrease in rates of anxiety or PTSD, no study has shown an increase in these psychologic morbidities.⁸

Caveats to keep in mind. Not all studies have shown unambiguous benefits related to ACP. Among the systematic reviews previously noted, there was significant variability in quality of data. Additionally, some experts argue that the traditional view of ACP (ie, completion of a single advance directive/living will) is outdated and should be replaced with a method that prepares patients and families to anticipate “in-the-moment decision making.”¹³ While we still believe that completion of an advance directive is useful, the experts’ point is well taken, especially since many patients change their preferences over time (and typically toward more aggressive care).^14,15 While the advance directive serves a role, it is more important to help patients recognize their goals and preferences and to facilitate ongoing discussions between the patient and his or her family/surrogate decision-maker and providers.

A SNAPSHOT OF PARTICIPATION IN ACP

Despite the ACP movement and the likely benefits associated with it, most individuals have not participated. Rates of completion do seem to be rising, but there is still room for improvement. Among all individuals older than 18, only 26.3% have an advance directive.¹⁶ In a cohort of older patients seen in an emergency department, only 40% had a living will, while nearly 54% had a designated health care power of attorney.¹⁷ Perhaps more alarming is the lack of ACP for those patients almost all providers would agree need it: the long-term care population. The National Center for Health Statistics has reported that only 28% of home health care patients, 65% of nursing home residents, and 88% of hospice patients have an advance directive on file.¹⁸

PROVIDER AND PATIENT BARRIERS TO ACP

If ACP can decrease resource utilization and improve caregiver compliance with a patient’s wishes for end of life, the obvious question is: Why isn’t it done more often? A longstanding barrier for providers has been that these types of discussions are time intensive and have not been billable. However, since January 1, 2016, we are now able to bill for these discussions. (More on this in a bit.) Providers do cite other barriers, though.

A recent systematic review showed that ACP is hindered by time constraints imposed by other clinical and administrative tasks that are heavily monitored.¹⁹ Barriers to engaging in ACP reported by patients include a reluctance to think about dying, a belief that family or providers will know what to do, difficulty understanding ACP forms, and the absence of a person who can serve as a surrogate decision-maker.^20,21

NATIONAL MODELS TO HELP WITH IMPLEMENTATION

The percentage of individuals with an advance directive in the US has not increased significantly over the past decade.²² The lack of traction in completion and use of advance directives has led several authors to question the utility of this older model of ACP.²² Several experts in the field believe that more robust, ongoing goals-of-care conversations between patients, families, and providers are equally, or even more, important than the completion of actual advance directive documents.^23,24

National models such as the POLST (Physician Orders for Life-Sustaining Treatment) paradigm have become popular in several states (www.polst.org). Intended for those with estimated life expectancy of less than one year, POLST is not an advance directive but a physician order for these seriously ill patients. Emergency medical service workers are legally able to follow a POLST document but not a living will or advance directive—a significant reason for those with end-stage illness to consider completing a POLST document with their health care provider. Programs such as “Respecting Choices” have incorporated POLST documentation as part of ongoing goals-of-care conversations between patients and health care providers (www.gundersenhealth.org/respecting-choices).

Many groups have developed products to encourage patients and their families to initiate conversations at home. An example is the Conversation Project, a free online resource available in multiple languages that can help break the ice for patients and get them talking about their wishes for end-of-life care (www.theconversationproject.org). It poses simple stimulating questions such as “What kind of role do you want to have in the decision-making process?” and “What are your concerns about treatment?”

HOW-TO TIPS FOR ACP IN OUTPATIENT SETTINGS

When approaching the topic of ACP with patients, it’s important to do so over time, starting as soon as possible with older patients and those with chronic illness that confers a high risk for significant morbidity or mortality. Assess each patient’s understanding of ACP and readiness to discuss the topic. Many patients think of ACP in the context of a document (eg, living will), so asking about the existence of a living will may help to start the conversation. Alternatively, consider inquiring about whether the patient has had experience with family or friends at the end of life or during a difficult medical situation, and whether the patient has thought about making personal plans for such a situation.²⁵

When a patient is ready to have this conversation, your goal should be three-fold:²⁶

1. Help the patient articulate personal values, goals, and preferences.
2. Ask the patient to formally assign health care power of attorney (POA) to a trusted individual or to name a surrogate decision-maker. Document this decision in the medical record.
3. Help the patient translate expressed values into specific medical care plans, if applicable.

Because ACP conversations are often time consuming, it’s a good idea to schedule separate appointments to focus on this alone. If, however, a patient is unable to return for a dedicated ACP visit, a first step that can be completed in a reasonably short period would be choosing a surrogate decision-maker.

Helping a patient articulate personal values may be eased by asking such questions as, “Have you ever thought about what kind of care you would want if the time came when you could not make your own decisions?” or “What worries you the most about possibly not being able to make your own decisions?”²⁷ If the patient is able to identify a surrogate decision-maker before the ACP appointment, ask that this person attend. A family member or close friend may remember instances in which the patient expressed health care preferences, and their presence can help to minimize gaps in communication.

Once the patient’s preferences are clear, document them in the medical record. Some preferences may be suitable for translation into POLST orders or an advance directive, but this is less important than the overall discussion. ACP should be an ongoing conversation, since a patient’s goals may change over time. And encourage the patient to share any desired change in plans with their surrogate decision-maker or update the POA document.

BE SURE TO BILL FOR ACP SERVICES

To encourage office-based providers to conduct ACP, the Centers for Medicare and Medicaid Services (CMS) implemented payment for CPT codes 99497 and 99498.

CPT code 99497 covers the first 30 minutes of face-to-face time with patients or their family members or medical decision-makers. This time can be used to discuss living wills or advance directives.

CPT code 99498 can be applied to each additional 30 minutes of ACP services. Typically, this billing code would be used as an add-on for a particular diagnosis, such as heart failure, chronic obstructive pulmonary disease, or pancreatic cancer.

CPT Code 99497 equates to 2.40 relative-value units (RVU) with an estimated payment of $85.99, while CPT code 99498 equates to 2.09 RVU with an estimated payment of $74.88.²⁸

According to CMS, there is no annual limit to the number of times the ACP codes can be billed for a particular patient. And there are no restrictions regarding location of service, meaning a provider could perform this in an outpatient setting, an inpatient setting, or a long-term care facility. All health care providers are allowed to bill with this code. Also worth noting: You don’t need to complete any particular documentation for a visit to be billed as an ACP service. CMS provides a helpful Q & A at www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/PhysicianFeeSched/Downloads/FAQ-Advance-Care-Planning.pdf.

With the number of aging Americans projected to grow dramatically in the next several years, the need for primary palliative care and advance care planning (ACP) is more important than ever. Patients and their families want and expect palliative care when needed, but initial conversations about ACP can be difficult for them. Appropriate timing in raising this subject and clear communication can give patients the opportunity, while they are still independent, to set their goals for medical care.

For the past several decades, political decisions and judicial cases have shaped palliative care as we know it today. And its shape is still evolving. In support of ACP, advocacy groups at a national level are developing models that practitioners can use to engage patients in setting goals. And Medicare is now reimbursing primary care providers for this work that they have been doing for years (although many still may not be billing for the service).

Finally, the busy primary care office may have its own set of challenges in addressing ACP. Our aim in this review is to identify the barriers we face and the solutions we can implement to make a difference in our patients’ end-of-life care planning.

LANDMARK EVENTS HAVE DEFINED ACP TODAY

In 1969, Luis Kutner, an Illinois attorney, proposed the idea of a “living will,” envisioned as a document specifying the types of treatment a person would be willing to receive were he or she unable at a later time to participate in making a decision.¹ In 1976, California became the first state to give living wills the power of the law through the Natural Death Act.²

Throughout the 1970s and ‘80s, several high-profile court cases brought this idea into the national spotlight. In 1975, the New Jersey Supreme Court granted the parents of 21-year-old Karen Ann Quinlan the right to discontinue the treatment sustaining her in a persistent vegetative state. Ms. Quinlan was removed from the ventilator and lived nine more months before dying in a nursing home.

In 1983, age 25, Nancy Cruzan was involved in a motor vehicle accident that left her in a persistent vegetative state. She remained so until 1988, when her parents asked that her feeding tube be removed. The hospital refused, indicating that it would lead to her death. The family sued, and the case eventually went to the US Supreme Court in 1989.

In a 5-to-4 decision, the Supreme Court ruled that a state was legally able to require “clear and convincing evidence” of a patient’s wish for removal of life-sustaining therapies. Cruzan’s family was able to provide such evidence, and her artificial nutrition was withheld. She died 12 days later.

The Cruzan case was instrumental in furthering ACP, leading to the passage of the Patient Self Determination Act by ­Congress in 1990. All federally funded health care facilities were now required to educate ­patients of their rights in determining their medical care and to ask about advance directives.³ The ACP movement gained ad­ditional momentum from the landmark SUPPORT study that documented short­comings in communication between phys­icians and patients/families about treat­ment preferences and end-of-life care in US hospitals.⁴

In the Terri Schiavo case, the patient’s husband disagreed with the life-sustaining decisions of his wife’s parents, given her persistent vegetative state and the fact that she had no chance of meaningful recovery. After a prolonged national debate, it was ultimately decided that the husband could elect to withhold artificial nutrition. (She died in 2005.) The Schiavo case, as well as the Institute of Medicine’s report on Dying in America, influenced Congress in 2016 to pass legislation funding ACP conversations.⁵

THE DEMONSTRATED BENEFITS OF ACP

When done comprehensively, ACP yields many benefits for patients and families and for the health care system. A systematic review demonstrated that, despite the few studies examining the economic cost of ACP, the process may lead to decreased health care costs in certain populations (nursing home residents, community-dwelling adults with dementia, and those living in high health care–spending regions) and at the very least does not increase health care costs.⁶ ACP has increased the number of do-not-resuscitate orders and has decreased hospitalizations, admissions to intensive care units, and rates of cardiopulmonary resuscitation, mechanical ventilation, and use of tube feeding.^6-8

More noteworthy than the decrease in resource utilization and potential cost savings is the impact that ACP can have on a patient’s quality of life. Patients who receive aggressive care at the end of life tend to experience decreased quality of life compared with those receiving hospice care.⁷ Quality-of-life scores for patients in hospice improved with the length of enrollment in that care.⁷ When ACP discussions have taken place, the care patients receive at the end of life tends to conform more closely to their wishes and to increase family satis­faction.^9-11

One reason that practitioners often give for not completing ACP is the fear of increasing patient or family anxiety or post-traumatic stress disorder (PTSD). However, studies have shown this concern to be unfounded.^7,12 While ACP studies have not shown a decrease in rates of anxiety or PTSD, no study has shown an increase in these psychologic morbidities.⁸

Caveats to keep in mind. Not all studies have shown unambiguous benefits related to ACP. Among the systematic reviews previously noted, there was significant variability in quality of data. Additionally, some experts argue that the traditional view of ACP (ie, completion of a single advance directive/living will) is outdated and should be replaced with a method that prepares patients and families to anticipate “in-the-moment decision making.”¹³ While we still believe that completion of an advance directive is useful, the experts’ point is well taken, especially since many patients change their preferences over time (and typically toward more aggressive care).^14,15 While the advance directive serves a role, it is more important to help patients recognize their goals and preferences and to facilitate ongoing discussions between the patient and his or her family/surrogate decision-maker and providers.

A SNAPSHOT OF PARTICIPATION IN ACP

Despite the ACP movement and the likely benefits associated with it, most individuals have not participated. Rates of completion do seem to be rising, but there is still room for improvement. Among all individuals older than 18, only 26.3% have an advance directive.¹⁶ In a cohort of older patients seen in an emergency department, only 40% had a living will, while nearly 54% had a designated health care power of attorney.¹⁷ Perhaps more alarming is the lack of ACP for those patients almost all providers would agree need it: the long-term care population. The National Center for Health Statistics has reported that only 28% of home health care patients, 65% of nursing home residents, and 88% of hospice patients have an advance directive on file.¹⁸

PROVIDER AND PATIENT BARRIERS TO ACP

If ACP can decrease resource utilization and improve caregiver compliance with a patient’s wishes for end of life, the obvious question is: Why isn’t it done more often? A longstanding barrier for providers has been that these types of discussions are time intensive and have not been billable. However, since January 1, 2016, we are now able to bill for these discussions. (More on this in a bit.) Providers do cite other barriers, though.

A recent systematic review showed that ACP is hindered by time constraints imposed by other clinical and administrative tasks that are heavily monitored.¹⁹ Barriers to engaging in ACP reported by patients include a reluctance to think about dying, a belief that family or providers will know what to do, difficulty understanding ACP forms, and the absence of a person who can serve as a surrogate decision-maker.^20,21

NATIONAL MODELS TO HELP WITH IMPLEMENTATION

The percentage of individuals with an advance directive in the US has not increased significantly over the past decade.²² The lack of traction in completion and use of advance directives has led several authors to question the utility of this older model of ACP.²² Several experts in the field believe that more robust, ongoing goals-of-care conversations between patients, families, and providers are equally, or even more, important than the completion of actual advance directive documents.^23,24

National models such as the POLST (Physician Orders for Life-Sustaining Treatment) paradigm have become popular in several states (www.polst.org). Intended for those with estimated life expectancy of less than one year, POLST is not an advance directive but a physician order for these seriously ill patients. Emergency medical service workers are legally able to follow a POLST document but not a living will or advance directive—a significant reason for those with end-stage illness to consider completing a POLST document with their health care provider. Programs such as “Respecting Choices” have incorporated POLST documentation as part of ongoing goals-of-care conversations between patients and health care providers (www.gundersenhealth.org/respecting-choices).

Many groups have developed products to encourage patients and their families to initiate conversations at home. An example is the Conversation Project, a free online resource available in multiple languages that can help break the ice for patients and get them talking about their wishes for end-of-life care (www.theconversationproject.org). It poses simple stimulating questions such as “What kind of role do you want to have in the decision-making process?” and “What are your concerns about treatment?”

HOW-TO TIPS FOR ACP IN OUTPATIENT SETTINGS

When approaching the topic of ACP with patients, it’s important to do so over time, starting as soon as possible with older patients and those with chronic illness that confers a high risk for significant morbidity or mortality. Assess each patient’s understanding of ACP and readiness to discuss the topic. Many patients think of ACP in the context of a document (eg, living will), so asking about the existence of a living will may help to start the conversation. Alternatively, consider inquiring about whether the patient has had experience with family or friends at the end of life or during a difficult medical situation, and whether the patient has thought about making personal plans for such a situation.²⁵

When a patient is ready to have this conversation, your goal should be three-fold:²⁶

1. Help the patient articulate personal values, goals, and preferences.
2. Ask the patient to formally assign health care power of attorney (POA) to a trusted individual or to name a surrogate decision-maker. Document this decision in the medical record.
3. Help the patient translate expressed values into specific medical care plans, if applicable.

Because ACP conversations are often time consuming, it’s a good idea to schedule separate appointments to focus on this alone. If, however, a patient is unable to return for a dedicated ACP visit, a first step that can be completed in a reasonably short period would be choosing a surrogate decision-maker.

Helping a patient articulate personal values may be eased by asking such questions as, “Have you ever thought about what kind of care you would want if the time came when you could not make your own decisions?” or “What worries you the most about possibly not being able to make your own decisions?”²⁷ If the patient is able to identify a surrogate decision-maker before the ACP appointment, ask that this person attend. A family member or close friend may remember instances in which the patient expressed health care preferences, and their presence can help to minimize gaps in communication.

Once the patient’s preferences are clear, document them in the medical record. Some preferences may be suitable for translation into POLST orders or an advance directive, but this is less important than the overall discussion. ACP should be an ongoing conversation, since a patient’s goals may change over time. And encourage the patient to share any desired change in plans with their surrogate decision-maker or update the POA document.

BE SURE TO BILL FOR ACP SERVICES

To encourage office-based providers to conduct ACP, the Centers for Medicare and Medicaid Services (CMS) implemented payment for CPT codes 99497 and 99498.

CPT code 99497 covers the first 30 minutes of face-to-face time with patients or their family members or medical decision-makers. This time can be used to discuss living wills or advance directives.

CPT code 99498 can be applied to each additional 30 minutes of ACP services. Typically, this billing code would be used as an add-on for a particular diagnosis, such as heart failure, chronic obstructive pulmonary disease, or pancreatic cancer.

CPT Code 99497 equates to 2.40 relative-value units (RVU) with an estimated payment of $85.99, while CPT code 99498 equates to 2.09 RVU with an estimated payment of $74.88.²⁸

According to CMS, there is no annual limit to the number of times the ACP codes can be billed for a particular patient. And there are no restrictions regarding location of service, meaning a provider could perform this in an outpatient setting, an inpatient setting, or a long-term care facility. All health care providers are allowed to bill with this code. Also worth noting: You don’t need to complete any particular documentation for a visit to be billed as an ACP service. CMS provides a helpful Q & A at www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/PhysicianFeeSched/Downloads/FAQ-Advance-Care-Planning.pdf.

With the number of aging Americans projected to grow dramatically in the next several years, the need for primary palliative care and advance care planning (ACP) is more important than ever. Patients and their families want and expect palliative care when needed, but initial conversations about ACP can be difficult for them. Appropriate timing in raising this subject and clear communication can give patients the opportunity, while they are still independent, to set their goals for medical care.

For the past several decades, political decisions and judicial cases have shaped palliative care as we know it today. And its shape is still evolving. In support of ACP, advocacy groups at a national level are developing models that practitioners can use to engage patients in setting goals. And Medicare is now reimbursing primary care providers for this work that they have been doing for years (although many still may not be billing for the service).

Finally, the busy primary care office may have its own set of challenges in addressing ACP. Our aim in this review is to identify the barriers we face and the solutions we can implement to make a difference in our patients’ end-of-life care planning.

LANDMARK EVENTS HAVE DEFINED ACP TODAY

In 1969, Luis Kutner, an Illinois attorney, proposed the idea of a “living will,” envisioned as a document specifying the types of treatment a person would be willing to receive were he or she unable at a later time to participate in making a decision.¹ In 1976, California became the first state to give living wills the power of the law through the Natural Death Act.²

Throughout the 1970s and ‘80s, several high-profile court cases brought this idea into the national spotlight. In 1975, the New Jersey Supreme Court granted the parents of 21-year-old Karen Ann Quinlan the right to discontinue the treatment sustaining her in a persistent vegetative state. Ms. Quinlan was removed from the ventilator and lived nine more months before dying in a nursing home.

In 1983, age 25, Nancy Cruzan was involved in a motor vehicle accident that left her in a persistent vegetative state. She remained so until 1988, when her parents asked that her feeding tube be removed. The hospital refused, indicating that it would lead to her death. The family sued, and the case eventually went to the US Supreme Court in 1989.

In a 5-to-4 decision, the Supreme Court ruled that a state was legally able to require “clear and convincing evidence” of a patient’s wish for removal of life-sustaining therapies. Cruzan’s family was able to provide such evidence, and her artificial nutrition was withheld. She died 12 days later.

The Cruzan case was instrumental in furthering ACP, leading to the passage of the Patient Self Determination Act by ­Congress in 1990. All federally funded health care facilities were now required to educate ­patients of their rights in determining their medical care and to ask about advance directives.³ The ACP movement gained ad­ditional momentum from the landmark SUPPORT study that documented short­comings in communication between phys­icians and patients/families about treat­ment preferences and end-of-life care in US hospitals.⁴

In the Terri Schiavo case, the patient’s husband disagreed with the life-sustaining decisions of his wife’s parents, given her persistent vegetative state and the fact that she had no chance of meaningful recovery. After a prolonged national debate, it was ultimately decided that the husband could elect to withhold artificial nutrition. (She died in 2005.) The Schiavo case, as well as the Institute of Medicine’s report on Dying in America, influenced Congress in 2016 to pass legislation funding ACP conversations.⁵

THE DEMONSTRATED BENEFITS OF ACP

When done comprehensively, ACP yields many benefits for patients and families and for the health care system. A systematic review demonstrated that, despite the few studies examining the economic cost of ACP, the process may lead to decreased health care costs in certain populations (nursing home residents, community-dwelling adults with dementia, and those living in high health care–spending regions) and at the very least does not increase health care costs.⁶ ACP has increased the number of do-not-resuscitate orders and has decreased hospitalizations, admissions to intensive care units, and rates of cardiopulmonary resuscitation, mechanical ventilation, and use of tube feeding.^6-8

More noteworthy than the decrease in resource utilization and potential cost savings is the impact that ACP can have on a patient’s quality of life. Patients who receive aggressive care at the end of life tend to experience decreased quality of life compared with those receiving hospice care.⁷ Quality-of-life scores for patients in hospice improved with the length of enrollment in that care.⁷ When ACP discussions have taken place, the care patients receive at the end of life tends to conform more closely to their wishes and to increase family satis­faction.^9-11

One reason that practitioners often give for not completing ACP is the fear of increasing patient or family anxiety or post-traumatic stress disorder (PTSD). However, studies have shown this concern to be unfounded.^7,12 While ACP studies have not shown a decrease in rates of anxiety or PTSD, no study has shown an increase in these psychologic morbidities.⁸

Caveats to keep in mind. Not all studies have shown unambiguous benefits related to ACP. Among the systematic reviews previously noted, there was significant variability in quality of data. Additionally, some experts argue that the traditional view of ACP (ie, completion of a single advance directive/living will) is outdated and should be replaced with a method that prepares patients and families to anticipate “in-the-moment decision making.”¹³ While we still believe that completion of an advance directive is useful, the experts’ point is well taken, especially since many patients change their preferences over time (and typically toward more aggressive care).^14,15 While the advance directive serves a role, it is more important to help patients recognize their goals and preferences and to facilitate ongoing discussions between the patient and his or her family/surrogate decision-maker and providers.

A SNAPSHOT OF PARTICIPATION IN ACP

Despite the ACP movement and the likely benefits associated with it, most individuals have not participated. Rates of completion do seem to be rising, but there is still room for improvement. Among all individuals older than 18, only 26.3% have an advance directive.¹⁶ In a cohort of older patients seen in an emergency department, only 40% had a living will, while nearly 54% had a designated health care power of attorney.¹⁷ Perhaps more alarming is the lack of ACP for those patients almost all providers would agree need it: the long-term care population. The National Center for Health Statistics has reported that only 28% of home health care patients, 65% of nursing home residents, and 88% of hospice patients have an advance directive on file.¹⁸

PROVIDER AND PATIENT BARRIERS TO ACP

If ACP can decrease resource utilization and improve caregiver compliance with a patient’s wishes for end of life, the obvious question is: Why isn’t it done more often? A longstanding barrier for providers has been that these types of discussions are time intensive and have not been billable. However, since January 1, 2016, we are now able to bill for these discussions. (More on this in a bit.) Providers do cite other barriers, though.

A recent systematic review showed that ACP is hindered by time constraints imposed by other clinical and administrative tasks that are heavily monitored.¹⁹ Barriers to engaging in ACP reported by patients include a reluctance to think about dying, a belief that family or providers will know what to do, difficulty understanding ACP forms, and the absence of a person who can serve as a surrogate decision-maker.^20,21

NATIONAL MODELS TO HELP WITH IMPLEMENTATION

The percentage of individuals with an advance directive in the US has not increased significantly over the past decade.²² The lack of traction in completion and use of advance directives has led several authors to question the utility of this older model of ACP.²² Several experts in the field believe that more robust, ongoing goals-of-care conversations between patients, families, and providers are equally, or even more, important than the completion of actual advance directive documents.^23,24

National models such as the POLST (Physician Orders for Life-Sustaining Treatment) paradigm have become popular in several states (www.polst.org). Intended for those with estimated life expectancy of less than one year, POLST is not an advance directive but a physician order for these seriously ill patients. Emergency medical service workers are legally able to follow a POLST document but not a living will or advance directive—a significant reason for those with end-stage illness to consider completing a POLST document with their health care provider. Programs such as “Respecting Choices” have incorporated POLST documentation as part of ongoing goals-of-care conversations between patients and health care providers (www.gundersenhealth.org/respecting-choices).

Many groups have developed products to encourage patients and their families to initiate conversations at home. An example is the Conversation Project, a free online resource available in multiple languages that can help break the ice for patients and get them talking about their wishes for end-of-life care (www.theconversationproject.org). It poses simple stimulating questions such as “What kind of role do you want to have in the decision-making process?” and “What are your concerns about treatment?”

HOW-TO TIPS FOR ACP IN OUTPATIENT SETTINGS

When approaching the topic of ACP with patients, it’s important to do so over time, starting as soon as possible with older patients and those with chronic illness that confers a high risk for significant morbidity or mortality. Assess each patient’s understanding of ACP and readiness to discuss the topic. Many patients think of ACP in the context of a document (eg, living will), so asking about the existence of a living will may help to start the conversation. Alternatively, consider inquiring about whether the patient has had experience with family or friends at the end of life or during a difficult medical situation, and whether the patient has thought about making personal plans for such a situation.²⁵

When a patient is ready to have this conversation, your goal should be three-fold:²⁶

1. Help the patient articulate personal values, goals, and preferences.
2. Ask the patient to formally assign health care power of attorney (POA) to a trusted individual or to name a surrogate decision-maker. Document this decision in the medical record.
3. Help the patient translate expressed values into specific medical care plans, if applicable.

Because ACP conversations are often time consuming, it’s a good idea to schedule separate appointments to focus on this alone. If, however, a patient is unable to return for a dedicated ACP visit, a first step that can be completed in a reasonably short period would be choosing a surrogate decision-maker.

Helping a patient articulate personal values may be eased by asking such questions as, “Have you ever thought about what kind of care you would want if the time came when you could not make your own decisions?” or “What worries you the most about possibly not being able to make your own decisions?”²⁷ If the patient is able to identify a surrogate decision-maker before the ACP appointment, ask that this person attend. A family member or close friend may remember instances in which the patient expressed health care preferences, and their presence can help to minimize gaps in communication.

Once the patient’s preferences are clear, document them in the medical record. Some preferences may be suitable for translation into POLST orders or an advance directive, but this is less important than the overall discussion. ACP should be an ongoing conversation, since a patient’s goals may change over time. And encourage the patient to share any desired change in plans with their surrogate decision-maker or update the POA document.

BE SURE TO BILL FOR ACP SERVICES

To encourage office-based providers to conduct ACP, the Centers for Medicare and Medicaid Services (CMS) implemented payment for CPT codes 99497 and 99498.

CPT code 99497 covers the first 30 minutes of face-to-face time with patients or their family members or medical decision-makers. This time can be used to discuss living wills or advance directives.

CPT code 99498 can be applied to each additional 30 minutes of ACP services. Typically, this billing code would be used as an add-on for a particular diagnosis, such as heart failure, chronic obstructive pulmonary disease, or pancreatic cancer.

CPT Code 99497 equates to 2.40 relative-value units (RVU) with an estimated payment of $85.99, while CPT code 99498 equates to 2.09 RVU with an estimated payment of $74.88.²⁸

According to CMS, there is no annual limit to the number of times the ACP codes can be billed for a particular patient. And there are no restrictions regarding location of service, meaning a provider could perform this in an outpatient setting, an inpatient setting, or a long-term care facility. All health care providers are allowed to bill with this code. Also worth noting: You don’t need to complete any particular documentation for a visit to be billed as an ACP service. CMS provides a helpful Q & A at www.cms.gov/Medicare/Medicare-Fee-for-Service-Payment/PhysicianFeeSched/Downloads/FAQ-Advance-Care-Planning.pdf.

This column picks up with a recent literature review suggesting potential benefits of topically applied or orally administered flavonoid polyphenolic substances. The discussion is based on at least one sample compound from each flavonoid category.

Flavonols: quercetin

Known to exert substantial antioxidant and anti-inflammatory activities, quercetin has been shown in various cellular and animal-based models to deliver photoprotection from UV and contribute to wound healing.¹ In a single center, single-blind trial with 30 healthy volunteers, a 1% topical quercetin cream was found to be effective in reducing erythema, itching, and wheal diameter in experimentally-induced skin stress.² Quercetin also has been reported to have the capacity to inhibit melanin production.³

Flavones: apigenin

rafaelaraujopa/Thinkstock

Flavanones: naringenin

The citrus flavanone naringenin shows promise as a preventive agent against cutaneous aging as well as carcinogenesis. In a 2008 study, naringenin exerted an anti-apoptotic effect in UVB-damaged cells, significantly extending long-term cellular survival, and facilitating the removal of cyclobutane pyrimidine dimers from the genome.⁷ More recently, topical naringenin has been shown in mice to mitigate the cutaneous inflammation and oxidative stress caused by UVB irradiation,⁸ and, present in Lippia graveolens, to protect against chronic UVB-induced damage including phototumorigenesis.⁹

Isoflavones: red clover, genistein, and daidzein

Red clover, the isoflavones of which have been demonstrated – in high dietary concentrations – to contribute to low incidence of osteoporosis and menopausal symptoms, was shown in a 2006 study to exert anti-aging effects in mice, indicating potential for alleviating the cutaneous aging brought on by declines in estrogen.¹⁰ In 2011, Lipovac et al. showed that oral supplementation with red clover extract improved scalp hair and skin status as well as libido, mood, sleep, and fatigue in a study with 109 postmenopausal women.¹¹

The topical application of the soy isoflavones genistein, daidzein, and glycitein has shown promise as a treatment for photoaging and photodamage.¹² Genistein has been noted for its antioxidant and antibrowning activity, and has exhibited anti-aging properties in mouse studies and photoprotective activity in humans.¹³ A 2015 study by Zhao et al. in cultured skin fibroblasts and nude mouse skin indicated that daidzein treatment appears to increase skin collagen production and suppress collagen degradation.¹⁴

Flavan-3-ols (catechins): epigallocatechin 3-gallate

Already considered a potent antioxidant, epigallocatechin 3-gallate (EGCG) continues to receive attention for conferring an expanding range of health benefits. This catechin, which is the most abundant and potent of such compounds in green tea, has exhibited the capacity to hinder UVB-induced collagen-degrading matrix metalloproteinases (MMPs).¹⁵ EGCG also has been proposed as a preventive and therapeutic agent for keloids, given findings indicating that it hampered the proliferation and migration of keloid fibroblasts in vitro, as well as in vivo by interrupting the signal transducer and activator of transcription 3 (STAT3) signaling pathway.¹⁶ Further, EGCG has been suggested as a potential therapeutic approach to atopic dermatitis (AD) given success against AD-like skin lesions in a murine model.¹⁷ An investigation of the anti-aging cutaneous effects of EGCG on d-galactose-induced aging in mice revealed that subcutaneously injected EGCG yielded overall improvement in the structure and function of the skin.¹⁸ EGCG also is known to yield improvements in skin condition by providing DNA protection, reactivating damaged cells, and increasing cellular energy production.³

Perhaps most importantly, formulations containing green tea extracts have been shown in a small study of 20 volunteers to exert protection against photoaging and photoimmunosuppression, with the extract hindering the expression of MMP-9 and MMP-2.¹⁹ Wrinkle reduction also was observed in another clinical study involving topical green tea.²⁰ The tea plant Camellia sinensis is one of the best sources of antioxidant catechins, particularly green tea (unfermented), but also white (unfermented), black (fermented), and oolong (semifermented) tea.²¹

Anthocyanins: cyanidin

A 2017 in vivo study in mice found that cyanidin hindered the binding of the cytokine interleukin-17A to the IL-17RA subunit to reduce inflammation.²² In a 2007 study, methanol extracts of black raspberries, strawberries, and blueberries were tested for the capacity to inhibit UV-induced activation of nuclear factor–kappa B (NF-kappaB) and activator protein–1 (AP-1) in mouse epidermal cells. The methanol fractions of black raspberries, which contain the anthocyanin cyanidin-3-rutinoside, were found to time- and dose-dependently inhibit the UV effects on NF-kappaB and AP-1, unlike the other berries, which do not contain cyanidin-3-rutinoside.²³ The pretreatment of human keratinocytes with the anthocyanin cyanidin-3-O-glucoside also has been demonstrated to protect against a wide array of UVB-induced damage,²⁴ and acai fruit–derived cyanidin and malvidin have been shown recently to thwart UVA-induced stress in immortalized fibroblasts.²⁵ Further, cyanidin derived from elderberries has exhibited antiproliferative and apoptotic potential on melanoma cells in a 2017 mouse model, indicating a potential role in skin cancer treatment.²⁶

Conclusion

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

References

1. Eur J Pharm Biopharm. 2016 Nov;108:41-53.

2. Clin Cosmet Investig Dermatol. 2016 Feb 26;9:55-62.

3. Int J Mol Sci. 2016 Feb 18;17(2):160-201.

4. Cancer Res. 2008 Apr 15:68(8):3057-65.

5. J Acupunct Meridian Stud. 2013 Oct;6(5):252-62.

6. Evid Based Complement Alternat Med. 2012;2012:912028.

7. Photochem Photobiol. 2008 Mar-Apr;84(2):307-16.

8. PLoS One. 2016 Jan 7;11(1):e0146296.

9. J Photochem Photobiol B. 2017 Feb;167:72-81.

10. Phytother Res. 2006 Dec;20(12):1096-9.

11. Obstet Gynecol Int. 2011;2011:949302.

12. Int J Pharm. 2008 Nov 19;364(1):36-44.

13. Biomed Pharmacother. 2016 Aug;82:379-92.

14. Australas J Dermatol. 2015 Feb;56(1):e7-14.

15. Food Chem Toxicol. 2008 Apr;46(4):1298-307.

16. J Invest Dermatol. 2008 Oct;128(10):2429-41.

17. Int Immunopharmacol. 2008 Sep;8(9):1172-82.

18. Mech Ageing Dev. 2017 Mar 24;164:1-7.

19. Skin Res Technol. 2009 Aug;15(3):338-45.

20. Int J Cosmet Sci. 2010 Apr;32(2):99-106.

21. Int J Cosmet Sci. 2015 Oct;37(5):455-64.

22. Sci Signal. 2017 Feb 21;10(467). eaaf8823.

23. Nutr Cancer. 2007;58(2):205-12.

24. J Agric Food Chem. 2006 May 31;54(11):4041-7.

25. J Photochem Photobiol B. 2017 Jul;172:42-51.

26. Int J Mol Sci. 2017 Apr 30;18(5):949.

This column picks up with a recent literature review suggesting potential benefits of topically applied or orally administered flavonoid polyphenolic substances. The discussion is based on at least one sample compound from each flavonoid category.

Flavonols: quercetin

Known to exert substantial antioxidant and anti-inflammatory activities, quercetin has been shown in various cellular and animal-based models to deliver photoprotection from UV and contribute to wound healing.¹ In a single center, single-blind trial with 30 healthy volunteers, a 1% topical quercetin cream was found to be effective in reducing erythema, itching, and wheal diameter in experimentally-induced skin stress.² Quercetin also has been reported to have the capacity to inhibit melanin production.³

Flavones: apigenin

rafaelaraujopa/Thinkstock

Flavanones: naringenin

The citrus flavanone naringenin shows promise as a preventive agent against cutaneous aging as well as carcinogenesis. In a 2008 study, naringenin exerted an anti-apoptotic effect in UVB-damaged cells, significantly extending long-term cellular survival, and facilitating the removal of cyclobutane pyrimidine dimers from the genome.⁷ More recently, topical naringenin has been shown in mice to mitigate the cutaneous inflammation and oxidative stress caused by UVB irradiation,⁸ and, present in Lippia graveolens, to protect against chronic UVB-induced damage including phototumorigenesis.⁹

Isoflavones: red clover, genistein, and daidzein

Red clover, the isoflavones of which have been demonstrated – in high dietary concentrations – to contribute to low incidence of osteoporosis and menopausal symptoms, was shown in a 2006 study to exert anti-aging effects in mice, indicating potential for alleviating the cutaneous aging brought on by declines in estrogen.¹⁰ In 2011, Lipovac et al. showed that oral supplementation with red clover extract improved scalp hair and skin status as well as libido, mood, sleep, and fatigue in a study with 109 postmenopausal women.¹¹

The topical application of the soy isoflavones genistein, daidzein, and glycitein has shown promise as a treatment for photoaging and photodamage.¹² Genistein has been noted for its antioxidant and antibrowning activity, and has exhibited anti-aging properties in mouse studies and photoprotective activity in humans.¹³ A 2015 study by Zhao et al. in cultured skin fibroblasts and nude mouse skin indicated that daidzein treatment appears to increase skin collagen production and suppress collagen degradation.¹⁴

Flavan-3-ols (catechins): epigallocatechin 3-gallate

Already considered a potent antioxidant, epigallocatechin 3-gallate (EGCG) continues to receive attention for conferring an expanding range of health benefits. This catechin, which is the most abundant and potent of such compounds in green tea, has exhibited the capacity to hinder UVB-induced collagen-degrading matrix metalloproteinases (MMPs).¹⁵ EGCG also has been proposed as a preventive and therapeutic agent for keloids, given findings indicating that it hampered the proliferation and migration of keloid fibroblasts in vitro, as well as in vivo by interrupting the signal transducer and activator of transcription 3 (STAT3) signaling pathway.¹⁶ Further, EGCG has been suggested as a potential therapeutic approach to atopic dermatitis (AD) given success against AD-like skin lesions in a murine model.¹⁷ An investigation of the anti-aging cutaneous effects of EGCG on d-galactose-induced aging in mice revealed that subcutaneously injected EGCG yielded overall improvement in the structure and function of the skin.¹⁸ EGCG also is known to yield improvements in skin condition by providing DNA protection, reactivating damaged cells, and increasing cellular energy production.³

Perhaps most importantly, formulations containing green tea extracts have been shown in a small study of 20 volunteers to exert protection against photoaging and photoimmunosuppression, with the extract hindering the expression of MMP-9 and MMP-2.¹⁹ Wrinkle reduction also was observed in another clinical study involving topical green tea.²⁰ The tea plant Camellia sinensis is one of the best sources of antioxidant catechins, particularly green tea (unfermented), but also white (unfermented), black (fermented), and oolong (semifermented) tea.²¹

Anthocyanins: cyanidin

A 2017 in vivo study in mice found that cyanidin hindered the binding of the cytokine interleukin-17A to the IL-17RA subunit to reduce inflammation.²² In a 2007 study, methanol extracts of black raspberries, strawberries, and blueberries were tested for the capacity to inhibit UV-induced activation of nuclear factor–kappa B (NF-kappaB) and activator protein–1 (AP-1) in mouse epidermal cells. The methanol fractions of black raspberries, which contain the anthocyanin cyanidin-3-rutinoside, were found to time- and dose-dependently inhibit the UV effects on NF-kappaB and AP-1, unlike the other berries, which do not contain cyanidin-3-rutinoside.²³ The pretreatment of human keratinocytes with the anthocyanin cyanidin-3-O-glucoside also has been demonstrated to protect against a wide array of UVB-induced damage,²⁴ and acai fruit–derived cyanidin and malvidin have been shown recently to thwart UVA-induced stress in immortalized fibroblasts.²⁵ Further, cyanidin derived from elderberries has exhibited antiproliferative and apoptotic potential on melanoma cells in a 2017 mouse model, indicating a potential role in skin cancer treatment.²⁶

Conclusion

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

References

1. Eur J Pharm Biopharm. 2016 Nov;108:41-53.

2. Clin Cosmet Investig Dermatol. 2016 Feb 26;9:55-62.

3. Int J Mol Sci. 2016 Feb 18;17(2):160-201.

4. Cancer Res. 2008 Apr 15:68(8):3057-65.

5. J Acupunct Meridian Stud. 2013 Oct;6(5):252-62.

6. Evid Based Complement Alternat Med. 2012;2012:912028.

7. Photochem Photobiol. 2008 Mar-Apr;84(2):307-16.

8. PLoS One. 2016 Jan 7;11(1):e0146296.

9. J Photochem Photobiol B. 2017 Feb;167:72-81.

10. Phytother Res. 2006 Dec;20(12):1096-9.

11. Obstet Gynecol Int. 2011;2011:949302.

12. Int J Pharm. 2008 Nov 19;364(1):36-44.

13. Biomed Pharmacother. 2016 Aug;82:379-92.

14. Australas J Dermatol. 2015 Feb;56(1):e7-14.

15. Food Chem Toxicol. 2008 Apr;46(4):1298-307.

16. J Invest Dermatol. 2008 Oct;128(10):2429-41.

17. Int Immunopharmacol. 2008 Sep;8(9):1172-82.

18. Mech Ageing Dev. 2017 Mar 24;164:1-7.

19. Skin Res Technol. 2009 Aug;15(3):338-45.

20. Int J Cosmet Sci. 2010 Apr;32(2):99-106.

21. Int J Cosmet Sci. 2015 Oct;37(5):455-64.

22. Sci Signal. 2017 Feb 21;10(467). eaaf8823.

23. Nutr Cancer. 2007;58(2):205-12.

24. J Agric Food Chem. 2006 May 31;54(11):4041-7.

25. J Photochem Photobiol B. 2017 Jul;172:42-51.

26. Int J Mol Sci. 2017 Apr 30;18(5):949.

This column picks up with a recent literature review suggesting potential benefits of topically applied or orally administered flavonoid polyphenolic substances. The discussion is based on at least one sample compound from each flavonoid category.

Flavonols: quercetin

Known to exert substantial antioxidant and anti-inflammatory activities, quercetin has been shown in various cellular and animal-based models to deliver photoprotection from UV and contribute to wound healing.¹ In a single center, single-blind trial with 30 healthy volunteers, a 1% topical quercetin cream was found to be effective in reducing erythema, itching, and wheal diameter in experimentally-induced skin stress.² Quercetin also has been reported to have the capacity to inhibit melanin production.³

Flavones: apigenin

rafaelaraujopa/Thinkstock

Flavanones: naringenin

The citrus flavanone naringenin shows promise as a preventive agent against cutaneous aging as well as carcinogenesis. In a 2008 study, naringenin exerted an anti-apoptotic effect in UVB-damaged cells, significantly extending long-term cellular survival, and facilitating the removal of cyclobutane pyrimidine dimers from the genome.⁷ More recently, topical naringenin has been shown in mice to mitigate the cutaneous inflammation and oxidative stress caused by UVB irradiation,⁸ and, present in Lippia graveolens, to protect against chronic UVB-induced damage including phototumorigenesis.⁹

Isoflavones: red clover, genistein, and daidzein

Red clover, the isoflavones of which have been demonstrated – in high dietary concentrations – to contribute to low incidence of osteoporosis and menopausal symptoms, was shown in a 2006 study to exert anti-aging effects in mice, indicating potential for alleviating the cutaneous aging brought on by declines in estrogen.¹⁰ In 2011, Lipovac et al. showed that oral supplementation with red clover extract improved scalp hair and skin status as well as libido, mood, sleep, and fatigue in a study with 109 postmenopausal women.¹¹

The topical application of the soy isoflavones genistein, daidzein, and glycitein has shown promise as a treatment for photoaging and photodamage.¹² Genistein has been noted for its antioxidant and antibrowning activity, and has exhibited anti-aging properties in mouse studies and photoprotective activity in humans.¹³ A 2015 study by Zhao et al. in cultured skin fibroblasts and nude mouse skin indicated that daidzein treatment appears to increase skin collagen production and suppress collagen degradation.¹⁴

Flavan-3-ols (catechins): epigallocatechin 3-gallate

Already considered a potent antioxidant, epigallocatechin 3-gallate (EGCG) continues to receive attention for conferring an expanding range of health benefits. This catechin, which is the most abundant and potent of such compounds in green tea, has exhibited the capacity to hinder UVB-induced collagen-degrading matrix metalloproteinases (MMPs).¹⁵ EGCG also has been proposed as a preventive and therapeutic agent for keloids, given findings indicating that it hampered the proliferation and migration of keloid fibroblasts in vitro, as well as in vivo by interrupting the signal transducer and activator of transcription 3 (STAT3) signaling pathway.¹⁶ Further, EGCG has been suggested as a potential therapeutic approach to atopic dermatitis (AD) given success against AD-like skin lesions in a murine model.¹⁷ An investigation of the anti-aging cutaneous effects of EGCG on d-galactose-induced aging in mice revealed that subcutaneously injected EGCG yielded overall improvement in the structure and function of the skin.¹⁸ EGCG also is known to yield improvements in skin condition by providing DNA protection, reactivating damaged cells, and increasing cellular energy production.³

Perhaps most importantly, formulations containing green tea extracts have been shown in a small study of 20 volunteers to exert protection against photoaging and photoimmunosuppression, with the extract hindering the expression of MMP-9 and MMP-2.¹⁹ Wrinkle reduction also was observed in another clinical study involving topical green tea.²⁰ The tea plant Camellia sinensis is one of the best sources of antioxidant catechins, particularly green tea (unfermented), but also white (unfermented), black (fermented), and oolong (semifermented) tea.²¹

Anthocyanins: cyanidin

A 2017 in vivo study in mice found that cyanidin hindered the binding of the cytokine interleukin-17A to the IL-17RA subunit to reduce inflammation.²² In a 2007 study, methanol extracts of black raspberries, strawberries, and blueberries were tested for the capacity to inhibit UV-induced activation of nuclear factor–kappa B (NF-kappaB) and activator protein–1 (AP-1) in mouse epidermal cells. The methanol fractions of black raspberries, which contain the anthocyanin cyanidin-3-rutinoside, were found to time- and dose-dependently inhibit the UV effects on NF-kappaB and AP-1, unlike the other berries, which do not contain cyanidin-3-rutinoside.²³ The pretreatment of human keratinocytes with the anthocyanin cyanidin-3-O-glucoside also has been demonstrated to protect against a wide array of UVB-induced damage,²⁴ and acai fruit–derived cyanidin and malvidin have been shown recently to thwart UVA-induced stress in immortalized fibroblasts.²⁵ Further, cyanidin derived from elderberries has exhibited antiproliferative and apoptotic potential on melanoma cells in a 2017 mouse model, indicating a potential role in skin cancer treatment.²⁶

Conclusion

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

References

1. Eur J Pharm Biopharm. 2016 Nov;108:41-53.

2. Clin Cosmet Investig Dermatol. 2016 Feb 26;9:55-62.

3. Int J Mol Sci. 2016 Feb 18;17(2):160-201.

4. Cancer Res. 2008 Apr 15:68(8):3057-65.

5. J Acupunct Meridian Stud. 2013 Oct;6(5):252-62.

6. Evid Based Complement Alternat Med. 2012;2012:912028.

7. Photochem Photobiol. 2008 Mar-Apr;84(2):307-16.

8. PLoS One. 2016 Jan 7;11(1):e0146296.

9. J Photochem Photobiol B. 2017 Feb;167:72-81.

10. Phytother Res. 2006 Dec;20(12):1096-9.

11. Obstet Gynecol Int. 2011;2011:949302.

12. Int J Pharm. 2008 Nov 19;364(1):36-44.

13. Biomed Pharmacother. 2016 Aug;82:379-92.

14. Australas J Dermatol. 2015 Feb;56(1):e7-14.

15. Food Chem Toxicol. 2008 Apr;46(4):1298-307.

16. J Invest Dermatol. 2008 Oct;128(10):2429-41.

17. Int Immunopharmacol. 2008 Sep;8(9):1172-82.

18. Mech Ageing Dev. 2017 Mar 24;164:1-7.

19. Skin Res Technol. 2009 Aug;15(3):338-45.

20. Int J Cosmet Sci. 2010 Apr;32(2):99-106.

21. Int J Cosmet Sci. 2015 Oct;37(5):455-64.

22. Sci Signal. 2017 Feb 21;10(467). eaaf8823.

23. Nutr Cancer. 2007;58(2):205-12.

24. J Agric Food Chem. 2006 May 31;54(11):4041-7.

25. J Photochem Photobiol B. 2017 Jul;172:42-51.

26. Int J Mol Sci. 2017 Apr 30;18(5):949.

Risk-adjusted adverse outcomes for elective colorectal surgery vary significantly across regions in the United States, and, therefore, regionally based Medicare payments could disadvantage some hospitals.

The findings, presented at the annual Central Surgical Association meeting, suggest that alternative payment models (APMs) should consider regional benchmarks as a variable when evaluating quality and pricing of episodes of care to level the playing field among hospitals, the study authors said.

A total of 1,497 hospitals had 86,624 patients for the comparative analysis of hospitals with 20 or more qualifying cases. Hospitals averaged 57.9 cases with a median of 43 for the study period. Among the AOs, there were 947 IpD (1.1%), 7,268 prLOS (8.4%), 762 PD90 (0.9%), and 14,552 RA90 (16.8%) patients. An additional 1,130 patients died during or following readmission within the 90-day postdischarge period for total postoperative deaths including inpatient and 90 days following discharge of 2,839 (3.3%). Total patients with one or more AOs were 21,064 (24.3%).

Among the hospitals, 49 (3.3%) had z scores of –2.0 or less. These best-performing hospitals had a median z score of –2.24 and a median risk-adjusted AO rate of 10.8%. A total of 159 hospitals (10.6%) had z scores that were greater than –2.0 but less than or equal to –1.0. These hospitals had a median risk-adjusted AO rate of 15.1%. There were 66 hospitals (4.4%) with z scores greater than +2.0. These suboptimal-performing hospitals had a z score of +2.39 and a median risk-adjusted AO rate of 38.8%. A total of 209 hospitals (14.0%) had z scores greater than or equal to +1.0 but less than +2.0. They had a median risk-adjusted AO rate of 32.5%.

Findings showed a nearly 5-SD difference between the Pacific region and the New England region. In addition, the results showed a 2.5% absolute risk–adjusted adverse outcome rate difference between the top- and the lowest-performing regions.
 

What findings could mean for bundled payments

The findings raise concerns about a lopsided playing field for hospitals when it comes to bundled payments, according to the study authors.

“What that means is if you have more readmissions and more complications and your historical profile is being used to pay for care going forward, regions of the country with poorer outcomes would get higher prices than those areas with better outcomes,” Dr. Fry, executive vice president, clinical outcomes management, MPA Healthcare Solutions, Chicago, said in an interview.

The Centers for Medicare & Medicaid Services has used performance of the Census Bureau region as a major factor in defining target price at the beginning of the Comprehensive Care for Joint Replacement bundled payment program. Regional performance will become the exclusive basis for the target price as the program matures into successive years, the study authors noted. A colorectal surgery bundle has not yet been proposed by Medicare, but because it’s a common operation with relatively high adverse outcomes rates, it is expected to be included in a future bundled payment strategy, according to the investigators.

Dr. Fry and his coauthors concluded that hospitals and surgeons may find meeting the target price of a bundled payment to improve margins or avoid losses more difficult for any inpatient operation if they are in a best-performing region.

A 2.5% adverse outcome rate difference between regions may not seem like much, but the variance could mean a wide disparity in payments, Dr. Fry said.

“We have done previous research with colon operations and identified that a readmission after an elective colon operation costs about an additional $30,000,” he said. “If cases being done in poorer-performing areas of the country have two or three more readmissions per 100 patients, then it means those areas are going to be paid on average $1,000 more per case than would be the circumstance for those areas where outcomes are better.”

By these parameters, the CMS would basically be rewarding care that is suboptimal in the regions with high adverse outcome rates, he said.

“APMs are going to evolve in health care,” Dr. Fry said. “I feel that regional and local outcomes, as illustrated in this article, are different, and that a national standard for expected outcomes needs to be the benchmark. The national benchmark becomes a method to stimulate hospitals and surgeons to know what the results of their care really are and how they compare nationally.”
 

Perspectives on the study

However, it remains unclear whether adjustment for quality measures should be based on regions, and, if so, how those regions should be broken down, said Dr. Whitcomb, who is cofounder and past president of the Society of Hospital Medicine. Another question is whether adjustments should take into consideration the characteristics of hospitals, he said, for example, the general demographics of patients who visit academic medical centers, compared with the demographics of community hospitals. Dr. Whitcomb also noted that programs such as the Hospital Readmissions Reduction Program has faced criticism for not factoring in the disproportionately high share of low socioeconomic status patients at some hospitals.

“The paper raises the important issue of comparing apples to apples when quality measures are used to determine payment under alternative payment models,” Dr. Whitcomb said in an interview. “But a number of questions remain about how risk should be adjusted and how benchmarking should occur between hospitals.”

[email protected]

On Twitter @legal_med

Risk-adjusted adverse outcomes for elective colorectal surgery vary significantly across regions in the United States, and, therefore, regionally based Medicare payments could disadvantage some hospitals.

The findings, presented at the annual Central Surgical Association meeting, suggest that alternative payment models (APMs) should consider regional benchmarks as a variable when evaluating quality and pricing of episodes of care to level the playing field among hospitals, the study authors said.

A total of 1,497 hospitals had 86,624 patients for the comparative analysis of hospitals with 20 or more qualifying cases. Hospitals averaged 57.9 cases with a median of 43 for the study period. Among the AOs, there were 947 IpD (1.1%), 7,268 prLOS (8.4%), 762 PD90 (0.9%), and 14,552 RA90 (16.8%) patients. An additional 1,130 patients died during or following readmission within the 90-day postdischarge period for total postoperative deaths including inpatient and 90 days following discharge of 2,839 (3.3%). Total patients with one or more AOs were 21,064 (24.3%).

Among the hospitals, 49 (3.3%) had z scores of –2.0 or less. These best-performing hospitals had a median z score of –2.24 and a median risk-adjusted AO rate of 10.8%. A total of 159 hospitals (10.6%) had z scores that were greater than –2.0 but less than or equal to –1.0. These hospitals had a median risk-adjusted AO rate of 15.1%. There were 66 hospitals (4.4%) with z scores greater than +2.0. These suboptimal-performing hospitals had a z score of +2.39 and a median risk-adjusted AO rate of 38.8%. A total of 209 hospitals (14.0%) had z scores greater than or equal to +1.0 but less than +2.0. They had a median risk-adjusted AO rate of 32.5%.

Findings showed a nearly 5-SD difference between the Pacific region and the New England region. In addition, the results showed a 2.5% absolute risk–adjusted adverse outcome rate difference between the top- and the lowest-performing regions.
 

What findings could mean for bundled payments

The findings raise concerns about a lopsided playing field for hospitals when it comes to bundled payments, according to the study authors.

“What that means is if you have more readmissions and more complications and your historical profile is being used to pay for care going forward, regions of the country with poorer outcomes would get higher prices than those areas with better outcomes,” Dr. Fry, executive vice president, clinical outcomes management, MPA Healthcare Solutions, Chicago, said in an interview.

The Centers for Medicare & Medicaid Services has used performance of the Census Bureau region as a major factor in defining target price at the beginning of the Comprehensive Care for Joint Replacement bundled payment program. Regional performance will become the exclusive basis for the target price as the program matures into successive years, the study authors noted. A colorectal surgery bundle has not yet been proposed by Medicare, but because it’s a common operation with relatively high adverse outcomes rates, it is expected to be included in a future bundled payment strategy, according to the investigators.

Dr. Fry and his coauthors concluded that hospitals and surgeons may find meeting the target price of a bundled payment to improve margins or avoid losses more difficult for any inpatient operation if they are in a best-performing region.

A 2.5% adverse outcome rate difference between regions may not seem like much, but the variance could mean a wide disparity in payments, Dr. Fry said.

“We have done previous research with colon operations and identified that a readmission after an elective colon operation costs about an additional $30,000,” he said. “If cases being done in poorer-performing areas of the country have two or three more readmissions per 100 patients, then it means those areas are going to be paid on average $1,000 more per case than would be the circumstance for those areas where outcomes are better.”

By these parameters, the CMS would basically be rewarding care that is suboptimal in the regions with high adverse outcome rates, he said.

“APMs are going to evolve in health care,” Dr. Fry said. “I feel that regional and local outcomes, as illustrated in this article, are different, and that a national standard for expected outcomes needs to be the benchmark. The national benchmark becomes a method to stimulate hospitals and surgeons to know what the results of their care really are and how they compare nationally.”
 

Perspectives on the study

However, it remains unclear whether adjustment for quality measures should be based on regions, and, if so, how those regions should be broken down, said Dr. Whitcomb, who is cofounder and past president of the Society of Hospital Medicine. Another question is whether adjustments should take into consideration the characteristics of hospitals, he said, for example, the general demographics of patients who visit academic medical centers, compared with the demographics of community hospitals. Dr. Whitcomb also noted that programs such as the Hospital Readmissions Reduction Program has faced criticism for not factoring in the disproportionately high share of low socioeconomic status patients at some hospitals.

“The paper raises the important issue of comparing apples to apples when quality measures are used to determine payment under alternative payment models,” Dr. Whitcomb said in an interview. “But a number of questions remain about how risk should be adjusted and how benchmarking should occur between hospitals.”

[email protected]

On Twitter @legal_med

Risk-adjusted adverse outcomes for elective colorectal surgery vary significantly across regions in the United States, and, therefore, regionally based Medicare payments could disadvantage some hospitals.

The findings, presented at the annual Central Surgical Association meeting, suggest that alternative payment models (APMs) should consider regional benchmarks as a variable when evaluating quality and pricing of episodes of care to level the playing field among hospitals, the study authors said.

A total of 1,497 hospitals had 86,624 patients for the comparative analysis of hospitals with 20 or more qualifying cases. Hospitals averaged 57.9 cases with a median of 43 for the study period. Among the AOs, there were 947 IpD (1.1%), 7,268 prLOS (8.4%), 762 PD90 (0.9%), and 14,552 RA90 (16.8%) patients. An additional 1,130 patients died during or following readmission within the 90-day postdischarge period for total postoperative deaths including inpatient and 90 days following discharge of 2,839 (3.3%). Total patients with one or more AOs were 21,064 (24.3%).

Among the hospitals, 49 (3.3%) had z scores of –2.0 or less. These best-performing hospitals had a median z score of –2.24 and a median risk-adjusted AO rate of 10.8%. A total of 159 hospitals (10.6%) had z scores that were greater than –2.0 but less than or equal to –1.0. These hospitals had a median risk-adjusted AO rate of 15.1%. There were 66 hospitals (4.4%) with z scores greater than +2.0. These suboptimal-performing hospitals had a z score of +2.39 and a median risk-adjusted AO rate of 38.8%. A total of 209 hospitals (14.0%) had z scores greater than or equal to +1.0 but less than +2.0. They had a median risk-adjusted AO rate of 32.5%.

Findings showed a nearly 5-SD difference between the Pacific region and the New England region. In addition, the results showed a 2.5% absolute risk–adjusted adverse outcome rate difference between the top- and the lowest-performing regions.
 

What findings could mean for bundled payments

The findings raise concerns about a lopsided playing field for hospitals when it comes to bundled payments, according to the study authors.

“What that means is if you have more readmissions and more complications and your historical profile is being used to pay for care going forward, regions of the country with poorer outcomes would get higher prices than those areas with better outcomes,” Dr. Fry, executive vice president, clinical outcomes management, MPA Healthcare Solutions, Chicago, said in an interview.

The Centers for Medicare & Medicaid Services has used performance of the Census Bureau region as a major factor in defining target price at the beginning of the Comprehensive Care for Joint Replacement bundled payment program. Regional performance will become the exclusive basis for the target price as the program matures into successive years, the study authors noted. A colorectal surgery bundle has not yet been proposed by Medicare, but because it’s a common operation with relatively high adverse outcomes rates, it is expected to be included in a future bundled payment strategy, according to the investigators.

Dr. Fry and his coauthors concluded that hospitals and surgeons may find meeting the target price of a bundled payment to improve margins or avoid losses more difficult for any inpatient operation if they are in a best-performing region.

A 2.5% adverse outcome rate difference between regions may not seem like much, but the variance could mean a wide disparity in payments, Dr. Fry said.

“We have done previous research with colon operations and identified that a readmission after an elective colon operation costs about an additional $30,000,” he said. “If cases being done in poorer-performing areas of the country have two or three more readmissions per 100 patients, then it means those areas are going to be paid on average $1,000 more per case than would be the circumstance for those areas where outcomes are better.”

By these parameters, the CMS would basically be rewarding care that is suboptimal in the regions with high adverse outcome rates, he said.

“APMs are going to evolve in health care,” Dr. Fry said. “I feel that regional and local outcomes, as illustrated in this article, are different, and that a national standard for expected outcomes needs to be the benchmark. The national benchmark becomes a method to stimulate hospitals and surgeons to know what the results of their care really are and how they compare nationally.”
 

Perspectives on the study

However, it remains unclear whether adjustment for quality measures should be based on regions, and, if so, how those regions should be broken down, said Dr. Whitcomb, who is cofounder and past president of the Society of Hospital Medicine. Another question is whether adjustments should take into consideration the characteristics of hospitals, he said, for example, the general demographics of patients who visit academic medical centers, compared with the demographics of community hospitals. Dr. Whitcomb also noted that programs such as the Hospital Readmissions Reduction Program has faced criticism for not factoring in the disproportionately high share of low socioeconomic status patients at some hospitals.

“The paper raises the important issue of comparing apples to apples when quality measures are used to determine payment under alternative payment models,” Dr. Whitcomb said in an interview. “But a number of questions remain about how risk should be adjusted and how benchmarking should occur between hospitals.”

[email protected]

On Twitter @legal_med

Approximately 3% of patients developed adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study published online ahead of print September 5 in JAMA Neurology.

These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, asymmetric vasculitic neuropathy, cerebellar ataxia, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, said Justin C. Kao, MBChB, a neurologist at Mayo Clinic in Rochester, Minnesota, and his coinvestigators.

Nivolumab and pembrolizumab are anti-programmed death–1 (PD-1) antibodies. In response to an increase in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Cancer Pharmacy Database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%, two women) developed neurologic complications within 12 months of anti–PD-1 exposure. The median age was 71. None of their neurologic symptoms could be attributed directly to other treatments or to metastatic disease. Median modified Rankin Scale (mRS) score was 2.5. Symptom severity peaked at between one day and more than three months after starting anti–PD-1 treatment.

Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to neurologic improvements (median mRS score, 2). A patient with necrotizing myopathy who had been receiving pembrolizumab for stage 4 melanoma developed extraocular, bulbar, and respiratory muscle weakness. These symptoms worsened over three weeks and did not respond to prednisone (80 mg/day) or to three sessions of plasmapheresis. The patient subsequently died.

If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full workup, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify the underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said.

—Amy Karon

Suggested Reading

Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017 Sep 5 [Epub ahead of print].

Approximately 3% of patients developed adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study published online ahead of print September 5 in JAMA Neurology.

These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, asymmetric vasculitic neuropathy, cerebellar ataxia, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, said Justin C. Kao, MBChB, a neurologist at Mayo Clinic in Rochester, Minnesota, and his coinvestigators.

Nivolumab and pembrolizumab are anti-programmed death–1 (PD-1) antibodies. In response to an increase in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Cancer Pharmacy Database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%, two women) developed neurologic complications within 12 months of anti–PD-1 exposure. The median age was 71. None of their neurologic symptoms could be attributed directly to other treatments or to metastatic disease. Median modified Rankin Scale (mRS) score was 2.5. Symptom severity peaked at between one day and more than three months after starting anti–PD-1 treatment.

Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to neurologic improvements (median mRS score, 2). A patient with necrotizing myopathy who had been receiving pembrolizumab for stage 4 melanoma developed extraocular, bulbar, and respiratory muscle weakness. These symptoms worsened over three weeks and did not respond to prednisone (80 mg/day) or to three sessions of plasmapheresis. The patient subsequently died.

If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full workup, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify the underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said.

—Amy Karon

Suggested Reading

Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017 Sep 5 [Epub ahead of print].

Approximately 3% of patients developed adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study published online ahead of print September 5 in JAMA Neurology.

These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, asymmetric vasculitic neuropathy, cerebellar ataxia, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, said Justin C. Kao, MBChB, a neurologist at Mayo Clinic in Rochester, Minnesota, and his coinvestigators.

Nivolumab and pembrolizumab are anti-programmed death–1 (PD-1) antibodies. In response to an increase in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Cancer Pharmacy Database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%, two women) developed neurologic complications within 12 months of anti–PD-1 exposure. The median age was 71. None of their neurologic symptoms could be attributed directly to other treatments or to metastatic disease. Median modified Rankin Scale (mRS) score was 2.5. Symptom severity peaked at between one day and more than three months after starting anti–PD-1 treatment.

Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to neurologic improvements (median mRS score, 2). A patient with necrotizing myopathy who had been receiving pembrolizumab for stage 4 melanoma developed extraocular, bulbar, and respiratory muscle weakness. These symptoms worsened over three weeks and did not respond to prednisone (80 mg/day) or to three sessions of plasmapheresis. The patient subsequently died.

If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full workup, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify the underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said.

—Amy Karon

Suggested Reading

Kao JC, Liao B, Markovic SN, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017 Sep 5 [Epub ahead of print].

MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.

Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.

Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.

The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.

Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.

The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.

The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.

“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.

In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.

The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”

MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.

Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.

Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.

The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.

Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.

The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.

The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.

“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.

In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.

The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”

MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.

Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.

Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.

The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.

Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.

The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.

The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.

“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.

In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.

The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”

Research and development costs for cancer drugs are far lower than previous estimates, according to a new analysis, casting doubt on the common justifications by drug companies for the high prices of such medications.

The median cost to develop a cancer drug was $648 million, compared with the widely publicized figure of $2.7 billion, the study’s researchers said.

Lead investigator Vinay Prasad, MD, of Oregon Health and Science University in Portland, and Sham Mailankody, MBBS, of Memorial Sloan Kettering Cancer Center in New York, studied U.S. Securities and Exchange Commission filings for drug companies with no drugs on the market that received Food and Drug Administration approval for a cancer drug from Jan. 1, 2006, through Dec. 31, 2015. Researchers estimated cumulative research and development spending from initiation of drug development activity to date of approval. Earnings were identified from the time of approval to the present. Ten drugs and companies were included in the analysis.

Investigators found that the median time to develop a drug was 7.3 years. Five companies (50%) developed drugs that received accelerated approval from the FDA, and five drugs (50%) received regular approval. Five of the 10 drugs (50%) act on a novel target (ibrutinib, brentuximab vedotin, ruxolitinib, cabozantinib, and eculizumab), whereas the other five drugs (50%) are next-in-class drugs with a mechanism of action similar to that of a previously approved drug.

Results showed the median cost of developing a single drug in 2017 U.S. dollars was $648 million (range, $157.3 million to $1.95 billion), and the mean development cost was $719.8 million (JAMA Intern Med. 2017 Sep 11 doi: 10.1001/jamainternmed.2017.3601).

Drugs that received accelerated approval cost less to develop than did those that received regular approval, although that finding was not statistically significant, according to the study. From the time of approval to December 2016 – or until the company sold or licensed the compound to another company – the total revenue of the 10 drugs was $67 billion. The median revenue for these companies was $1.66 billion (range, $204.1 million to $22.3 billion), and the average revenue was $6.7 billion. Nine of the 10 drugs had revenues greater than their research and development spending. Revenue from sales of four drugs (ponatinib, ibrutinib, enzalutamide, and eculizumab) was more than 10-fold higher than research and development spending.

The analysis offers a transparent estimate of research and development spending on cancer drugs, the study authors said, and has implications for the current debate on drug pricing. They noted that prior estimates for the cost to develop one new drug range from $320 million to $2.7 billion, markedly lower than the study’s $648 million finding.

“In a short period, development cost is more than recouped, and some companies boast more than a 10-fold higher revenue than [research and development] spending – a sum not seen in other sectors of the economy,” the researchers explained. “Future work regarding the cost of cancer drugs may be facilitated by more, not less, transparency in the biopharmaceutical industry.”

Regarding their work, the authors noted that the data set is small, the filings studied are subject to strict guidelines and regulation, the analysis pertains only to cancer drugs, and potential tax breaks applied to research and development costs for drug companies are not accounted for.

Dr. Mailankody reported serving as a principal investigator for clinical trials with research funding from Juno Therapeutics and Takeda Oncology. He also reported receiving personal fees for speaking at the Wedbush Pacgrow Healthcare Conference 2016. No other disclosures were reported.

[email protected]

On Twitter @legal_med

Research and development costs for cancer drugs are far lower than previous estimates, according to a new analysis, casting doubt on the common justifications by drug companies for the high prices of such medications.

The median cost to develop a cancer drug was $648 million, compared with the widely publicized figure of $2.7 billion, the study’s researchers said.

Lead investigator Vinay Prasad, MD, of Oregon Health and Science University in Portland, and Sham Mailankody, MBBS, of Memorial Sloan Kettering Cancer Center in New York, studied U.S. Securities and Exchange Commission filings for drug companies with no drugs on the market that received Food and Drug Administration approval for a cancer drug from Jan. 1, 2006, through Dec. 31, 2015. Researchers estimated cumulative research and development spending from initiation of drug development activity to date of approval. Earnings were identified from the time of approval to the present. Ten drugs and companies were included in the analysis.

Investigators found that the median time to develop a drug was 7.3 years. Five companies (50%) developed drugs that received accelerated approval from the FDA, and five drugs (50%) received regular approval. Five of the 10 drugs (50%) act on a novel target (ibrutinib, brentuximab vedotin, ruxolitinib, cabozantinib, and eculizumab), whereas the other five drugs (50%) are next-in-class drugs with a mechanism of action similar to that of a previously approved drug.

Results showed the median cost of developing a single drug in 2017 U.S. dollars was $648 million (range, $157.3 million to $1.95 billion), and the mean development cost was $719.8 million (JAMA Intern Med. 2017 Sep 11 doi: 10.1001/jamainternmed.2017.3601).

Drugs that received accelerated approval cost less to develop than did those that received regular approval, although that finding was not statistically significant, according to the study. From the time of approval to December 2016 – or until the company sold or licensed the compound to another company – the total revenue of the 10 drugs was $67 billion. The median revenue for these companies was $1.66 billion (range, $204.1 million to $22.3 billion), and the average revenue was $6.7 billion. Nine of the 10 drugs had revenues greater than their research and development spending. Revenue from sales of four drugs (ponatinib, ibrutinib, enzalutamide, and eculizumab) was more than 10-fold higher than research and development spending.

The analysis offers a transparent estimate of research and development spending on cancer drugs, the study authors said, and has implications for the current debate on drug pricing. They noted that prior estimates for the cost to develop one new drug range from $320 million to $2.7 billion, markedly lower than the study’s $648 million finding.

“In a short period, development cost is more than recouped, and some companies boast more than a 10-fold higher revenue than [research and development] spending – a sum not seen in other sectors of the economy,” the researchers explained. “Future work regarding the cost of cancer drugs may be facilitated by more, not less, transparency in the biopharmaceutical industry.”

Regarding their work, the authors noted that the data set is small, the filings studied are subject to strict guidelines and regulation, the analysis pertains only to cancer drugs, and potential tax breaks applied to research and development costs for drug companies are not accounted for.

Dr. Mailankody reported serving as a principal investigator for clinical trials with research funding from Juno Therapeutics and Takeda Oncology. He also reported receiving personal fees for speaking at the Wedbush Pacgrow Healthcare Conference 2016. No other disclosures were reported.

[email protected]

On Twitter @legal_med

Research and development costs for cancer drugs are far lower than previous estimates, according to a new analysis, casting doubt on the common justifications by drug companies for the high prices of such medications.

The median cost to develop a cancer drug was $648 million, compared with the widely publicized figure of $2.7 billion, the study’s researchers said.

Lead investigator Vinay Prasad, MD, of Oregon Health and Science University in Portland, and Sham Mailankody, MBBS, of Memorial Sloan Kettering Cancer Center in New York, studied U.S. Securities and Exchange Commission filings for drug companies with no drugs on the market that received Food and Drug Administration approval for a cancer drug from Jan. 1, 2006, through Dec. 31, 2015. Researchers estimated cumulative research and development spending from initiation of drug development activity to date of approval. Earnings were identified from the time of approval to the present. Ten drugs and companies were included in the analysis.

Investigators found that the median time to develop a drug was 7.3 years. Five companies (50%) developed drugs that received accelerated approval from the FDA, and five drugs (50%) received regular approval. Five of the 10 drugs (50%) act on a novel target (ibrutinib, brentuximab vedotin, ruxolitinib, cabozantinib, and eculizumab), whereas the other five drugs (50%) are next-in-class drugs with a mechanism of action similar to that of a previously approved drug.

Results showed the median cost of developing a single drug in 2017 U.S. dollars was $648 million (range, $157.3 million to $1.95 billion), and the mean development cost was $719.8 million (JAMA Intern Med. 2017 Sep 11 doi: 10.1001/jamainternmed.2017.3601).

Drugs that received accelerated approval cost less to develop than did those that received regular approval, although that finding was not statistically significant, according to the study. From the time of approval to December 2016 – or until the company sold or licensed the compound to another company – the total revenue of the 10 drugs was $67 billion. The median revenue for these companies was $1.66 billion (range, $204.1 million to $22.3 billion), and the average revenue was $6.7 billion. Nine of the 10 drugs had revenues greater than their research and development spending. Revenue from sales of four drugs (ponatinib, ibrutinib, enzalutamide, and eculizumab) was more than 10-fold higher than research and development spending.

The analysis offers a transparent estimate of research and development spending on cancer drugs, the study authors said, and has implications for the current debate on drug pricing. They noted that prior estimates for the cost to develop one new drug range from $320 million to $2.7 billion, markedly lower than the study’s $648 million finding.

“In a short period, development cost is more than recouped, and some companies boast more than a 10-fold higher revenue than [research and development] spending – a sum not seen in other sectors of the economy,” the researchers explained. “Future work regarding the cost of cancer drugs may be facilitated by more, not less, transparency in the biopharmaceutical industry.”

Regarding their work, the authors noted that the data set is small, the filings studied are subject to strict guidelines and regulation, the analysis pertains only to cancer drugs, and potential tax breaks applied to research and development costs for drug companies are not accounted for.

Dr. Mailankody reported serving as a principal investigator for clinical trials with research funding from Juno Therapeutics and Takeda Oncology. He also reported receiving personal fees for speaking at the Wedbush Pacgrow Healthcare Conference 2016. No other disclosures were reported.

[email protected]

On Twitter @legal_med

Postmenopausal women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years, or with CEE alone for a median of 7.2 years had no increased risk of all-cause, cardiovascular, or cancer mortality over a cumulative follow-up of 18 years, according to the latest report from the Women’s Health Initiative hormone therapy trials.

All-cause mortality among the 27,347 participants in the two randomized, double-blind, placebo-controlled trials was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99), JoAnn E. Manson, MD, Harvard Medical School, Boston, and her colleagues reported.

For those who received CEE plus MPA, the hazard ratio was 1.02, while for CEE alone the hazard ratio was 0.94 (JAMA. 2017 Sep;318[10]:927-38).

Cardiovascular mortality among the pooled cohort was 8.9% with hormone therapy and 9.0% with placebo (HR, 1.00), and total cancer mortality was 8.2% and 8.0%, respectively (HR, 1.03). Mortality from other causes was 10.0% with hormone therapy, compared with 10.7% with placebo (HR, 0.95). The results did not differ significantly between the trials, the investigators noted.

An analysis by age showed that women aged 50-59 years tended to have lower hazard ratios for mortality from cardiovascular disease, cancer, and other causes during the intervention phases of the trials, but only the difference for “other” causes in the CEE-alone trial showed a statistically significant trend with age. This was influenced in part by adverse effects of the treatment in women aged 70-79 years. During cumulative follow-up, trends related to mortality across age groups were not statistically significantly different.

The trials included women aged 50-79 years who were enrolled between 1993 and 1998 and followed through 2014. Given the hormone-therapy-related risks identified in the CEE plus MPA and CEE-alone trials – which were stopped early because of increased risk of breast cancer/overall risks exceeding benefits, and for increased stroke risk, respectively – the absence of an increase in all-cause mortality during the intervention and cumulative follow-up phases of the trials is noteworthy, the investigators wrote.

“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate to severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” they wrote. “Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment.”

They added that “in clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”

The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no financial disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.

[email protected]

Postmenopausal women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years, or with CEE alone for a median of 7.2 years had no increased risk of all-cause, cardiovascular, or cancer mortality over a cumulative follow-up of 18 years, according to the latest report from the Women’s Health Initiative hormone therapy trials.

All-cause mortality among the 27,347 participants in the two randomized, double-blind, placebo-controlled trials was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99), JoAnn E. Manson, MD, Harvard Medical School, Boston, and her colleagues reported.

For those who received CEE plus MPA, the hazard ratio was 1.02, while for CEE alone the hazard ratio was 0.94 (JAMA. 2017 Sep;318[10]:927-38).

Cardiovascular mortality among the pooled cohort was 8.9% with hormone therapy and 9.0% with placebo (HR, 1.00), and total cancer mortality was 8.2% and 8.0%, respectively (HR, 1.03). Mortality from other causes was 10.0% with hormone therapy, compared with 10.7% with placebo (HR, 0.95). The results did not differ significantly between the trials, the investigators noted.

An analysis by age showed that women aged 50-59 years tended to have lower hazard ratios for mortality from cardiovascular disease, cancer, and other causes during the intervention phases of the trials, but only the difference for “other” causes in the CEE-alone trial showed a statistically significant trend with age. This was influenced in part by adverse effects of the treatment in women aged 70-79 years. During cumulative follow-up, trends related to mortality across age groups were not statistically significantly different.

The trials included women aged 50-79 years who were enrolled between 1993 and 1998 and followed through 2014. Given the hormone-therapy-related risks identified in the CEE plus MPA and CEE-alone trials – which were stopped early because of increased risk of breast cancer/overall risks exceeding benefits, and for increased stroke risk, respectively – the absence of an increase in all-cause mortality during the intervention and cumulative follow-up phases of the trials is noteworthy, the investigators wrote.

“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate to severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” they wrote. “Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment.”

They added that “in clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”

The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no financial disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.

[email protected]

Postmenopausal women treated with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for a median of 5.6 years, or with CEE alone for a median of 7.2 years had no increased risk of all-cause, cardiovascular, or cancer mortality over a cumulative follow-up of 18 years, according to the latest report from the Women’s Health Initiative hormone therapy trials.

All-cause mortality among the 27,347 participants in the two randomized, double-blind, placebo-controlled trials was 27.1% in the hormone therapy group versus 27.6% in the placebo group (hazard ratio, 0.99), JoAnn E. Manson, MD, Harvard Medical School, Boston, and her colleagues reported.

For those who received CEE plus MPA, the hazard ratio was 1.02, while for CEE alone the hazard ratio was 0.94 (JAMA. 2017 Sep;318[10]:927-38).

Cardiovascular mortality among the pooled cohort was 8.9% with hormone therapy and 9.0% with placebo (HR, 1.00), and total cancer mortality was 8.2% and 8.0%, respectively (HR, 1.03). Mortality from other causes was 10.0% with hormone therapy, compared with 10.7% with placebo (HR, 0.95). The results did not differ significantly between the trials, the investigators noted.

An analysis by age showed that women aged 50-59 years tended to have lower hazard ratios for mortality from cardiovascular disease, cancer, and other causes during the intervention phases of the trials, but only the difference for “other” causes in the CEE-alone trial showed a statistically significant trend with age. This was influenced in part by adverse effects of the treatment in women aged 70-79 years. During cumulative follow-up, trends related to mortality across age groups were not statistically significantly different.

The trials included women aged 50-79 years who were enrolled between 1993 and 1998 and followed through 2014. Given the hormone-therapy-related risks identified in the CEE plus MPA and CEE-alone trials – which were stopped early because of increased risk of breast cancer/overall risks exceeding benefits, and for increased stroke risk, respectively – the absence of an increase in all-cause mortality during the intervention and cumulative follow-up phases of the trials is noteworthy, the investigators wrote.

“Although these findings lend support to practice guidelines endorsing use of hormone therapy for recently menopausal women with moderate to severe symptoms, in the absence of contraindications, the attenuation of age differences with longer follow-up and potential health risks of treatment would not support use of hormone therapy for reducing chronic disease or mortality,” they wrote. “Moreover, it is unclear whether benefits would outweigh risks with longer duration of treatment.”

They added that “in clinical decision making, these considerations must be weighed against the evidence linking untreated vasomotor symptoms in midlife women to impaired health and quality of life, disrupted sleep, reduced work productivity, and increased health care expenditures.”

The Women’s Health Initiative is funded by the U.S. Department of Health & Human Services. Study drugs were donated by Wyeth Ayerst. Dr. Manson reported having no financial disclosures. Several of her coauthors reported receiving grants and research funding from the National Institutes of Health, and receiving personal fees, speaking fees, and honoraria from various pharmaceutical companies.

[email protected]

A blood test can detect glucose transporter type 1 (GLUT1) deficiency syndrome accurately and rapidly, according to a brief communication published in the July issue of Annals of Neurology. The new test has a diagnostic rate comparable to that of CSF glucose and may be more cost-effective than the combination of lumbar puncture and genetic testing, according to the researchers.

To confirm the diagnosis in a patient whose phenotype suggests GLUT1 deficiency syndrome, neurologists traditionally measure CSF glucose concentration and perform SLC2A1 molecular analysis. Lumbar puncture requires fasting and may entail complications, however, and analysis of the coding regions of SLC2A1 can be tedious and may fail to identify variants.

Analysis of Red Blood Cells

Domitille Gras, MD, a neurologist at Robert-Debré University Hospital in Paris, and colleagues tested a novel diagnostic method based on flow cytometry analysis of red blood cells. For their proof-of-concept study, the researchers enrolled 30 patients (13 females) between ages 2 and 50 with GLUT1 deficiency syndrome. They also enrolled 18 patients (six females) with paroxysmal movement disorders attributed to genetic defects other than in SLC2A1. Finally, the investigators examined 346 healthy controls.

For all participants, Dr. Gras and colleagues measured CSF glucose concentration, performed SLC2A1 molecular analysis, and used flow cytometry to analyze GLUT1 surface expression on circulating red blood cells. To perform the latter method, researchers who were blinded to patients’ disease condition collected at least 0.5 mL of nonfasted venous blood from each participant. Results were available within 24 hours.

Age Did Not Affect Test Results

GLUT1 expression on red blood cells varied by 15% among healthy controls. The blood test identified 23 (78%) of the patients with GLUT1 deficiency syndrome who had a decrease in GLUT1 expression of at least 20%. Dr. Gras and colleagues saw no overlap between the test results of patients and those of controls. The new test detected three patients with GLUT1 deficiency syndrome who had a CSF glucose concentration greater than 2.2 mM, which is the most commonly used cutoff. Two patients with a presentation suggestive of GLUT1 deficiency syndrome and low CSF glucose and lactate, but no SLC2A1 mutation, had an abnormal blood test.

The blood test detected GLUT1 deficiency syndrome regardless of the patient’s age and disease severity. Patients not detected by the test may have mutations that mildly affect glucose uptake, but not GLUT1 expression, or may have a GLUT1 deficiency restricted to the brain. Most patients were analyzed at least twice, and blood test results were consistent for each patient.

Measuring GLUT1 at the surface of red blood cells could avoid diagnostic delays that currently are considerable, said Dr. Gras and colleagues. “Although more studies are required to establish the diagnostic gain of the red blood cell test on a larger cohort, such a simple diagnostic test, readily available in clinical practice, ought to greatly enlarge the screening of GLUT1 deficiency syndrome in any patient, child, or adult presenting with cognitive impairment, epilepsy, ataxia and/or dystonia, or paroxysmal movement disorder,” they concluded.

—Erik Greb

Suggested Reading

Gras D, Cousin C, Kappeler C, et al. A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome. Ann Neurol. 2017;82(1):133-138.

A blood test can detect glucose transporter type 1 (GLUT1) deficiency syndrome accurately and rapidly, according to a brief communication published in the July issue of Annals of Neurology. The new test has a diagnostic rate comparable to that of CSF glucose and may be more cost-effective than the combination of lumbar puncture and genetic testing, according to the researchers.

To confirm the diagnosis in a patient whose phenotype suggests GLUT1 deficiency syndrome, neurologists traditionally measure CSF glucose concentration and perform SLC2A1 molecular analysis. Lumbar puncture requires fasting and may entail complications, however, and analysis of the coding regions of SLC2A1 can be tedious and may fail to identify variants.

Analysis of Red Blood Cells

Domitille Gras, MD, a neurologist at Robert-Debré University Hospital in Paris, and colleagues tested a novel diagnostic method based on flow cytometry analysis of red blood cells. For their proof-of-concept study, the researchers enrolled 30 patients (13 females) between ages 2 and 50 with GLUT1 deficiency syndrome. They also enrolled 18 patients (six females) with paroxysmal movement disorders attributed to genetic defects other than in SLC2A1. Finally, the investigators examined 346 healthy controls.

For all participants, Dr. Gras and colleagues measured CSF glucose concentration, performed SLC2A1 molecular analysis, and used flow cytometry to analyze GLUT1 surface expression on circulating red blood cells. To perform the latter method, researchers who were blinded to patients’ disease condition collected at least 0.5 mL of nonfasted venous blood from each participant. Results were available within 24 hours.

Age Did Not Affect Test Results

GLUT1 expression on red blood cells varied by 15% among healthy controls. The blood test identified 23 (78%) of the patients with GLUT1 deficiency syndrome who had a decrease in GLUT1 expression of at least 20%. Dr. Gras and colleagues saw no overlap between the test results of patients and those of controls. The new test detected three patients with GLUT1 deficiency syndrome who had a CSF glucose concentration greater than 2.2 mM, which is the most commonly used cutoff. Two patients with a presentation suggestive of GLUT1 deficiency syndrome and low CSF glucose and lactate, but no SLC2A1 mutation, had an abnormal blood test.

The blood test detected GLUT1 deficiency syndrome regardless of the patient’s age and disease severity. Patients not detected by the test may have mutations that mildly affect glucose uptake, but not GLUT1 expression, or may have a GLUT1 deficiency restricted to the brain. Most patients were analyzed at least twice, and blood test results were consistent for each patient.

Measuring GLUT1 at the surface of red blood cells could avoid diagnostic delays that currently are considerable, said Dr. Gras and colleagues. “Although more studies are required to establish the diagnostic gain of the red blood cell test on a larger cohort, such a simple diagnostic test, readily available in clinical practice, ought to greatly enlarge the screening of GLUT1 deficiency syndrome in any patient, child, or adult presenting with cognitive impairment, epilepsy, ataxia and/or dystonia, or paroxysmal movement disorder,” they concluded.

—Erik Greb

Suggested Reading

Gras D, Cousin C, Kappeler C, et al. A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome. Ann Neurol. 2017;82(1):133-138.

A blood test can detect glucose transporter type 1 (GLUT1) deficiency syndrome accurately and rapidly, according to a brief communication published in the July issue of Annals of Neurology. The new test has a diagnostic rate comparable to that of CSF glucose and may be more cost-effective than the combination of lumbar puncture and genetic testing, according to the researchers.

To confirm the diagnosis in a patient whose phenotype suggests GLUT1 deficiency syndrome, neurologists traditionally measure CSF glucose concentration and perform SLC2A1 molecular analysis. Lumbar puncture requires fasting and may entail complications, however, and analysis of the coding regions of SLC2A1 can be tedious and may fail to identify variants.

Analysis of Red Blood Cells

Domitille Gras, MD, a neurologist at Robert-Debré University Hospital in Paris, and colleagues tested a novel diagnostic method based on flow cytometry analysis of red blood cells. For their proof-of-concept study, the researchers enrolled 30 patients (13 females) between ages 2 and 50 with GLUT1 deficiency syndrome. They also enrolled 18 patients (six females) with paroxysmal movement disorders attributed to genetic defects other than in SLC2A1. Finally, the investigators examined 346 healthy controls.

For all participants, Dr. Gras and colleagues measured CSF glucose concentration, performed SLC2A1 molecular analysis, and used flow cytometry to analyze GLUT1 surface expression on circulating red blood cells. To perform the latter method, researchers who were blinded to patients’ disease condition collected at least 0.5 mL of nonfasted venous blood from each participant. Results were available within 24 hours.

Age Did Not Affect Test Results

GLUT1 expression on red blood cells varied by 15% among healthy controls. The blood test identified 23 (78%) of the patients with GLUT1 deficiency syndrome who had a decrease in GLUT1 expression of at least 20%. Dr. Gras and colleagues saw no overlap between the test results of patients and those of controls. The new test detected three patients with GLUT1 deficiency syndrome who had a CSF glucose concentration greater than 2.2 mM, which is the most commonly used cutoff. Two patients with a presentation suggestive of GLUT1 deficiency syndrome and low CSF glucose and lactate, but no SLC2A1 mutation, had an abnormal blood test.

The blood test detected GLUT1 deficiency syndrome regardless of the patient’s age and disease severity. Patients not detected by the test may have mutations that mildly affect glucose uptake, but not GLUT1 expression, or may have a GLUT1 deficiency restricted to the brain. Most patients were analyzed at least twice, and blood test results were consistent for each patient.

Measuring GLUT1 at the surface of red blood cells could avoid diagnostic delays that currently are considerable, said Dr. Gras and colleagues. “Although more studies are required to establish the diagnostic gain of the red blood cell test on a larger cohort, such a simple diagnostic test, readily available in clinical practice, ought to greatly enlarge the screening of GLUT1 deficiency syndrome in any patient, child, or adult presenting with cognitive impairment, epilepsy, ataxia and/or dystonia, or paroxysmal movement disorder,” they concluded.

—Erik Greb

Suggested Reading

Gras D, Cousin C, Kappeler C, et al. A simple blood test expedites the diagnosis of glucose transporter type 1 deficiency syndrome. Ann Neurol. 2017;82(1):133-138.

ROCKVILLE, MD – The majority of a Food and Drug Administration advisory panel agreed the benefit versus risk of prescription opioid cough suppressants for pediatric patients was not favorable.

The voting was broken into multiple votes based on age range of patients and the specific opioid present in the cough syrup. Unlike other advisory committee meetings, this meeting did not focus on a the treatment of a disease state, but rather on the treatment of a symptom.

On Sept. 11, 2017, the FDA’s Pediatric Advisory Committee voted 21 no, 2 yes, with one abstention, that the benefit versus the risk of opioid cough suppressants for pediatric patients was not favorable.

This vote was preceded by two previous votes specifically questioning the use of codeine and hydrocodone in medications for pediatric patients. For codeine, the committee voted unanimously with 24 against that the benefit versus risk was not favorable in pediatric patients aged 12 years to less than 18 years.

copyright pictore/iStockphoto

[email protected]

On Twitter @ilacy_19

ROCKVILLE, MD – The majority of a Food and Drug Administration advisory panel agreed the benefit versus risk of prescription opioid cough suppressants for pediatric patients was not favorable.

The voting was broken into multiple votes based on age range of patients and the specific opioid present in the cough syrup. Unlike other advisory committee meetings, this meeting did not focus on a the treatment of a disease state, but rather on the treatment of a symptom.

On Sept. 11, 2017, the FDA’s Pediatric Advisory Committee voted 21 no, 2 yes, with one abstention, that the benefit versus the risk of opioid cough suppressants for pediatric patients was not favorable.

This vote was preceded by two previous votes specifically questioning the use of codeine and hydrocodone in medications for pediatric patients. For codeine, the committee voted unanimously with 24 against that the benefit versus risk was not favorable in pediatric patients aged 12 years to less than 18 years.

copyright pictore/iStockphoto

[email protected]

On Twitter @ilacy_19

ROCKVILLE, MD – The majority of a Food and Drug Administration advisory panel agreed the benefit versus risk of prescription opioid cough suppressants for pediatric patients was not favorable.

The voting was broken into multiple votes based on age range of patients and the specific opioid present in the cough syrup. Unlike other advisory committee meetings, this meeting did not focus on a the treatment of a disease state, but rather on the treatment of a symptom.

On Sept. 11, 2017, the FDA’s Pediatric Advisory Committee voted 21 no, 2 yes, with one abstention, that the benefit versus the risk of opioid cough suppressants for pediatric patients was not favorable.

This vote was preceded by two previous votes specifically questioning the use of codeine and hydrocodone in medications for pediatric patients. For codeine, the committee voted unanimously with 24 against that the benefit versus risk was not favorable in pediatric patients aged 12 years to less than 18 years.

copyright pictore/iStockphoto

[email protected]

On Twitter @ilacy_19

A follow-up to a study showing the noninferiority of sentinel lymph node dissection to axillary lymph node dissection for breast cancer in overall and disease-free survival at a median of 6.3 years found similar noninferiority in overall survival at 10 years.

Axillary lymph node dissection has a risk of complications including lymphedema, numbness, axillary web syndrome, and decreased upper-extremity range of motion. The American College of Surgeons Oncology Group Z0011 trial sought to determine if the procedure could be avoided without inferior survival outcomes.

Criticism of the study focused on the potential for later recurrence, particularly in patients with hormone receptor–positive breast cancer. All enrolled patients had one or two sentinel nodes with metastases. At randomization, 436 received sentinel lymph node dissection alone, and 420 received the additional axillary lymph node dissection. The patients were assessed every 6 months for the first 3 years, then annually.

After a median of 9.3 years, 110 of the patients had died of any cause – 51 in the sentinel lymph node dissection group and 59 in the axillary lymph node dissection group – a 10-year overall survival rate of 86.3% and 83.6%, respectively. This met the study’s primary endpoint of showing noninferior overall survival without the riskier procedure. In the study’s secondary endpoint, disease-free survival, there was not a significant difference either (80.2% vs. 78.2%).

“Axillary dissections are associated with considerable morbidity, and the results of this trial demonstrated that this morbidity can be avoided without decreasing cancer control. … These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes,” wrote Armando E. Guiliano, MD, of Cedars-Sinai Medical, Los Angeles and his coauthors (JAMA. 2017;318[10]:918-26. doi: 10.1001/jama.2017.11470).

[email protected]

A follow-up to a study showing the noninferiority of sentinel lymph node dissection to axillary lymph node dissection for breast cancer in overall and disease-free survival at a median of 6.3 years found similar noninferiority in overall survival at 10 years.

Axillary lymph node dissection has a risk of complications including lymphedema, numbness, axillary web syndrome, and decreased upper-extremity range of motion. The American College of Surgeons Oncology Group Z0011 trial sought to determine if the procedure could be avoided without inferior survival outcomes.

Criticism of the study focused on the potential for later recurrence, particularly in patients with hormone receptor–positive breast cancer. All enrolled patients had one or two sentinel nodes with metastases. At randomization, 436 received sentinel lymph node dissection alone, and 420 received the additional axillary lymph node dissection. The patients were assessed every 6 months for the first 3 years, then annually.

After a median of 9.3 years, 110 of the patients had died of any cause – 51 in the sentinel lymph node dissection group and 59 in the axillary lymph node dissection group – a 10-year overall survival rate of 86.3% and 83.6%, respectively. This met the study’s primary endpoint of showing noninferior overall survival without the riskier procedure. In the study’s secondary endpoint, disease-free survival, there was not a significant difference either (80.2% vs. 78.2%).

“Axillary dissections are associated with considerable morbidity, and the results of this trial demonstrated that this morbidity can be avoided without decreasing cancer control. … These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes,” wrote Armando E. Guiliano, MD, of Cedars-Sinai Medical, Los Angeles and his coauthors (JAMA. 2017;318[10]:918-26. doi: 10.1001/jama.2017.11470).

[email protected]

A follow-up to a study showing the noninferiority of sentinel lymph node dissection to axillary lymph node dissection for breast cancer in overall and disease-free survival at a median of 6.3 years found similar noninferiority in overall survival at 10 years.

Axillary lymph node dissection has a risk of complications including lymphedema, numbness, axillary web syndrome, and decreased upper-extremity range of motion. The American College of Surgeons Oncology Group Z0011 trial sought to determine if the procedure could be avoided without inferior survival outcomes.

Criticism of the study focused on the potential for later recurrence, particularly in patients with hormone receptor–positive breast cancer. All enrolled patients had one or two sentinel nodes with metastases. At randomization, 436 received sentinel lymph node dissection alone, and 420 received the additional axillary lymph node dissection. The patients were assessed every 6 months for the first 3 years, then annually.

After a median of 9.3 years, 110 of the patients had died of any cause – 51 in the sentinel lymph node dissection group and 59 in the axillary lymph node dissection group – a 10-year overall survival rate of 86.3% and 83.6%, respectively. This met the study’s primary endpoint of showing noninferior overall survival without the riskier procedure. In the study’s secondary endpoint, disease-free survival, there was not a significant difference either (80.2% vs. 78.2%).

“Axillary dissections are associated with considerable morbidity, and the results of this trial demonstrated that this morbidity can be avoided without decreasing cancer control. … These findings do not support routine use of axillary lymph node dissection in this patient population based on 10-year outcomes,” wrote Armando E. Guiliano, MD, of Cedars-Sinai Medical, Los Angeles and his coauthors (JAMA. 2017;318[10]:918-26. doi: 10.1001/jama.2017.11470).

[email protected]