ED Visits by Older Patients Increase in the Weeks After a Disaster

BY KELLIE DESANTIS

Visits to an ED by adults ages 65 years and older increase significantly in the weeks following a disaster, according to a study published in Disaster Medicine and Public Health Preparedness.¹

Older adults are vulnerable to the effects of disasters because of their diminished ability to adequately prepare for and respond to the effects of a disaster. Older adults suffering from visual, auditory, proprioceptive, and cognitive impairments are especially vulnerable and have the most difficulty complying with evacuation and preparatory warnings. Individuals with multiple chronic diseases, living in long-term care facilities or suffering from cognitive impairments are among the most vulnerable.

To better understand the impact of natural disasters on this vulnerable population, researchers examined the effects of the 2012 disaster, Hurricane Sandy, on older adults living in New York City (NYC) during the disaster. Researchers turned to the New York State Department of Health (NYSDOH) for data. The NYSDOH compiles a comprehensive database of claims from all ED visits in the Statewide Planning and Research Cooperative System (SPARCS), which is the most complete source for ED utilization in New York state, and includes primary and secondary diagnosis codes and patient addresses.

Researchers evaluated ED utilization by adults 65 years and older in the weeks immediately before and after the Hurricane Sandy landfall. They excluded patients who lived in a nursing home, were incarcerated, or visited an ED associated with a specialty hospital (surgical subspecialty, oncological, or Veterans Administration). By using geographic distribution information available from SPARCS and the NYC Office of Emergency Management evacuation zones, researchers were able to compare the ED utilization for older adults living in the evacuation zones before the landfall of Hurricane Sandy and in the weeks shortly after the storm.

The analysis revealed a significant increase in ED utilization for older adults living in the evacuation zones in the 3 weeks after the storm compared to ED use before the storm. The number of weekly ED visits by older adults from all evacuation zones was 9,852 in the weeks before Hurricane Sandy and increased in the first week after the storm to 10,073. Among the most severely impacted were older adults in evacuation zone one, where ED utilization increased from 552 visits to 1,111 visits. The number of ED visits remained elevated for 3 weeks after the storm but returned to normal by the fourth week.

Researchers suggested several reasons for this increase in ED visits, including seeking refuge in the ED as a result of homelessness due to the disaster, the interruption of ongoing care for chronic illness, environmental exposure, and the lack of preparation for the lasting effect of the disaster.

To improve the response to such a disaster in the future, a NYC Hurricane Sandy Assessment report² recommended developing a door-to-door service task force for older adults to improve preparedness for this vulnerable population. The task force would be responsible for implementing an action plan to ensure that healthcare services, communication, and provisions for this population continue without interruption in the weeks following a disaster. Legal and regulatory changes would allow for Medicare recipients to be eligible for "early medication refill" and pre-storm "early dialysis" programs to improve the continuity of care of the chronically ill.

1. Malik S, Lee DC, Doran KM, et al. Vulnerability of older adults in disasters: emergency department utilization by geriatric patients after hurricane sandy. Disaster Med Public Health Prep. 2017:1-10. doi:10.1017/dmp.2017.44

2. The City of New York, Office of the Mayor. Hurricane Sandy After Action Report. Published May 2013. http://www.nyc.gov/html/recovery/downlaods/pdf/sandy_aar_5.2.13.pdf. Accessed September 1, 2017.

Digital Rectal Examination of ED Patients with Acute GI Bleeding Cuts Rates of Admissions, Pharmacotherapy, and Endoscopy

BY JEFF BAUER

Patients presenting to the ED with acute gastrointestinal (GI) bleeding who receive a digital rectal examination have significantly lower rates of admissions, pharmacotherapy, and endoscopies, according to a retrospective study published in The American Journal of Medicine. Digital rectal examinations are an established part of the physical examination of a patient with GI bleeding, but physicians often are reluctant to conduct such examinations. Previous studies have found that 10% to 35% of patients with acute GI bleeding do not receive digital rectal examinations.

In the current study, researchers analyzed data from the electronic health records (EHRs) of patients ages 18 years and older who presented to the ED of a single institution with acute GI bleeding, as identified by International Classification of Diseases, Ninth Edition codes. They collected patients’ medical histories, demographic information, and clinical and laboratory data. ED clinician notes were used to determine which patients received a digital rectal examination. The outcomes researchers assessed were hospital admission, intensive care unit (ICU) admission, initiation of medical therapy (a proton pump inhibitor or octreotide), inpatient endoscopy (upper endoscopy or colonoscopy), and packed red blood cell (RBC) transfusion.

Overall, 1237 patients presented with acute GI bleeding. Most patients were Caucasian (49.2%) or Hispanic (38.4%), 44.9% were female, and the median age was 53 years.

Slightly more than one-half of patients (55.6%) received a digital rectal examination. In total, 736 patients were admitted—including 222 admissions to the ICU; 751 were started on a proton pump inhibitor or octreotide, 274 underwent endoscopy, and 321 received an RBC transfusion.

Patients were more likely to receive a digital rectal examination if they were older, Hispanic, or receiving an anticoagulant. Patients were less likely to undergo such examinations if they presented with altered mental status or hematemesis. Compared to patients who did not receive a digital rectal examination, those who did were significantly less likely to be admitted to the hospital (P = .004), to be starting on medical therapy (P = .04), or to undergo endoscopy (P = .02). There were no significant differences between these two groups in terms of ICU admissions, gastroenterology consultations, or transfusions.

Researchers suggested that the 44% rate of patients with acute GI bleeding who did not receive digital rectal examinations was higher than had been reported in previous studies. The difference had been the result of relying solely on ED clinician notes for this data, without including notes from admitting or consulting clinicians. The authors also were unable to determine the reasons these examinations were not conducted.

Shrestha MP, Borgstrom M, Trowers E. Digital rectal examination reduces hospital admissions, endoscopies, and medical therapy in patients with acute gastrointestinal bleeding. Am J Med. 2017;130(7):819-825. doi: 10.1016/j.amjmed.2017.01.036.

ED Visits by Older Patients Increase in the Weeks After a Disaster

BY KELLIE DESANTIS

Visits to an ED by adults ages 65 years and older increase significantly in the weeks following a disaster, according to a study published in Disaster Medicine and Public Health Preparedness.¹

Older adults are vulnerable to the effects of disasters because of their diminished ability to adequately prepare for and respond to the effects of a disaster. Older adults suffering from visual, auditory, proprioceptive, and cognitive impairments are especially vulnerable and have the most difficulty complying with evacuation and preparatory warnings. Individuals with multiple chronic diseases, living in long-term care facilities or suffering from cognitive impairments are among the most vulnerable.

To better understand the impact of natural disasters on this vulnerable population, researchers examined the effects of the 2012 disaster, Hurricane Sandy, on older adults living in New York City (NYC) during the disaster. Researchers turned to the New York State Department of Health (NYSDOH) for data. The NYSDOH compiles a comprehensive database of claims from all ED visits in the Statewide Planning and Research Cooperative System (SPARCS), which is the most complete source for ED utilization in New York state, and includes primary and secondary diagnosis codes and patient addresses.

Researchers evaluated ED utilization by adults 65 years and older in the weeks immediately before and after the Hurricane Sandy landfall. They excluded patients who lived in a nursing home, were incarcerated, or visited an ED associated with a specialty hospital (surgical subspecialty, oncological, or Veterans Administration). By using geographic distribution information available from SPARCS and the NYC Office of Emergency Management evacuation zones, researchers were able to compare the ED utilization for older adults living in the evacuation zones before the landfall of Hurricane Sandy and in the weeks shortly after the storm.

The analysis revealed a significant increase in ED utilization for older adults living in the evacuation zones in the 3 weeks after the storm compared to ED use before the storm. The number of weekly ED visits by older adults from all evacuation zones was 9,852 in the weeks before Hurricane Sandy and increased in the first week after the storm to 10,073. Among the most severely impacted were older adults in evacuation zone one, where ED utilization increased from 552 visits to 1,111 visits. The number of ED visits remained elevated for 3 weeks after the storm but returned to normal by the fourth week.

Researchers suggested several reasons for this increase in ED visits, including seeking refuge in the ED as a result of homelessness due to the disaster, the interruption of ongoing care for chronic illness, environmental exposure, and the lack of preparation for the lasting effect of the disaster.

To improve the response to such a disaster in the future, a NYC Hurricane Sandy Assessment report² recommended developing a door-to-door service task force for older adults to improve preparedness for this vulnerable population. The task force would be responsible for implementing an action plan to ensure that healthcare services, communication, and provisions for this population continue without interruption in the weeks following a disaster. Legal and regulatory changes would allow for Medicare recipients to be eligible for "early medication refill" and pre-storm "early dialysis" programs to improve the continuity of care of the chronically ill.

1. Malik S, Lee DC, Doran KM, et al. Vulnerability of older adults in disasters: emergency department utilization by geriatric patients after hurricane sandy. Disaster Med Public Health Prep. 2017:1-10. doi:10.1017/dmp.2017.44

2. The City of New York, Office of the Mayor. Hurricane Sandy After Action Report. Published May 2013. http://www.nyc.gov/html/recovery/downlaods/pdf/sandy_aar_5.2.13.pdf. Accessed September 1, 2017.

Digital Rectal Examination of ED Patients with Acute GI Bleeding Cuts Rates of Admissions, Pharmacotherapy, and Endoscopy

BY JEFF BAUER

Patients presenting to the ED with acute gastrointestinal (GI) bleeding who receive a digital rectal examination have significantly lower rates of admissions, pharmacotherapy, and endoscopies, according to a retrospective study published in The American Journal of Medicine. Digital rectal examinations are an established part of the physical examination of a patient with GI bleeding, but physicians often are reluctant to conduct such examinations. Previous studies have found that 10% to 35% of patients with acute GI bleeding do not receive digital rectal examinations.

In the current study, researchers analyzed data from the electronic health records (EHRs) of patients ages 18 years and older who presented to the ED of a single institution with acute GI bleeding, as identified by International Classification of Diseases, Ninth Edition codes. They collected patients’ medical histories, demographic information, and clinical and laboratory data. ED clinician notes were used to determine which patients received a digital rectal examination. The outcomes researchers assessed were hospital admission, intensive care unit (ICU) admission, initiation of medical therapy (a proton pump inhibitor or octreotide), inpatient endoscopy (upper endoscopy or colonoscopy), and packed red blood cell (RBC) transfusion.

Overall, 1237 patients presented with acute GI bleeding. Most patients were Caucasian (49.2%) or Hispanic (38.4%), 44.9% were female, and the median age was 53 years.

Slightly more than one-half of patients (55.6%) received a digital rectal examination. In total, 736 patients were admitted—including 222 admissions to the ICU; 751 were started on a proton pump inhibitor or octreotide, 274 underwent endoscopy, and 321 received an RBC transfusion.

Patients were more likely to receive a digital rectal examination if they were older, Hispanic, or receiving an anticoagulant. Patients were less likely to undergo such examinations if they presented with altered mental status or hematemesis. Compared to patients who did not receive a digital rectal examination, those who did were significantly less likely to be admitted to the hospital (P = .004), to be starting on medical therapy (P = .04), or to undergo endoscopy (P = .02). There were no significant differences between these two groups in terms of ICU admissions, gastroenterology consultations, or transfusions.

Researchers suggested that the 44% rate of patients with acute GI bleeding who did not receive digital rectal examinations was higher than had been reported in previous studies. The difference had been the result of relying solely on ED clinician notes for this data, without including notes from admitting or consulting clinicians. The authors also were unable to determine the reasons these examinations were not conducted.

Shrestha MP, Borgstrom M, Trowers E. Digital rectal examination reduces hospital admissions, endoscopies, and medical therapy in patients with acute gastrointestinal bleeding. Am J Med. 2017;130(7):819-825. doi: 10.1016/j.amjmed.2017.01.036.

ED Visits by Older Patients Increase in the Weeks After a Disaster

BY KELLIE DESANTIS

Visits to an ED by adults ages 65 years and older increase significantly in the weeks following a disaster, according to a study published in Disaster Medicine and Public Health Preparedness.¹

Older adults are vulnerable to the effects of disasters because of their diminished ability to adequately prepare for and respond to the effects of a disaster. Older adults suffering from visual, auditory, proprioceptive, and cognitive impairments are especially vulnerable and have the most difficulty complying with evacuation and preparatory warnings. Individuals with multiple chronic diseases, living in long-term care facilities or suffering from cognitive impairments are among the most vulnerable.

To better understand the impact of natural disasters on this vulnerable population, researchers examined the effects of the 2012 disaster, Hurricane Sandy, on older adults living in New York City (NYC) during the disaster. Researchers turned to the New York State Department of Health (NYSDOH) for data. The NYSDOH compiles a comprehensive database of claims from all ED visits in the Statewide Planning and Research Cooperative System (SPARCS), which is the most complete source for ED utilization in New York state, and includes primary and secondary diagnosis codes and patient addresses.

Researchers evaluated ED utilization by adults 65 years and older in the weeks immediately before and after the Hurricane Sandy landfall. They excluded patients who lived in a nursing home, were incarcerated, or visited an ED associated with a specialty hospital (surgical subspecialty, oncological, or Veterans Administration). By using geographic distribution information available from SPARCS and the NYC Office of Emergency Management evacuation zones, researchers were able to compare the ED utilization for older adults living in the evacuation zones before the landfall of Hurricane Sandy and in the weeks shortly after the storm.

The analysis revealed a significant increase in ED utilization for older adults living in the evacuation zones in the 3 weeks after the storm compared to ED use before the storm. The number of weekly ED visits by older adults from all evacuation zones was 9,852 in the weeks before Hurricane Sandy and increased in the first week after the storm to 10,073. Among the most severely impacted were older adults in evacuation zone one, where ED utilization increased from 552 visits to 1,111 visits. The number of ED visits remained elevated for 3 weeks after the storm but returned to normal by the fourth week.

Researchers suggested several reasons for this increase in ED visits, including seeking refuge in the ED as a result of homelessness due to the disaster, the interruption of ongoing care for chronic illness, environmental exposure, and the lack of preparation for the lasting effect of the disaster.

To improve the response to such a disaster in the future, a NYC Hurricane Sandy Assessment report² recommended developing a door-to-door service task force for older adults to improve preparedness for this vulnerable population. The task force would be responsible for implementing an action plan to ensure that healthcare services, communication, and provisions for this population continue without interruption in the weeks following a disaster. Legal and regulatory changes would allow for Medicare recipients to be eligible for "early medication refill" and pre-storm "early dialysis" programs to improve the continuity of care of the chronically ill.

1. Malik S, Lee DC, Doran KM, et al. Vulnerability of older adults in disasters: emergency department utilization by geriatric patients after hurricane sandy. Disaster Med Public Health Prep. 2017:1-10. doi:10.1017/dmp.2017.44

2. The City of New York, Office of the Mayor. Hurricane Sandy After Action Report. Published May 2013. http://www.nyc.gov/html/recovery/downlaods/pdf/sandy_aar_5.2.13.pdf. Accessed September 1, 2017.

Digital Rectal Examination of ED Patients with Acute GI Bleeding Cuts Rates of Admissions, Pharmacotherapy, and Endoscopy

BY JEFF BAUER

Patients presenting to the ED with acute gastrointestinal (GI) bleeding who receive a digital rectal examination have significantly lower rates of admissions, pharmacotherapy, and endoscopies, according to a retrospective study published in The American Journal of Medicine. Digital rectal examinations are an established part of the physical examination of a patient with GI bleeding, but physicians often are reluctant to conduct such examinations. Previous studies have found that 10% to 35% of patients with acute GI bleeding do not receive digital rectal examinations.

In the current study, researchers analyzed data from the electronic health records (EHRs) of patients ages 18 years and older who presented to the ED of a single institution with acute GI bleeding, as identified by International Classification of Diseases, Ninth Edition codes. They collected patients’ medical histories, demographic information, and clinical and laboratory data. ED clinician notes were used to determine which patients received a digital rectal examination. The outcomes researchers assessed were hospital admission, intensive care unit (ICU) admission, initiation of medical therapy (a proton pump inhibitor or octreotide), inpatient endoscopy (upper endoscopy or colonoscopy), and packed red blood cell (RBC) transfusion.

Overall, 1237 patients presented with acute GI bleeding. Most patients were Caucasian (49.2%) or Hispanic (38.4%), 44.9% were female, and the median age was 53 years.

Slightly more than one-half of patients (55.6%) received a digital rectal examination. In total, 736 patients were admitted—including 222 admissions to the ICU; 751 were started on a proton pump inhibitor or octreotide, 274 underwent endoscopy, and 321 received an RBC transfusion.

Patients were more likely to receive a digital rectal examination if they were older, Hispanic, or receiving an anticoagulant. Patients were less likely to undergo such examinations if they presented with altered mental status or hematemesis. Compared to patients who did not receive a digital rectal examination, those who did were significantly less likely to be admitted to the hospital (P = .004), to be starting on medical therapy (P = .04), or to undergo endoscopy (P = .02). There were no significant differences between these two groups in terms of ICU admissions, gastroenterology consultations, or transfusions.

Researchers suggested that the 44% rate of patients with acute GI bleeding who did not receive digital rectal examinations was higher than had been reported in previous studies. The difference had been the result of relying solely on ED clinician notes for this data, without including notes from admitting or consulting clinicians. The authors also were unable to determine the reasons these examinations were not conducted.

Shrestha MP, Borgstrom M, Trowers E. Digital rectal examination reduces hospital admissions, endoscopies, and medical therapy in patients with acute gastrointestinal bleeding. Am J Med. 2017;130(7):819-825. doi: 10.1016/j.amjmed.2017.01.036.

Following the successful use of ambulances during the Civil War to transport wounded soldiers from the battlefield to safer and better equipped field hospital facilities, many communities adopted the practice for their civilian populations. Between the Civil War and World War II (WWII) "teaching hospitals" sent interns on their ambulances both to improve patient care at the scene, and to further their interns’ postgraduate education. However, as described by Ryan Corbett Bell in his book The Ambulance (Jefferson, NC: McFarland; 2009), by the 1930s, relatively poor reimbursement for ambulance calls followed by the severe doctor shortage due to WWII, effectively ended this practice. Though the interns were initially replaced by "ambulance attendants" or "orderlies," since the 1960s, ambulances have been staffed by trained EMTs and (later) paramedics to provide basic and advanced prehospital care both at the scene and during transport. For almost half a century, paramedics operating with standing protocols and physician medical control have conclusively demonstrated their ability to improve care and save lives.

At present, the increased demand for access to medical care brought about by the Affordable Care Act, an aging homebound population, overcrowded EDs, and inpatient services filled to capacity, along with, in some areas, insufficient numbers of visiting nurses, NPs, and PAs to provide needed home care services, prompted many to consider expanding the role of paramedics and EMTs to provide "community paramedicine," without afterward requiring them to transport patients to hospitals.

Community paramedicine was defined in 2012 by the US Department of Health and Human Services Administration as "an emerging field in health care where EMTs and Paramedics operate in expanded roles in an effort to connect underutilized resources to underserved populations" (https://www.hrsa.gov). A standard curriculum consisting of 114 hours of education in social determinants of health, public health, and tailored learning about chronic diseases, together with 200 hours of laboratory and clinical experiences has been developed and made available free of charge to colleges and universities (https://www.ruralhealthinfo.org).

Among the many individuals and organizations weighing in on the subject of community paramedicine, the American College of Emergency Physicians 2015 policy statement supports the development of properly designed expanded scope of practice programs for EMS personnel with medical oversight, that do not compromise existing emergency response systems (https://www.acep.org/). Dr Bryan Bledsoe, an editorial board member of JEMS (Journal of Emergency Medical Services), provides a thoughtful analysis of the pros and cons of community paramedicine (http://www.jems.com), hile Iyah K. Romm and colleagues, writing in the NEJM Catalyst, offer concrete evidence of the effectiveness of one such mobile integrated healthcare and community paramedicine program (http://catalyst.nejm.org).

Properly trained, experienced paramedics with careful supervision by emergency medical control physicians and consultation with the patients’ primary care physicians, supported by telemedicine and bedside diagnostic tests, can provide essential care in a patient’s home environment. Depending on local circumstances, EMTs and paramedics can provide that care 24/7, supplementing other available home health care to support posthospital-discharge care for congestive heart failure, wound healing, etc, obviating the need for repeated ED and clinic visits or hospitalizations.

In addition to patient benefits, community paramedicine offers an opportunity for experienced paramedics to extend their years of practice similar to the way urgent care clinics have enabled experienced EPs to extend theirs. For all of these reasons, we support an expanded role for EMTs and paramedics in safe, carefully planned community paramedicine programs.

Following the successful use of ambulances during the Civil War to transport wounded soldiers from the battlefield to safer and better equipped field hospital facilities, many communities adopted the practice for their civilian populations. Between the Civil War and World War II (WWII) "teaching hospitals" sent interns on their ambulances both to improve patient care at the scene, and to further their interns’ postgraduate education. However, as described by Ryan Corbett Bell in his book The Ambulance (Jefferson, NC: McFarland; 2009), by the 1930s, relatively poor reimbursement for ambulance calls followed by the severe doctor shortage due to WWII, effectively ended this practice. Though the interns were initially replaced by "ambulance attendants" or "orderlies," since the 1960s, ambulances have been staffed by trained EMTs and (later) paramedics to provide basic and advanced prehospital care both at the scene and during transport. For almost half a century, paramedics operating with standing protocols and physician medical control have conclusively demonstrated their ability to improve care and save lives.

At present, the increased demand for access to medical care brought about by the Affordable Care Act, an aging homebound population, overcrowded EDs, and inpatient services filled to capacity, along with, in some areas, insufficient numbers of visiting nurses, NPs, and PAs to provide needed home care services, prompted many to consider expanding the role of paramedics and EMTs to provide "community paramedicine," without afterward requiring them to transport patients to hospitals.

Community paramedicine was defined in 2012 by the US Department of Health and Human Services Administration as "an emerging field in health care where EMTs and Paramedics operate in expanded roles in an effort to connect underutilized resources to underserved populations" (https://www.hrsa.gov). A standard curriculum consisting of 114 hours of education in social determinants of health, public health, and tailored learning about chronic diseases, together with 200 hours of laboratory and clinical experiences has been developed and made available free of charge to colleges and universities (https://www.ruralhealthinfo.org).

Among the many individuals and organizations weighing in on the subject of community paramedicine, the American College of Emergency Physicians 2015 policy statement supports the development of properly designed expanded scope of practice programs for EMS personnel with medical oversight, that do not compromise existing emergency response systems (https://www.acep.org/). Dr Bryan Bledsoe, an editorial board member of JEMS (Journal of Emergency Medical Services), provides a thoughtful analysis of the pros and cons of community paramedicine (http://www.jems.com), hile Iyah K. Romm and colleagues, writing in the NEJM Catalyst, offer concrete evidence of the effectiveness of one such mobile integrated healthcare and community paramedicine program (http://catalyst.nejm.org).

Properly trained, experienced paramedics with careful supervision by emergency medical control physicians and consultation with the patients’ primary care physicians, supported by telemedicine and bedside diagnostic tests, can provide essential care in a patient’s home environment. Depending on local circumstances, EMTs and paramedics can provide that care 24/7, supplementing other available home health care to support posthospital-discharge care for congestive heart failure, wound healing, etc, obviating the need for repeated ED and clinic visits or hospitalizations.

In addition to patient benefits, community paramedicine offers an opportunity for experienced paramedics to extend their years of practice similar to the way urgent care clinics have enabled experienced EPs to extend theirs. For all of these reasons, we support an expanded role for EMTs and paramedics in safe, carefully planned community paramedicine programs.

Following the successful use of ambulances during the Civil War to transport wounded soldiers from the battlefield to safer and better equipped field hospital facilities, many communities adopted the practice for their civilian populations. Between the Civil War and World War II (WWII) "teaching hospitals" sent interns on their ambulances both to improve patient care at the scene, and to further their interns’ postgraduate education. However, as described by Ryan Corbett Bell in his book The Ambulance (Jefferson, NC: McFarland; 2009), by the 1930s, relatively poor reimbursement for ambulance calls followed by the severe doctor shortage due to WWII, effectively ended this practice. Though the interns were initially replaced by "ambulance attendants" or "orderlies," since the 1960s, ambulances have been staffed by trained EMTs and (later) paramedics to provide basic and advanced prehospital care both at the scene and during transport. For almost half a century, paramedics operating with standing protocols and physician medical control have conclusively demonstrated their ability to improve care and save lives.

At present, the increased demand for access to medical care brought about by the Affordable Care Act, an aging homebound population, overcrowded EDs, and inpatient services filled to capacity, along with, in some areas, insufficient numbers of visiting nurses, NPs, and PAs to provide needed home care services, prompted many to consider expanding the role of paramedics and EMTs to provide "community paramedicine," without afterward requiring them to transport patients to hospitals.

Community paramedicine was defined in 2012 by the US Department of Health and Human Services Administration as "an emerging field in health care where EMTs and Paramedics operate in expanded roles in an effort to connect underutilized resources to underserved populations" (https://www.hrsa.gov). A standard curriculum consisting of 114 hours of education in social determinants of health, public health, and tailored learning about chronic diseases, together with 200 hours of laboratory and clinical experiences has been developed and made available free of charge to colleges and universities (https://www.ruralhealthinfo.org).

Among the many individuals and organizations weighing in on the subject of community paramedicine, the American College of Emergency Physicians 2015 policy statement supports the development of properly designed expanded scope of practice programs for EMS personnel with medical oversight, that do not compromise existing emergency response systems (https://www.acep.org/). Dr Bryan Bledsoe, an editorial board member of JEMS (Journal of Emergency Medical Services), provides a thoughtful analysis of the pros and cons of community paramedicine (http://www.jems.com), hile Iyah K. Romm and colleagues, writing in the NEJM Catalyst, offer concrete evidence of the effectiveness of one such mobile integrated healthcare and community paramedicine program (http://catalyst.nejm.org).

Properly trained, experienced paramedics with careful supervision by emergency medical control physicians and consultation with the patients’ primary care physicians, supported by telemedicine and bedside diagnostic tests, can provide essential care in a patient’s home environment. Depending on local circumstances, EMTs and paramedics can provide that care 24/7, supplementing other available home health care to support posthospital-discharge care for congestive heart failure, wound healing, etc, obviating the need for repeated ED and clinic visits or hospitalizations.

In addition to patient benefits, community paramedicine offers an opportunity for experienced paramedics to extend their years of practice similar to the way urgent care clinics have enabled experienced EPs to extend theirs. For all of these reasons, we support an expanded role for EMTs and paramedics in safe, carefully planned community paramedicine programs.

In 2014 the suicide rate in the U.S. was 13/100,000, the highest recorded in 28 years.¹ Suicide is now considered the 10th leading cause of death for all ages, and the rate has increased every year from 2000 to 2014 among both women and men and in every age group except those aged ≥ 75 years.^1-3 For those aged 15 to 44 years, suicide is among the top 3 causes of death worldwide.^4-6

Background

In 2013, more than 490,000 hospital visits related to suicide attempts were reported in the U.S.⁴ Health care expenditures related to suicide are estimated at $56.9 billion in combined medical and work loss costs annually and an unmeasurable cost to the affected families.⁷ The mental health care community is desperate for ways to address this epidemic, and the National Academies of Medicine (NAM) has declared that research that directly addresses comparative effectiveness of treatment strategies following a suicide attempt should be a national priority.⁸

The most recent reports from 2014 indicate that the suicide rates are higher for male veterans than for male nonveterans (32.1 vs 20.9 per 100,000, respectively) and are much higher for female veterans than for female nonveterans (28.7 vs 5.2 per 100,000, respectively).³ Suicide rates also may be associated with veteran-specific comorbidities, such as higher rates of depression, anxiety, posttraumatic stress disorder (PTSD), and war-related trauma.³ According to the VHA, the suicide rate for veterans aged > 30 years also is rapidly increasing, and VHA has echoed the calls from NAM to make suicide prevention research a national priority.³

The VA has tried to stem the tide of suicides in veterans by implementing many advances in suicide prevention, including hiring suicide prevention coordinators at every VA hospital, enhanced monitoring, and the availability of 24-hour crisis hotline services. Yet the suicide rates for veterans continue to rise and remain higher than the rates in the general population.³

About 90% of deaths by suicide are by persons who have a treatable psychiatric disorder, most commonly a mood disorder, such as depression.⁴ However, most studies show that antidepressant therapy does not provide rapid or significant relief of suicidal ideation (SI).⁴ Therefore, the current standard of care for the treatment of acutely suicidal patients includes a combination of hospitalization, cognitive behavioral therapy or psychotherapy, case management, antidepressant medications, and electroconvulsive therapy (ECT).⁴ Even though these therapies have become more widely available over the past decade, rates of suicide continue to increase.^1,4 These interventions have limited effectiveness in acute settings. Although both intensive outpatient follow-up and routine outpatient care have been studied in relation to the decrease of suicidal behavior, neither intervention has been shown to immediately reduce suicidal behavior significantly in patients.

Suicidality Interventions

Therapy and case management require patients to be well enough to make office visits and follow through with care for periods as long as 1 year, which is often not possible for individuals with severe depression.⁵ One-third of patients who attended 6 months of outpatient therapy consistently still met the criteria for major depressive disorder (MDD), a major risk for suicide attempt.⁹ Antidepressant medications take a minimum of 4 weeks to reach full efficacy, and many patients stop taking the medications before that point because of concern that the medication is not helping or because of adverse effects (AEs), such as sleep disturbance, sexual dysfunction, or weight gain.⁹

Electroconvulsive therapy has been shown to be an effective treatment for patients with depression and suicidal behavior, but adherence with 12 weeks of recommended therapy has been a barrier for this intervention. Additionally, ECT may not provide reduction in SI for 1 to 2 weeks.^4,10 A review of research studies showed that nearly 50% of patients with high-expressed SI did not complete the prescribed amount of ECT due to the length of time to complete the recommended 12 sessions.¹⁰ Therefore, current treatment barriers for suicidal patients include: (1) long periods in treatment for therapy, medication, and ECT before any relief of symptoms is noted; (2) high recidivism rates for MDD symptoms and risk of suicide following treatment; and (3) high treatment dropout rates.

Pharmacologic treatments currently used in suicidal patients have not fared much better. Many have received FDA approval for treatment of associated mental health diagnoses such as bipolar disorder, schizophrenia, or MDD, but there are no approved treatments that specifically target suicidal behavior. Lithium is approved for reducing the long-term risk of SI primarily because it reduces the risk of mood disorders associated with SI, but lithium has not been shown to be effective in acute settings.¹¹ Clozapine is approved for reducing the long-term risk of recurrent suicide in patients with schizophrenia or schizoaffective disorder.⁴ Clozapine has not been shown to be effective in patients with mood disorders, which make up the majority of patients who attempt suicide.⁴ Additionally, both medications are plagued by the same barriers listed earlier, such as long time to effect (it takes an average 4 weeks to reach efficacy), lack of efficacy in acute settings, and AEs (eg, sleep problems, weight gain, and sexual dysfunction).⁹ Thus finding better pharmacologic interventions for suicidal patients is a priority for current research.

Ketamine

Recently, researchers have identified ketamine as a potential therapeutic option for depression and SI. A single ketamine infusion treatment has a rapid response, minimal AEs, and potentially long-lasting efficacy with SI, which would make it ideal for the treatment of acutely suicidal patients.⁴ Ketamine is an N-methyl-D-aspartate receptor (NMDAR) inhibitor that also has been found to be a weak μ- and κ-opioid receptor agonist and an inhibitor of the reuptake of serotonin, dopamine, and norepinephrine. Inhibition of the NMDAR results in analgesia, and ketamine is approved for the induction of anesthesia, pain relief, and sedation.¹²

Although AEs such as hallucinations and sedation create the potential for dangerous recreational use, ketamine is safely used in health care settings for a variety of indications. Effects are noted within 5 minutes of administration if given by infusion, and the main effects can last between 20 and 40 minutes.

Ketamine has a complex pharmacology and plays a role in other cell signaling mechanisms, but the significance of these additional mechanisms in the therapeutic effects of ketamine have only recently been elucidated. Preclinical studies indicate a probable NMDAR inhibition-independent mechanism responsible for the antidepressant response to ketamine.^13,14 The complex associations with rapamycin signaling, eukaryotic elongation factor 2 dephosphorylation, increased synthesis of brain-derived neurotrophic factor, and activation of glutamatergic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors have been linked to its rapid antidepressant effect and ketamine’s induction of synaptogenesis within the limbic system.^13,14

Clinical Research

Ketamine was studied as an adjunctive treatment to psychotherapy for addictions as far back as the 1970s.¹⁵ The available reports indicate a universally positive result, with increased rates of remission and decreased rates of relapse attributed to ketamine’s ability to alter one’s thought processes by reinforcing limbic-cortex interactions that facilitate the growth of more positive cognitive schemas and improved emotional attitudes about the self in support of the recovery process.¹⁵

Neurobiologic studies have shown that treatment with ketamine has a direct and immediate effect on neuronal pathways of the limbic system. It is known to regulate the mind’s reaction to positive stimuli by reversing the depressed subject’s blunted reaction to positive faces.¹⁶ This rapid normalization of the positive faces test is unique to ketamine infusion and is not seen in tests with traditional antidepressants.

In 2000, the first placebo-controlled trial using ketamine for treatment resistant depression (TRD) demonstrated the rapid antidepressant effects of a single dose of ketamine, but this study only looked at these effects for 1 week.¹⁷ In multiple double blind, placebo-controlled trials since then, IV infusion of ketamine was shown to be an effective intervention for TRD.^13,18,19 More recently, a published investigation involving the treatment of MDD showed that ketamine in conjunction with a selective serotonin reuptake inhibitor (SSRI) accelerated and enhanced the effectiveness of the SSRI in reducing depressive symptoms.²⁰

Based on the rapid resolution of depressive symptoms using ketamine, researchers have looked at its effect on suicidality as a secondary measure. A case study of a patient with severe depressive episodes and multiple previous suicidal attempts reported that the patient responded to a single dose of ketamine, described the experience as “being reborn,” and maintained complete remission of SI for the 6-month study period.²¹ In a larger study, 133 TRD patients received a single IV dose of ketamine with significant reductions in SI independent of depressive and anxiety symptoms.²²

Depression Treatment

These results have led to an excitement for ketamine therapy as a novel treatment of depression, and off-label use by treatment centers now exists in several countries to aid those with TRD.²³ This off-label use continues to be controversial, as research has yet to determine the safest most effective route and duration of treatment and whether the ketamine treatment AEs will exceed any accrued therapeutic benefit.¹³

The American Psychological Association Council of Research Task Force on Novel Biomarkers and Treatment critically examined the clinical evidence of ketamine use and has raised important concerns about the use of ketamine in the outpatient setting, administered in the absence of consensus therapeutic monitoring guidelines, and ambitiously marketed as a panacea for TRD.^13,24 A study showed permanent impairment of brain function for both groups compared with monkeys treated with saline infusions.²⁵ In 2016, the FDA gave fast-track approval for an intranasal ketamine that would make the treatment more easily available in the outpatient setting, but this could lead to certain patients developing a dependency on ketamine or engaging in its diversion for recreational use. There are case reports and anecdotes in the literature of patients and research subjects developing drug-seeking behaviors and overuse of ketamine.²⁴ Additionally, the comorbidities associated with TRD and SI have not been fully evaluated. For instance, there is evidence that depressed patients with obsessive compulsive disorder may have worse outcomes that include delayed onset SI.²⁶

There also is concern for the use of ketamine for chronic opioid users. The combination of ketamine with opioids may increase the response to the opioid in an otherwise drug tolerant patient, leading to risk of death by overdose in patients who have not increased their usual dose.²⁷ However, this effect was noted only when ketamine and opioids were administered together, and the effect does not seem to last postinfusion.²⁷

The challenges in treatment of TRD include finding an effective formulation—IV infusion of ketamine requires cardiovascular monitoring and is administered by anesthesiologists. The short duration of action for depression requires repeated infusions, and the frequency and quantity of infusions have not been determined. Efforts to find other NMDAR inhibitors (eg, memantine, nitrous oxide, D-cycloserine, and others) that match ketamine’s antidepressant efficacy but with easier delivery methods and fewer risks have thus far been unsuccessful.¹³ It is now believed that ketamine’s unique ability to activate intracellular signaling pathways linked to synaptic plasticity gives it the antidepressant function. Recent studies have further narrowed ketamine’s antidepressant function to the R- enantiomer of the ketamine metabolite, hydroxynorketamine.¹⁴ The nasal spray for ketamine is the S- enantiomer, which has better bioavailability but may have less antidepressant efficacy compared with the racemic mixture used in ketamine infusions.

Suicide Ideation Treatment

The many challenges faced by researchers and clinicians trying to develop ketamine treatment for TRD may not apply to the treatment of SI. Whereas repeated doses of ketamine cannot reliably produce sustained remission of depression, the few studies that have looked at the long-term effects of ketamine treatment on SI indicate the potential for long-term efficacy after a single IV infusion.^21,22 Although treatment with IV infusions have additional costs and logistics, if it is found beneficial, it could be given in the emergency department (ED) prior to hospitalization and potentially lead to better outcomes.

In 2011, a small preliminary observational study of patients with depression and SI presenting to the ED indicated that SI was rapidly reduced following an infusion of ketamine.²⁸ This study showed that both depressive symptoms and suicidality rapidly and significantly diminished within 40 minutes with no evidence of the recurrence of symptoms 10 days postadministration.

A more recent study used ketamine in a military field hospital to treat SI and also concluded that it could be effective and safe when administered in an ED setting. This preliminary study suggests that ketamine could be a safe and potentially effective medication for rapid reduction of depression and suicidality in a busy ED setting.²⁹ These limited studies involving the use of ketamine in patients with SI show promise with long-term effectiveness. However, more research is needed to clarify whether the efficacy with SI will be similar to the clinical experience seen in TRD; a duration of effect limited to 2 weeks with recurrence after treatment discontinued.²⁴

Conclusion

There has been a compelling accumulation of scientific data since 2000 to support the use of ketamine for the treatment of depression and SI. Ketamine use in patients with these diagnoses showed a rapid decrease of symptoms and minimal AEs among a significant number of patients.^22,30

Although the initial findings involving the use of ketamine in suicidal patients are promising, the clinical use of ketamine needs further research, using larger sample sizes and exploring both the short-term and long-term effects of this medication. Researchers need to further establish the safe and effective route, point of care, and patient type that would best respond to this novel treatment. The initial evidence would suggest that health care providers have every right to be hopeful that ketamine will become the first pharmacologic treatment of acute SI in a majority of patients presenting to EDs, mental health clinics, community hospitals, and VA medical centers.

In 2014 the suicide rate in the U.S. was 13/100,000, the highest recorded in 28 years.¹ Suicide is now considered the 10th leading cause of death for all ages, and the rate has increased every year from 2000 to 2014 among both women and men and in every age group except those aged ≥ 75 years.^1-3 For those aged 15 to 44 years, suicide is among the top 3 causes of death worldwide.^4-6

Background

In 2013, more than 490,000 hospital visits related to suicide attempts were reported in the U.S.⁴ Health care expenditures related to suicide are estimated at $56.9 billion in combined medical and work loss costs annually and an unmeasurable cost to the affected families.⁷ The mental health care community is desperate for ways to address this epidemic, and the National Academies of Medicine (NAM) has declared that research that directly addresses comparative effectiveness of treatment strategies following a suicide attempt should be a national priority.⁸

The most recent reports from 2014 indicate that the suicide rates are higher for male veterans than for male nonveterans (32.1 vs 20.9 per 100,000, respectively) and are much higher for female veterans than for female nonveterans (28.7 vs 5.2 per 100,000, respectively).³ Suicide rates also may be associated with veteran-specific comorbidities, such as higher rates of depression, anxiety, posttraumatic stress disorder (PTSD), and war-related trauma.³ According to the VHA, the suicide rate for veterans aged > 30 years also is rapidly increasing, and VHA has echoed the calls from NAM to make suicide prevention research a national priority.³

The VA has tried to stem the tide of suicides in veterans by implementing many advances in suicide prevention, including hiring suicide prevention coordinators at every VA hospital, enhanced monitoring, and the availability of 24-hour crisis hotline services. Yet the suicide rates for veterans continue to rise and remain higher than the rates in the general population.³

About 90% of deaths by suicide are by persons who have a treatable psychiatric disorder, most commonly a mood disorder, such as depression.⁴ However, most studies show that antidepressant therapy does not provide rapid or significant relief of suicidal ideation (SI).⁴ Therefore, the current standard of care for the treatment of acutely suicidal patients includes a combination of hospitalization, cognitive behavioral therapy or psychotherapy, case management, antidepressant medications, and electroconvulsive therapy (ECT).⁴ Even though these therapies have become more widely available over the past decade, rates of suicide continue to increase.^1,4 These interventions have limited effectiveness in acute settings. Although both intensive outpatient follow-up and routine outpatient care have been studied in relation to the decrease of suicidal behavior, neither intervention has been shown to immediately reduce suicidal behavior significantly in patients.

Suicidality Interventions

Therapy and case management require patients to be well enough to make office visits and follow through with care for periods as long as 1 year, which is often not possible for individuals with severe depression.⁵ One-third of patients who attended 6 months of outpatient therapy consistently still met the criteria for major depressive disorder (MDD), a major risk for suicide attempt.⁹ Antidepressant medications take a minimum of 4 weeks to reach full efficacy, and many patients stop taking the medications before that point because of concern that the medication is not helping or because of adverse effects (AEs), such as sleep disturbance, sexual dysfunction, or weight gain.⁹

Electroconvulsive therapy has been shown to be an effective treatment for patients with depression and suicidal behavior, but adherence with 12 weeks of recommended therapy has been a barrier for this intervention. Additionally, ECT may not provide reduction in SI for 1 to 2 weeks.^4,10 A review of research studies showed that nearly 50% of patients with high-expressed SI did not complete the prescribed amount of ECT due to the length of time to complete the recommended 12 sessions.¹⁰ Therefore, current treatment barriers for suicidal patients include: (1) long periods in treatment for therapy, medication, and ECT before any relief of symptoms is noted; (2) high recidivism rates for MDD symptoms and risk of suicide following treatment; and (3) high treatment dropout rates.

Pharmacologic treatments currently used in suicidal patients have not fared much better. Many have received FDA approval for treatment of associated mental health diagnoses such as bipolar disorder, schizophrenia, or MDD, but there are no approved treatments that specifically target suicidal behavior. Lithium is approved for reducing the long-term risk of SI primarily because it reduces the risk of mood disorders associated with SI, but lithium has not been shown to be effective in acute settings.¹¹ Clozapine is approved for reducing the long-term risk of recurrent suicide in patients with schizophrenia or schizoaffective disorder.⁴ Clozapine has not been shown to be effective in patients with mood disorders, which make up the majority of patients who attempt suicide.⁴ Additionally, both medications are plagued by the same barriers listed earlier, such as long time to effect (it takes an average 4 weeks to reach efficacy), lack of efficacy in acute settings, and AEs (eg, sleep problems, weight gain, and sexual dysfunction).⁹ Thus finding better pharmacologic interventions for suicidal patients is a priority for current research.

Ketamine

Recently, researchers have identified ketamine as a potential therapeutic option for depression and SI. A single ketamine infusion treatment has a rapid response, minimal AEs, and potentially long-lasting efficacy with SI, which would make it ideal for the treatment of acutely suicidal patients.⁴ Ketamine is an N-methyl-D-aspartate receptor (NMDAR) inhibitor that also has been found to be a weak μ- and κ-opioid receptor agonist and an inhibitor of the reuptake of serotonin, dopamine, and norepinephrine. Inhibition of the NMDAR results in analgesia, and ketamine is approved for the induction of anesthesia, pain relief, and sedation.¹²

Although AEs such as hallucinations and sedation create the potential for dangerous recreational use, ketamine is safely used in health care settings for a variety of indications. Effects are noted within 5 minutes of administration if given by infusion, and the main effects can last between 20 and 40 minutes.

Ketamine has a complex pharmacology and plays a role in other cell signaling mechanisms, but the significance of these additional mechanisms in the therapeutic effects of ketamine have only recently been elucidated. Preclinical studies indicate a probable NMDAR inhibition-independent mechanism responsible for the antidepressant response to ketamine.^13,14 The complex associations with rapamycin signaling, eukaryotic elongation factor 2 dephosphorylation, increased synthesis of brain-derived neurotrophic factor, and activation of glutamatergic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors have been linked to its rapid antidepressant effect and ketamine’s induction of synaptogenesis within the limbic system.^13,14

Clinical Research

Ketamine was studied as an adjunctive treatment to psychotherapy for addictions as far back as the 1970s.¹⁵ The available reports indicate a universally positive result, with increased rates of remission and decreased rates of relapse attributed to ketamine’s ability to alter one’s thought processes by reinforcing limbic-cortex interactions that facilitate the growth of more positive cognitive schemas and improved emotional attitudes about the self in support of the recovery process.¹⁵

Neurobiologic studies have shown that treatment with ketamine has a direct and immediate effect on neuronal pathways of the limbic system. It is known to regulate the mind’s reaction to positive stimuli by reversing the depressed subject’s blunted reaction to positive faces.¹⁶ This rapid normalization of the positive faces test is unique to ketamine infusion and is not seen in tests with traditional antidepressants.

In 2000, the first placebo-controlled trial using ketamine for treatment resistant depression (TRD) demonstrated the rapid antidepressant effects of a single dose of ketamine, but this study only looked at these effects for 1 week.¹⁷ In multiple double blind, placebo-controlled trials since then, IV infusion of ketamine was shown to be an effective intervention for TRD.^13,18,19 More recently, a published investigation involving the treatment of MDD showed that ketamine in conjunction with a selective serotonin reuptake inhibitor (SSRI) accelerated and enhanced the effectiveness of the SSRI in reducing depressive symptoms.²⁰

Based on the rapid resolution of depressive symptoms using ketamine, researchers have looked at its effect on suicidality as a secondary measure. A case study of a patient with severe depressive episodes and multiple previous suicidal attempts reported that the patient responded to a single dose of ketamine, described the experience as “being reborn,” and maintained complete remission of SI for the 6-month study period.²¹ In a larger study, 133 TRD patients received a single IV dose of ketamine with significant reductions in SI independent of depressive and anxiety symptoms.²²

Depression Treatment

These results have led to an excitement for ketamine therapy as a novel treatment of depression, and off-label use by treatment centers now exists in several countries to aid those with TRD.²³ This off-label use continues to be controversial, as research has yet to determine the safest most effective route and duration of treatment and whether the ketamine treatment AEs will exceed any accrued therapeutic benefit.¹³

The American Psychological Association Council of Research Task Force on Novel Biomarkers and Treatment critically examined the clinical evidence of ketamine use and has raised important concerns about the use of ketamine in the outpatient setting, administered in the absence of consensus therapeutic monitoring guidelines, and ambitiously marketed as a panacea for TRD.^13,24 A study showed permanent impairment of brain function for both groups compared with monkeys treated with saline infusions.²⁵ In 2016, the FDA gave fast-track approval for an intranasal ketamine that would make the treatment more easily available in the outpatient setting, but this could lead to certain patients developing a dependency on ketamine or engaging in its diversion for recreational use. There are case reports and anecdotes in the literature of patients and research subjects developing drug-seeking behaviors and overuse of ketamine.²⁴ Additionally, the comorbidities associated with TRD and SI have not been fully evaluated. For instance, there is evidence that depressed patients with obsessive compulsive disorder may have worse outcomes that include delayed onset SI.²⁶

There also is concern for the use of ketamine for chronic opioid users. The combination of ketamine with opioids may increase the response to the opioid in an otherwise drug tolerant patient, leading to risk of death by overdose in patients who have not increased their usual dose.²⁷ However, this effect was noted only when ketamine and opioids were administered together, and the effect does not seem to last postinfusion.²⁷

The challenges in treatment of TRD include finding an effective formulation—IV infusion of ketamine requires cardiovascular monitoring and is administered by anesthesiologists. The short duration of action for depression requires repeated infusions, and the frequency and quantity of infusions have not been determined. Efforts to find other NMDAR inhibitors (eg, memantine, nitrous oxide, D-cycloserine, and others) that match ketamine’s antidepressant efficacy but with easier delivery methods and fewer risks have thus far been unsuccessful.¹³ It is now believed that ketamine’s unique ability to activate intracellular signaling pathways linked to synaptic plasticity gives it the antidepressant function. Recent studies have further narrowed ketamine’s antidepressant function to the R- enantiomer of the ketamine metabolite, hydroxynorketamine.¹⁴ The nasal spray for ketamine is the S- enantiomer, which has better bioavailability but may have less antidepressant efficacy compared with the racemic mixture used in ketamine infusions.

Suicide Ideation Treatment

The many challenges faced by researchers and clinicians trying to develop ketamine treatment for TRD may not apply to the treatment of SI. Whereas repeated doses of ketamine cannot reliably produce sustained remission of depression, the few studies that have looked at the long-term effects of ketamine treatment on SI indicate the potential for long-term efficacy after a single IV infusion.^21,22 Although treatment with IV infusions have additional costs and logistics, if it is found beneficial, it could be given in the emergency department (ED) prior to hospitalization and potentially lead to better outcomes.

In 2011, a small preliminary observational study of patients with depression and SI presenting to the ED indicated that SI was rapidly reduced following an infusion of ketamine.²⁸ This study showed that both depressive symptoms and suicidality rapidly and significantly diminished within 40 minutes with no evidence of the recurrence of symptoms 10 days postadministration.

A more recent study used ketamine in a military field hospital to treat SI and also concluded that it could be effective and safe when administered in an ED setting. This preliminary study suggests that ketamine could be a safe and potentially effective medication for rapid reduction of depression and suicidality in a busy ED setting.²⁹ These limited studies involving the use of ketamine in patients with SI show promise with long-term effectiveness. However, more research is needed to clarify whether the efficacy with SI will be similar to the clinical experience seen in TRD; a duration of effect limited to 2 weeks with recurrence after treatment discontinued.²⁴

Conclusion

There has been a compelling accumulation of scientific data since 2000 to support the use of ketamine for the treatment of depression and SI. Ketamine use in patients with these diagnoses showed a rapid decrease of symptoms and minimal AEs among a significant number of patients.^22,30

Although the initial findings involving the use of ketamine in suicidal patients are promising, the clinical use of ketamine needs further research, using larger sample sizes and exploring both the short-term and long-term effects of this medication. Researchers need to further establish the safe and effective route, point of care, and patient type that would best respond to this novel treatment. The initial evidence would suggest that health care providers have every right to be hopeful that ketamine will become the first pharmacologic treatment of acute SI in a majority of patients presenting to EDs, mental health clinics, community hospitals, and VA medical centers.

In 2014 the suicide rate in the U.S. was 13/100,000, the highest recorded in 28 years.¹ Suicide is now considered the 10th leading cause of death for all ages, and the rate has increased every year from 2000 to 2014 among both women and men and in every age group except those aged ≥ 75 years.^1-3 For those aged 15 to 44 years, suicide is among the top 3 causes of death worldwide.^4-6

Background

In 2013, more than 490,000 hospital visits related to suicide attempts were reported in the U.S.⁴ Health care expenditures related to suicide are estimated at $56.9 billion in combined medical and work loss costs annually and an unmeasurable cost to the affected families.⁷ The mental health care community is desperate for ways to address this epidemic, and the National Academies of Medicine (NAM) has declared that research that directly addresses comparative effectiveness of treatment strategies following a suicide attempt should be a national priority.⁸

The most recent reports from 2014 indicate that the suicide rates are higher for male veterans than for male nonveterans (32.1 vs 20.9 per 100,000, respectively) and are much higher for female veterans than for female nonveterans (28.7 vs 5.2 per 100,000, respectively).³ Suicide rates also may be associated with veteran-specific comorbidities, such as higher rates of depression, anxiety, posttraumatic stress disorder (PTSD), and war-related trauma.³ According to the VHA, the suicide rate for veterans aged > 30 years also is rapidly increasing, and VHA has echoed the calls from NAM to make suicide prevention research a national priority.³

The VA has tried to stem the tide of suicides in veterans by implementing many advances in suicide prevention, including hiring suicide prevention coordinators at every VA hospital, enhanced monitoring, and the availability of 24-hour crisis hotline services. Yet the suicide rates for veterans continue to rise and remain higher than the rates in the general population.³

About 90% of deaths by suicide are by persons who have a treatable psychiatric disorder, most commonly a mood disorder, such as depression.⁴ However, most studies show that antidepressant therapy does not provide rapid or significant relief of suicidal ideation (SI).⁴ Therefore, the current standard of care for the treatment of acutely suicidal patients includes a combination of hospitalization, cognitive behavioral therapy or psychotherapy, case management, antidepressant medications, and electroconvulsive therapy (ECT).⁴ Even though these therapies have become more widely available over the past decade, rates of suicide continue to increase.^1,4 These interventions have limited effectiveness in acute settings. Although both intensive outpatient follow-up and routine outpatient care have been studied in relation to the decrease of suicidal behavior, neither intervention has been shown to immediately reduce suicidal behavior significantly in patients.

Suicidality Interventions

Therapy and case management require patients to be well enough to make office visits and follow through with care for periods as long as 1 year, which is often not possible for individuals with severe depression.⁵ One-third of patients who attended 6 months of outpatient therapy consistently still met the criteria for major depressive disorder (MDD), a major risk for suicide attempt.⁹ Antidepressant medications take a minimum of 4 weeks to reach full efficacy, and many patients stop taking the medications before that point because of concern that the medication is not helping or because of adverse effects (AEs), such as sleep disturbance, sexual dysfunction, or weight gain.⁹

Electroconvulsive therapy has been shown to be an effective treatment for patients with depression and suicidal behavior, but adherence with 12 weeks of recommended therapy has been a barrier for this intervention. Additionally, ECT may not provide reduction in SI for 1 to 2 weeks.^4,10 A review of research studies showed that nearly 50% of patients with high-expressed SI did not complete the prescribed amount of ECT due to the length of time to complete the recommended 12 sessions.¹⁰ Therefore, current treatment barriers for suicidal patients include: (1) long periods in treatment for therapy, medication, and ECT before any relief of symptoms is noted; (2) high recidivism rates for MDD symptoms and risk of suicide following treatment; and (3) high treatment dropout rates.

Pharmacologic treatments currently used in suicidal patients have not fared much better. Many have received FDA approval for treatment of associated mental health diagnoses such as bipolar disorder, schizophrenia, or MDD, but there are no approved treatments that specifically target suicidal behavior. Lithium is approved for reducing the long-term risk of SI primarily because it reduces the risk of mood disorders associated with SI, but lithium has not been shown to be effective in acute settings.¹¹ Clozapine is approved for reducing the long-term risk of recurrent suicide in patients with schizophrenia or schizoaffective disorder.⁴ Clozapine has not been shown to be effective in patients with mood disorders, which make up the majority of patients who attempt suicide.⁴ Additionally, both medications are plagued by the same barriers listed earlier, such as long time to effect (it takes an average 4 weeks to reach efficacy), lack of efficacy in acute settings, and AEs (eg, sleep problems, weight gain, and sexual dysfunction).⁹ Thus finding better pharmacologic interventions for suicidal patients is a priority for current research.

Ketamine

Recently, researchers have identified ketamine as a potential therapeutic option for depression and SI. A single ketamine infusion treatment has a rapid response, minimal AEs, and potentially long-lasting efficacy with SI, which would make it ideal for the treatment of acutely suicidal patients.⁴ Ketamine is an N-methyl-D-aspartate receptor (NMDAR) inhibitor that also has been found to be a weak μ- and κ-opioid receptor agonist and an inhibitor of the reuptake of serotonin, dopamine, and norepinephrine. Inhibition of the NMDAR results in analgesia, and ketamine is approved for the induction of anesthesia, pain relief, and sedation.¹²

Although AEs such as hallucinations and sedation create the potential for dangerous recreational use, ketamine is safely used in health care settings for a variety of indications. Effects are noted within 5 minutes of administration if given by infusion, and the main effects can last between 20 and 40 minutes.

Ketamine has a complex pharmacology and plays a role in other cell signaling mechanisms, but the significance of these additional mechanisms in the therapeutic effects of ketamine have only recently been elucidated. Preclinical studies indicate a probable NMDAR inhibition-independent mechanism responsible for the antidepressant response to ketamine.^13,14 The complex associations with rapamycin signaling, eukaryotic elongation factor 2 dephosphorylation, increased synthesis of brain-derived neurotrophic factor, and activation of glutamatergic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors have been linked to its rapid antidepressant effect and ketamine’s induction of synaptogenesis within the limbic system.^13,14

Clinical Research

Ketamine was studied as an adjunctive treatment to psychotherapy for addictions as far back as the 1970s.¹⁵ The available reports indicate a universally positive result, with increased rates of remission and decreased rates of relapse attributed to ketamine’s ability to alter one’s thought processes by reinforcing limbic-cortex interactions that facilitate the growth of more positive cognitive schemas and improved emotional attitudes about the self in support of the recovery process.¹⁵

Neurobiologic studies have shown that treatment with ketamine has a direct and immediate effect on neuronal pathways of the limbic system. It is known to regulate the mind’s reaction to positive stimuli by reversing the depressed subject’s blunted reaction to positive faces.¹⁶ This rapid normalization of the positive faces test is unique to ketamine infusion and is not seen in tests with traditional antidepressants.

In 2000, the first placebo-controlled trial using ketamine for treatment resistant depression (TRD) demonstrated the rapid antidepressant effects of a single dose of ketamine, but this study only looked at these effects for 1 week.¹⁷ In multiple double blind, placebo-controlled trials since then, IV infusion of ketamine was shown to be an effective intervention for TRD.^13,18,19 More recently, a published investigation involving the treatment of MDD showed that ketamine in conjunction with a selective serotonin reuptake inhibitor (SSRI) accelerated and enhanced the effectiveness of the SSRI in reducing depressive symptoms.²⁰

Based on the rapid resolution of depressive symptoms using ketamine, researchers have looked at its effect on suicidality as a secondary measure. A case study of a patient with severe depressive episodes and multiple previous suicidal attempts reported that the patient responded to a single dose of ketamine, described the experience as “being reborn,” and maintained complete remission of SI for the 6-month study period.²¹ In a larger study, 133 TRD patients received a single IV dose of ketamine with significant reductions in SI independent of depressive and anxiety symptoms.²²

Depression Treatment

These results have led to an excitement for ketamine therapy as a novel treatment of depression, and off-label use by treatment centers now exists in several countries to aid those with TRD.²³ This off-label use continues to be controversial, as research has yet to determine the safest most effective route and duration of treatment and whether the ketamine treatment AEs will exceed any accrued therapeutic benefit.¹³

The American Psychological Association Council of Research Task Force on Novel Biomarkers and Treatment critically examined the clinical evidence of ketamine use and has raised important concerns about the use of ketamine in the outpatient setting, administered in the absence of consensus therapeutic monitoring guidelines, and ambitiously marketed as a panacea for TRD.^13,24 A study showed permanent impairment of brain function for both groups compared with monkeys treated with saline infusions.²⁵ In 2016, the FDA gave fast-track approval for an intranasal ketamine that would make the treatment more easily available in the outpatient setting, but this could lead to certain patients developing a dependency on ketamine or engaging in its diversion for recreational use. There are case reports and anecdotes in the literature of patients and research subjects developing drug-seeking behaviors and overuse of ketamine.²⁴ Additionally, the comorbidities associated with TRD and SI have not been fully evaluated. For instance, there is evidence that depressed patients with obsessive compulsive disorder may have worse outcomes that include delayed onset SI.²⁶

There also is concern for the use of ketamine for chronic opioid users. The combination of ketamine with opioids may increase the response to the opioid in an otherwise drug tolerant patient, leading to risk of death by overdose in patients who have not increased their usual dose.²⁷ However, this effect was noted only when ketamine and opioids were administered together, and the effect does not seem to last postinfusion.²⁷

The challenges in treatment of TRD include finding an effective formulation—IV infusion of ketamine requires cardiovascular monitoring and is administered by anesthesiologists. The short duration of action for depression requires repeated infusions, and the frequency and quantity of infusions have not been determined. Efforts to find other NMDAR inhibitors (eg, memantine, nitrous oxide, D-cycloserine, and others) that match ketamine’s antidepressant efficacy but with easier delivery methods and fewer risks have thus far been unsuccessful.¹³ It is now believed that ketamine’s unique ability to activate intracellular signaling pathways linked to synaptic plasticity gives it the antidepressant function. Recent studies have further narrowed ketamine’s antidepressant function to the R- enantiomer of the ketamine metabolite, hydroxynorketamine.¹⁴ The nasal spray for ketamine is the S- enantiomer, which has better bioavailability but may have less antidepressant efficacy compared with the racemic mixture used in ketamine infusions.

Suicide Ideation Treatment

The many challenges faced by researchers and clinicians trying to develop ketamine treatment for TRD may not apply to the treatment of SI. Whereas repeated doses of ketamine cannot reliably produce sustained remission of depression, the few studies that have looked at the long-term effects of ketamine treatment on SI indicate the potential for long-term efficacy after a single IV infusion.^21,22 Although treatment with IV infusions have additional costs and logistics, if it is found beneficial, it could be given in the emergency department (ED) prior to hospitalization and potentially lead to better outcomes.

In 2011, a small preliminary observational study of patients with depression and SI presenting to the ED indicated that SI was rapidly reduced following an infusion of ketamine.²⁸ This study showed that both depressive symptoms and suicidality rapidly and significantly diminished within 40 minutes with no evidence of the recurrence of symptoms 10 days postadministration.

A more recent study used ketamine in a military field hospital to treat SI and also concluded that it could be effective and safe when administered in an ED setting. This preliminary study suggests that ketamine could be a safe and potentially effective medication for rapid reduction of depression and suicidality in a busy ED setting.²⁹ These limited studies involving the use of ketamine in patients with SI show promise with long-term effectiveness. However, more research is needed to clarify whether the efficacy with SI will be similar to the clinical experience seen in TRD; a duration of effect limited to 2 weeks with recurrence after treatment discontinued.²⁴

Conclusion

There has been a compelling accumulation of scientific data since 2000 to support the use of ketamine for the treatment of depression and SI. Ketamine use in patients with these diagnoses showed a rapid decrease of symptoms and minimal AEs among a significant number of patients.^22,30

Although the initial findings involving the use of ketamine in suicidal patients are promising, the clinical use of ketamine needs further research, using larger sample sizes and exploring both the short-term and long-term effects of this medication. Researchers need to further establish the safe and effective route, point of care, and patient type that would best respond to this novel treatment. The initial evidence would suggest that health care providers have every right to be hopeful that ketamine will become the first pharmacologic treatment of acute SI in a majority of patients presenting to EDs, mental health clinics, community hospitals, and VA medical centers.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important component of the immune checkpoint pathway. CTLA-4 inhibition causes T-cell activation and proliferation, increases T-cell responsiveness, and enhances the anti-tumor immune response. CTLA-4 inhibition also results in immune-related adverse reactions such as colitis, hepatitis, and endocrinopathies. Preclinical investigations have recently shown that CTLA-4 inhibition can cause cytokine-mediated increase in bone remodeling.^1,2(p4) Ipilimumab, a recombinant IgG1 kappa antibody against human CTLA-4, has been approved for use in unresectable or metastatic melanoma. We hypothesize that ipilumumab results in increase in bone remodeling manifesting as an autoimmune reaction.

Methods

We conducted a retrospective case-control study of patients with stage III/IV melanoma treated at the University of New Mexico Comprehensive Cancer Center during April 2009-July 2014. The university’s Institutional Review Board approved the study.

Two cohorts were compared: an ipilumimab cohort receiving ipilumimab at 3 mg/kg every 3 weeks, and a chemotherapy cohort receiving an investigational chemotherapy regimen: carboplatin IV at an area under curve of 5 on day 1, paclitaxel IV at 175 mg/m² on day 1, and temozolomide orally at 125 mg/m² daily on days 2 to 6 every 21 days. Patients receiving at least 1 cycle of treatment were included. Those with known hepatic disease or concurrent malignancy were excluded from the study.

Serum ALP level (normal range, 38-150 international units per liter [IU/L]) and patient-reported bone pain measured by the 11-point numeric rating scale (NRS) for pain assessment were recorded before treatment initiation, on each cycle, and upon treatment completion.³ Clinical response was assessed per RECIST guidelines.⁴ Bone pain was dichotomized into Absent (pain intensity of 0 on the NRS, meaning no pain) or Present (pain intensity of 1-10 on the NRS, with 1 = mild pain and 10 = worst imaginable pain). Patients with a complete or partial response to the therapy were categorized as responders, and those with progressive or stable disease were categorized as nonresponders.

Descriptive statistics were generated for demographic and clinical characteristics. The primary outcome variables of interest were bone pain and mean ALP levels. Generalized linear mixed-effect models for proportion of patients with bone pain (with logit link function) and mean ALP levels (with identify link function) were used to evaluate for a difference in trends between the two cohorts over time. We used the Kenward-Roger approach to adjust for the small size of the degrees of freedom. To assess the significance of difference of the proportions of patients with bone pain and the mean ALP levels between responders and nonresponders in the ipilumimab cohort, the Fisher exact test and Wilcoxon rank-sum test were used, respectively. Statistical analyses were performed with statistical packages R (v3.1.3) and SAS (v9.4).

Results

A total of 281 patients were screened, and 51 met the inclusion criteria (39 in the ipilumimab and 12 in chemotherapy cohorts). Baseline parameters were well matched between the cohorts (Table). Of the 39 patients in the ipilimumab cohort, 14 (35.9%) had bone pain during at least one of the treatment cycles, compared with 3 of the 12 patients (25%) in the chemotherapy cohort. At baseline, 4 of 38 ipilimumab patients (10.5%; 95% confidence interval [CI], 2.9-24.8) and 2 of 12 chemotherapy patients (16.7%; 95% CI, 2.1-48.4) had bone pain. Upon treatment completion, 9 of 33 ipilimumab patients (27.3%; 95% CI, 13.3-45.5) and 0 of 12 chemotherapy patients (0%; 95% CI, 0-26.5) had bone pain. The trend of proportion of patients with bone pain over time was statistically significant between the two cohorts (P = .023, Figure 1). The trends of proportion of patients with bone pain were not statistically significant when stratified by the presence of bone metastasis at inclusion in the study (P = .418) or disease progression at treatment completion (P = .500).

At baseline, the mean ALP level was 89.39 IU/L (95% CI, 81.03-97.75) in the ipilumimab cohort and 114.33 IU/L (95% CI, 69.48-159.19) in the chemotherapy cohort. Upon treatment completion, the mean ALP level was 123.09 IU/L (95% C.I. 80.78-165.41) in the ipilumimab cohort and 124.24 IU/L (95% C.I. 90.88-157.62) in the chemotherapy cohort. The trend of mean ALP level over time was not statistically significant between the 2 cohorts (P = .653, Figure 2).

Discussion

Immune checkpoints are inhibitory pathways that are critical for maintenance of self-tolerance and regulation of appropriate immune response. CTLA-4 is present exclusively on T cells and interacts with its ligands B7.1 and B7.2. CTLA-4 competes with CD28 in binding with B7, leading to dampening of T-cell activation and function.^5,6 Development of checkpoint inhibitors such as ipilumimab have heralded a new era of immune targeted therapies for various malignancies including malignant melanoma.

Bone remodeling involves 4 distinct but overlapping phases. The first phase involves detection of loss of bone continuity by osteocytes and activation of osteoclast precursors derived from progenitors of the monocyte-macrophage lineage. The second phase involves osteoclast-medicated bone resorption and concurrent recruitment of mesenchymal stem cells and osteoprogenitors. The third phase involves osteoblast differentiation and osteoid synthesis, and the fourth phase results in mineralization of osteoid and termination of bone remodeling.^7,8

The role of T-lymphocytes and cytokines, such as IL-1 and TNF-α, and receptor activator of NF-κB ligand (RANK-L) in osteoclastogenesis is well studied. RANK-L is considered to be the final downstream effector of this process.⁹ T-lymphocytes have also been shown to promote osteoblast maturation and function.^9,10 These findings suggest a significant interaction between immune system activation and bone remodeling.

The search for a reliable biomarker for immune therapy is ongoing. Although ipilumimab-associated immune-related adverse events have been suggested to predict response to therapy,¹¹ there is considerable debate on the subject. Ipilumimab’s impact on bone remodeling could offer a solution.

In the current study, there was a statistically significant difference in proportion of patients with bone pain in the 2 cohorts. This was preserved with stratification based on bone metastasis at inclusion and disease progression on treatment completion making new or worsening skeletal metastasis. Furthermore, the proportion of patients with bone pain increased with each cycle for ipilumimab cohort. However, we were unable to detect an association between bone pain and response to ipilimumab.

We were not able to detect a difference in trend of mean ALP level with treatment in the two cohorts. Although it is possible that no such association exists, we believe our study was not powered to detect it. Finally, we were not able to study markers for osteoblast (bone-specific ALP) and osteoclasts (N- and C-telopeptides of type 1 collagen, deoxypyridinoline, etc) to better assess this interaction because they are not commonly clinically used.

Regarding the limitations of our study, we chose to dichotomize the patient-reported bone pain because it is a subjective measure and there is a significant variability of the perceived pain intensity among patients. We also excluded patients with hepatitis from receiving the ipilumimab therapy and those with known hepatic disease from the study to reduce the impact of hepatic ALP on total serum ALP levels.

In conclusion, as far as we know, this is the first clinical report suggesting a possible relationship between CTLA-4 inhibition and bone remodeling. Supported by a strong preclinical rationale, this side effect remains under-studied and under-recognized by clinicians. A prospective assessment of this interaction using bone specific markers is planned.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important component of the immune checkpoint pathway. CTLA-4 inhibition causes T-cell activation and proliferation, increases T-cell responsiveness, and enhances the anti-tumor immune response. CTLA-4 inhibition also results in immune-related adverse reactions such as colitis, hepatitis, and endocrinopathies. Preclinical investigations have recently shown that CTLA-4 inhibition can cause cytokine-mediated increase in bone remodeling.^1,2(p4) Ipilimumab, a recombinant IgG1 kappa antibody against human CTLA-4, has been approved for use in unresectable or metastatic melanoma. We hypothesize that ipilumumab results in increase in bone remodeling manifesting as an autoimmune reaction.

Methods

We conducted a retrospective case-control study of patients with stage III/IV melanoma treated at the University of New Mexico Comprehensive Cancer Center during April 2009-July 2014. The university’s Institutional Review Board approved the study.

Two cohorts were compared: an ipilumimab cohort receiving ipilumimab at 3 mg/kg every 3 weeks, and a chemotherapy cohort receiving an investigational chemotherapy regimen: carboplatin IV at an area under curve of 5 on day 1, paclitaxel IV at 175 mg/m² on day 1, and temozolomide orally at 125 mg/m² daily on days 2 to 6 every 21 days. Patients receiving at least 1 cycle of treatment were included. Those with known hepatic disease or concurrent malignancy were excluded from the study.

Serum ALP level (normal range, 38-150 international units per liter [IU/L]) and patient-reported bone pain measured by the 11-point numeric rating scale (NRS) for pain assessment were recorded before treatment initiation, on each cycle, and upon treatment completion.³ Clinical response was assessed per RECIST guidelines.⁴ Bone pain was dichotomized into Absent (pain intensity of 0 on the NRS, meaning no pain) or Present (pain intensity of 1-10 on the NRS, with 1 = mild pain and 10 = worst imaginable pain). Patients with a complete or partial response to the therapy were categorized as responders, and those with progressive or stable disease were categorized as nonresponders.

Descriptive statistics were generated for demographic and clinical characteristics. The primary outcome variables of interest were bone pain and mean ALP levels. Generalized linear mixed-effect models for proportion of patients with bone pain (with logit link function) and mean ALP levels (with identify link function) were used to evaluate for a difference in trends between the two cohorts over time. We used the Kenward-Roger approach to adjust for the small size of the degrees of freedom. To assess the significance of difference of the proportions of patients with bone pain and the mean ALP levels between responders and nonresponders in the ipilumimab cohort, the Fisher exact test and Wilcoxon rank-sum test were used, respectively. Statistical analyses were performed with statistical packages R (v3.1.3) and SAS (v9.4).

Results

A total of 281 patients were screened, and 51 met the inclusion criteria (39 in the ipilumimab and 12 in chemotherapy cohorts). Baseline parameters were well matched between the cohorts (Table). Of the 39 patients in the ipilimumab cohort, 14 (35.9%) had bone pain during at least one of the treatment cycles, compared with 3 of the 12 patients (25%) in the chemotherapy cohort. At baseline, 4 of 38 ipilimumab patients (10.5%; 95% confidence interval [CI], 2.9-24.8) and 2 of 12 chemotherapy patients (16.7%; 95% CI, 2.1-48.4) had bone pain. Upon treatment completion, 9 of 33 ipilimumab patients (27.3%; 95% CI, 13.3-45.5) and 0 of 12 chemotherapy patients (0%; 95% CI, 0-26.5) had bone pain. The trend of proportion of patients with bone pain over time was statistically significant between the two cohorts (P = .023, Figure 1). The trends of proportion of patients with bone pain were not statistically significant when stratified by the presence of bone metastasis at inclusion in the study (P = .418) or disease progression at treatment completion (P = .500).

At baseline, the mean ALP level was 89.39 IU/L (95% CI, 81.03-97.75) in the ipilumimab cohort and 114.33 IU/L (95% CI, 69.48-159.19) in the chemotherapy cohort. Upon treatment completion, the mean ALP level was 123.09 IU/L (95% C.I. 80.78-165.41) in the ipilumimab cohort and 124.24 IU/L (95% C.I. 90.88-157.62) in the chemotherapy cohort. The trend of mean ALP level over time was not statistically significant between the 2 cohorts (P = .653, Figure 2).

Discussion

Immune checkpoints are inhibitory pathways that are critical for maintenance of self-tolerance and regulation of appropriate immune response. CTLA-4 is present exclusively on T cells and interacts with its ligands B7.1 and B7.2. CTLA-4 competes with CD28 in binding with B7, leading to dampening of T-cell activation and function.^5,6 Development of checkpoint inhibitors such as ipilumimab have heralded a new era of immune targeted therapies for various malignancies including malignant melanoma.

Bone remodeling involves 4 distinct but overlapping phases. The first phase involves detection of loss of bone continuity by osteocytes and activation of osteoclast precursors derived from progenitors of the monocyte-macrophage lineage. The second phase involves osteoclast-medicated bone resorption and concurrent recruitment of mesenchymal stem cells and osteoprogenitors. The third phase involves osteoblast differentiation and osteoid synthesis, and the fourth phase results in mineralization of osteoid and termination of bone remodeling.^7,8

The role of T-lymphocytes and cytokines, such as IL-1 and TNF-α, and receptor activator of NF-κB ligand (RANK-L) in osteoclastogenesis is well studied. RANK-L is considered to be the final downstream effector of this process.⁹ T-lymphocytes have also been shown to promote osteoblast maturation and function.^9,10 These findings suggest a significant interaction between immune system activation and bone remodeling.

The search for a reliable biomarker for immune therapy is ongoing. Although ipilumimab-associated immune-related adverse events have been suggested to predict response to therapy,¹¹ there is considerable debate on the subject. Ipilumimab’s impact on bone remodeling could offer a solution.

In the current study, there was a statistically significant difference in proportion of patients with bone pain in the 2 cohorts. This was preserved with stratification based on bone metastasis at inclusion and disease progression on treatment completion making new or worsening skeletal metastasis. Furthermore, the proportion of patients with bone pain increased with each cycle for ipilumimab cohort. However, we were unable to detect an association between bone pain and response to ipilimumab.

We were not able to detect a difference in trend of mean ALP level with treatment in the two cohorts. Although it is possible that no such association exists, we believe our study was not powered to detect it. Finally, we were not able to study markers for osteoblast (bone-specific ALP) and osteoclasts (N- and C-telopeptides of type 1 collagen, deoxypyridinoline, etc) to better assess this interaction because they are not commonly clinically used.

Regarding the limitations of our study, we chose to dichotomize the patient-reported bone pain because it is a subjective measure and there is a significant variability of the perceived pain intensity among patients. We also excluded patients with hepatitis from receiving the ipilumimab therapy and those with known hepatic disease from the study to reduce the impact of hepatic ALP on total serum ALP levels.

In conclusion, as far as we know, this is the first clinical report suggesting a possible relationship between CTLA-4 inhibition and bone remodeling. Supported by a strong preclinical rationale, this side effect remains under-studied and under-recognized by clinicians. A prospective assessment of this interaction using bone specific markers is planned.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important component of the immune checkpoint pathway. CTLA-4 inhibition causes T-cell activation and proliferation, increases T-cell responsiveness, and enhances the anti-tumor immune response. CTLA-4 inhibition also results in immune-related adverse reactions such as colitis, hepatitis, and endocrinopathies. Preclinical investigations have recently shown that CTLA-4 inhibition can cause cytokine-mediated increase in bone remodeling.^1,2(p4) Ipilimumab, a recombinant IgG1 kappa antibody against human CTLA-4, has been approved for use in unresectable or metastatic melanoma. We hypothesize that ipilumumab results in increase in bone remodeling manifesting as an autoimmune reaction.

Methods

We conducted a retrospective case-control study of patients with stage III/IV melanoma treated at the University of New Mexico Comprehensive Cancer Center during April 2009-July 2014. The university’s Institutional Review Board approved the study.

Two cohorts were compared: an ipilumimab cohort receiving ipilumimab at 3 mg/kg every 3 weeks, and a chemotherapy cohort receiving an investigational chemotherapy regimen: carboplatin IV at an area under curve of 5 on day 1, paclitaxel IV at 175 mg/m² on day 1, and temozolomide orally at 125 mg/m² daily on days 2 to 6 every 21 days. Patients receiving at least 1 cycle of treatment were included. Those with known hepatic disease or concurrent malignancy were excluded from the study.

Serum ALP level (normal range, 38-150 international units per liter [IU/L]) and patient-reported bone pain measured by the 11-point numeric rating scale (NRS) for pain assessment were recorded before treatment initiation, on each cycle, and upon treatment completion.³ Clinical response was assessed per RECIST guidelines.⁴ Bone pain was dichotomized into Absent (pain intensity of 0 on the NRS, meaning no pain) or Present (pain intensity of 1-10 on the NRS, with 1 = mild pain and 10 = worst imaginable pain). Patients with a complete or partial response to the therapy were categorized as responders, and those with progressive or stable disease were categorized as nonresponders.

Descriptive statistics were generated for demographic and clinical characteristics. The primary outcome variables of interest were bone pain and mean ALP levels. Generalized linear mixed-effect models for proportion of patients with bone pain (with logit link function) and mean ALP levels (with identify link function) were used to evaluate for a difference in trends between the two cohorts over time. We used the Kenward-Roger approach to adjust for the small size of the degrees of freedom. To assess the significance of difference of the proportions of patients with bone pain and the mean ALP levels between responders and nonresponders in the ipilumimab cohort, the Fisher exact test and Wilcoxon rank-sum test were used, respectively. Statistical analyses were performed with statistical packages R (v3.1.3) and SAS (v9.4).

Results

A total of 281 patients were screened, and 51 met the inclusion criteria (39 in the ipilumimab and 12 in chemotherapy cohorts). Baseline parameters were well matched between the cohorts (Table). Of the 39 patients in the ipilimumab cohort, 14 (35.9%) had bone pain during at least one of the treatment cycles, compared with 3 of the 12 patients (25%) in the chemotherapy cohort. At baseline, 4 of 38 ipilimumab patients (10.5%; 95% confidence interval [CI], 2.9-24.8) and 2 of 12 chemotherapy patients (16.7%; 95% CI, 2.1-48.4) had bone pain. Upon treatment completion, 9 of 33 ipilimumab patients (27.3%; 95% CI, 13.3-45.5) and 0 of 12 chemotherapy patients (0%; 95% CI, 0-26.5) had bone pain. The trend of proportion of patients with bone pain over time was statistically significant between the two cohorts (P = .023, Figure 1). The trends of proportion of patients with bone pain were not statistically significant when stratified by the presence of bone metastasis at inclusion in the study (P = .418) or disease progression at treatment completion (P = .500).

At baseline, the mean ALP level was 89.39 IU/L (95% CI, 81.03-97.75) in the ipilumimab cohort and 114.33 IU/L (95% CI, 69.48-159.19) in the chemotherapy cohort. Upon treatment completion, the mean ALP level was 123.09 IU/L (95% C.I. 80.78-165.41) in the ipilumimab cohort and 124.24 IU/L (95% C.I. 90.88-157.62) in the chemotherapy cohort. The trend of mean ALP level over time was not statistically significant between the 2 cohorts (P = .653, Figure 2).

Discussion

Immune checkpoints are inhibitory pathways that are critical for maintenance of self-tolerance and regulation of appropriate immune response. CTLA-4 is present exclusively on T cells and interacts with its ligands B7.1 and B7.2. CTLA-4 competes with CD28 in binding with B7, leading to dampening of T-cell activation and function.^5,6 Development of checkpoint inhibitors such as ipilumimab have heralded a new era of immune targeted therapies for various malignancies including malignant melanoma.

Bone remodeling involves 4 distinct but overlapping phases. The first phase involves detection of loss of bone continuity by osteocytes and activation of osteoclast precursors derived from progenitors of the monocyte-macrophage lineage. The second phase involves osteoclast-medicated bone resorption and concurrent recruitment of mesenchymal stem cells and osteoprogenitors. The third phase involves osteoblast differentiation and osteoid synthesis, and the fourth phase results in mineralization of osteoid and termination of bone remodeling.^7,8

The role of T-lymphocytes and cytokines, such as IL-1 and TNF-α, and receptor activator of NF-κB ligand (RANK-L) in osteoclastogenesis is well studied. RANK-L is considered to be the final downstream effector of this process.⁹ T-lymphocytes have also been shown to promote osteoblast maturation and function.^9,10 These findings suggest a significant interaction between immune system activation and bone remodeling.

The search for a reliable biomarker for immune therapy is ongoing. Although ipilumimab-associated immune-related adverse events have been suggested to predict response to therapy,¹¹ there is considerable debate on the subject. Ipilumimab’s impact on bone remodeling could offer a solution.

In the current study, there was a statistically significant difference in proportion of patients with bone pain in the 2 cohorts. This was preserved with stratification based on bone metastasis at inclusion and disease progression on treatment completion making new or worsening skeletal metastasis. Furthermore, the proportion of patients with bone pain increased with each cycle for ipilumimab cohort. However, we were unable to detect an association between bone pain and response to ipilimumab.

We were not able to detect a difference in trend of mean ALP level with treatment in the two cohorts. Although it is possible that no such association exists, we believe our study was not powered to detect it. Finally, we were not able to study markers for osteoblast (bone-specific ALP) and osteoclasts (N- and C-telopeptides of type 1 collagen, deoxypyridinoline, etc) to better assess this interaction because they are not commonly clinically used.

Regarding the limitations of our study, we chose to dichotomize the patient-reported bone pain because it is a subjective measure and there is a significant variability of the perceived pain intensity among patients. We also excluded patients with hepatitis from receiving the ipilumimab therapy and those with known hepatic disease from the study to reduce the impact of hepatic ALP on total serum ALP levels.

In conclusion, as far as we know, this is the first clinical report suggesting a possible relationship between CTLA-4 inhibition and bone remodeling. Supported by a strong preclinical rationale, this side effect remains under-studied and under-recognized by clinicians. A prospective assessment of this interaction using bone specific markers is planned.

Polycythemia vera, classified as a myeloproliferative neoplasm (MPN) and characterized by uncontrolled, clonal, myeloid expansion with predominant erythrocytosis,¹ affects about 100,000 individuals in the United States.² It is a chronic and burdensome disease associated with shortened survival.³ Patients are at an increased risk of cardiovascular events, solid tumors, and transformation to myelofibrosis (MF) and/or acute myeloid leukemia (AML).^4,5 Furthermore, patients generally have a reduced quality of life (QoL) stemming from prevalent and occasionally severe polycythemia vera–related signs and symptoms, including fatigue, pruritus, and splenomegaly.⁶ In general, the classical Philadelphia chromosome-negative MPNs are associated with driver mutations in the following three genes: Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL).⁷ Almost all patients with polycythemia vera have an activating mutation in the cytoplasmic signal transduction protein JAK2.⁴ Patients with essential thrombocythemia (ET) or MF can have mutations in JAK2, CALR, or MPL. However, CALR and MPL mutations are absent or exceedingly rare in patients with polycythemia vera.⁷ Diagnosis can be challenging and is currently based on 2016 World Health Organization (WHO) diagnostic criteria.¹

Management strategies include the use of aspirin, phlebotomy, and cytoreductive therapy. Ruxolitinib is a newer treatment option available for patients with polycythemia vera who are either resistant to or intolerant of hydroxyurea^8,9— a population that previously had few treatment options. It is important for community oncologists and other treating clinicians to understand current diagnostic strategy and management options based on established guidelines, recent clinical evidence, and regulatory updates.

Search and selection process for research sources

In September 2016, we searched PubMed for articles published since 2006 with polycythemia vera included in the abstract or title. The initial 1,730 publications were screened by eye to select 46 key articles that guide current management of polycythemia vera. Four studies published before 2006 were also included based on their continued relevance.

Epidemiology and pathophysiology

Based on a meta-analysis of patients from Europe and the United States, the annual incidence of polycythemia vera estimated to be between 0.7 and 2.6 per 100,000 people.¹⁰ The age-adjusted prevalence of polycythemia vera in the United States is about 45-57 per 100,000 people,² however, the true prevalence might be considerably greater.

Patients with polycythemia vera are at increased risk of cardiovascular events, thrombosis, and death.^3-5 Risk is highest among patients older than 60 years or with a history of thrombosis.¹¹ Uncontrolled myeloproliferation has also been identified as a risk factor for cardiovascular mortality and thrombosis. This was demonstrated in the prospective Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial, which reported more cardiovascular events in patients with hematocrit levels of 45%-50%, compared with those whose hematocrit levels were <45%.¹² In addition, retrospective data suggest leukocytosis is a potential risk factor for thromboembolic events and poor outcomes.¹³

Dysregulated JAK2 signaling is the principal driver of polycythemia vera pathophysiology. About 95% of patients with polycythemia vera will have an identifiable JAK2 V617F exon 14 mutation, with an additional 3%-5% demonstrating a JAK2 exon 12 mutation.^4,14 Under physiologic conditions, JAK2 interacts with the STAT family of signal transduction proteins and serves as an important regulator of normal hematopoiesis.¹⁵ Mutated, constitutively activated JAK2 signaling promotes the various polycythemia vera disease manifestations, including excessive myeloproliferation, splenomegaly,¹⁵ and constitutional symptoms.^14,16,17

Burden of disease for the individual

Mortality

Patients with polycythemia vera have an increased risk of mortality compared with an unaffected, age- and gender-matched cohort of the general population.³ A retrospective study of Medicare patients with polycythemia vera (mean age at diagnosis, 76.1 years) reported a median survival of 5.4 years, compared with 8.7 years for a matched cohort.³ A second retrospective study reported a median survival of 13.5 years (median age at diagnosis, 64 years; median follow-up time, 11.8 years).¹⁸

Leading causes of death for patients with polycythemia vera include cardiovascular and thrombotic events, the development of secondary solid tumors, and disease transformation to MF and/or AML. In the prospective European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study of 1,638 patients, 45% of deaths (74/164) resulted from cardiovascular causes (1.7 per 100 patient-years).⁵ Thirteen percent of deaths were related to either leukemic or myelofibrotic transformation, and 20% of deaths were attributed to secondary solid tumors.⁵ In a retrospective analysis of 1,545 patients with polycythemia vera followed for a median of 6.9 years after diagnosis, 347 had died, primarily from acute leukemia (10%), secondary malignancies (10%), and thrombotic events (9%).⁴ Arterial and venous thrombotic events occurred in 12% and 9% of patients, respectively, with disease transformation to MF and AML occurring in 9% and 3% of patients. Further support of an increased risk of secondary malignancies comes from a retrospective analysis of a large Swedish cancer registry (1958–2006) that found an increased risk of secondary endocrine, renal, and skin malignancies; MF; and leukemia among patients with polycythemia vera.¹⁹

Symptoms and quality of life

Symptoms of polycythemia vera vary in severity, and patients often fail to attribute symptoms to the disease.²⁰ Moreover, clinicians may underestimate a patient’s true disease burden or the effect it has on QoL.²⁰ Point-of-care metrics, such as the MPN Symptom Assessment Form (MPN-SAF), were developed to aid in identifying and grading symptom burden. Studies using this metric have reported fatigue as the most common and most severe symptom (incidence, 73%-92%), with a variety of other symptoms also affecting a majority of patients (Figure 1).^6,21-24 Although fatigue, pruritus, and a higher MPN-SAF total symptom score are significantly correlated with reduced QoL,^22,25 the recent MPN Landmark survey suggests that even patients with low symptom severity scores have a reduction in their QoL.⁶ This study also highlighted that polycythemia vera can adversely affect multiple aspects of daily living: 48% of patients reported disease interfering with daily activities; 63% with family or social life; and 37% with employment, feeling compelled to work reduced hours.⁶

Splenomegaly is a common feature of polycythemia vera, affecting an estimated one in three patients, which may result in discomfort and early satiety.⁴

Identification and diagnosis

Most patients diagnosed with polycythemia vera are between the ages of 60 and 76 years,^3-5 although about 25% are diagnosed before age 50.⁴ Tefferi and colleagues reported in a retrospective study that common features at presentation include JAK2 mutations (98%), elevated hemoglobin (73%), endogenous erythroid colony growth (73%), white blood cell count of >10.5 × 10⁹/L (49%), and platelet count of ≥450 × 10⁹/L (53%).⁴ In that same study, about a third of patients presented with a palpable spleen or polycythemia vera–related symptoms, including pruritus and vasomotor symptoms. However, many patients were asymptomatic at presentation, diagnosed incidentally by abnormal laboratory values.⁴ Patients can present with vascular thrombosis, occasionally involving atypical sites (eg, Budd-Chiari syndrome, other abdominal blood clots),²⁶ thus, a heightened awareness and testing for JAK2 mutations may be appropriate in the evaluation of such individuals.

Evidence suggests many clinicians may not rigidly apply the WHO diagnostic criteria to establish a diagnosis.^1,27,28 A recent retrospective claims analysis showed that only 40% of 121 patients diagnosed with polycythemia vera met the 2008 WHO diagnostic criteria, and for some patients, the diagnosis was based solely on the presence of the JAK2 V617F mutation.²⁹ One should be aware of individuals with “masked” polycythemia vera, who may present with characteristic polycythemia vera features but have hemoglobin levels below those established by the WHO in 2008, typically owing to iron deficiency and/or a disproportionate expansion of plasma volume.³⁰ To improve polycythemia vera diagnosis, the WHO diagnostic criteria were updated in 2016 with reduced hemoglobin diagnostic thresholds (Figure 2).¹

Management strategy

Treatment goals

The primary polycythemia vera–treatment goals are to reduce the risk of cardiovascular, thrombotic, and hemorrhagic events; reduce the risk of fibrotic and/or leukemic transformation; and alleviate polycythemia vera–related symptoms.^11,31

Traditional treatment options

Aspirin. To reduce the risk of death from cardiovascular events, patients with polycythemia vera should receive low-dose aspirin³² and undergo phlebotomy to maintain a target hematocrit <45%, as established by the ECLAP and CYTO-PV trials (Figure 3).^{4,5,12,13,16,32-36} Higher doses of aspirin (ie, 325 mg 2 or more times a week) are associated with a dose-dependent increased risk of gastrointestinal bleeding.³⁷ Low-dose aspirin is generally well tolerated; however, patients with extreme thrombocytosis may develop bleeding as a consequence of a well-described, thrombocytosis-associated acquired von Willebrand disease.^11,38

Most patients benefit from long-term treatment with hydroxyurea; however, 25% develop resistance to or intolerance of hydroxyurea therapy.⁴⁴ Intolerance typically manifests as leg ulcers or other mucocutaneous toxicity, gastrointestinal side effects, or fever.⁴⁴ Resistance to hydroxyurea is defined as failure to achieve phlebotomy independence, persistent leukothrombocytosis or splenomegaly despite adequate doses of hydroxyurea, or inability to deliver the drug owing to dose-limiting cytopenias. The European LeukemiaNet (ELN) formally codified and published a definition of hydroxyurea resistance/intolerance⁴⁵ (Table), which can be used to identify patients at high risk of poor outcomes.⁴⁴ In a retrospective chart review of 261 patients with polycythemia vera, those meeting the ELN definition of hydroxyurea resistance had a 5.6-fold greater risk of mortality and a 6.8-fold increased risk of fibrotic and/or leukemic disease transformation.⁴⁴

Allogenic transplantation. Although allogeneic transplantation is a potentially curative treatment option, it has been reserved primarily for younger patients with MPNs (age <60 years³¹). Furthermore, a recent systematic review concluded that overall survival was worse following allogeneic transplantation compared with a nontransplant approach (ie, phlebotomy and aspirin).⁴⁸

Ruxolitinib. The oral JAK1/JAK2 inhibitor ruxolitinib has been approved by the US Food and Drug Administration (FDA) for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea,⁸ and by the European Medicines Agency (EMA) for adult patients with polycythemia vera who are resistant to or intolerant of hydroxyurea.⁹ Ruxolitinib is also approved by the FDA for patients with intermediate- or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF,⁸ and for similar patient populations by the EMA.⁹

Approval of ruxolitinib for the treatment of patients with polycythemia vera was based on the phase 3 randomized, open-label, multicenter RESPONSE trial in which 222 patients with polycythemia vera who met the modified ELN criteria for hydroxyurea resistance or intolerance (Table)^16,31 were randomized to ruxolitinib or best available therapy (BAT). Compared with BAT, a greater proportion of patients treated with ruxolitinib achieved the primary composite endpoint of hematocrit control without the need for phlebotomy and ≥35% reduction in spleen volume by week 32 (22.7% vs 0.9%; P < .001).^16,49 When looked at individually, hematocrit control and reduction in spleen size favored ruxolitinib over BAT (hematocrit control, 60.0% vs 18.8%, ruxolitinib and BAT, respectively; ≥35% reduction in spleen volume, 40.0% vs 0.9%). Furthermore, more patients receiving ruxolitinib achieved the key secondary endpoint of complete hematologic remission than did those receiving BAT (ie, normalization of blood counts; 23.6% vs 8.0%; P = .0016).^16,49 Of note is that most patients who achieved primary treatment responses maintained disease control for ≥80 weeks.⁴⁹

Results from RESPONSE indicate that ruxolitinib may substantially improve polycythemia vera–related symptoms. Treatment with ruxolitinib was associated with a greater improvement in nearly all symptoms evaluated by the MPN-SAF as well as greater improvements in QoL and functional measures with the EORTC QLQ-C30 trial metric compared with BAT (Figure 1).¹⁶ In addition, a post hoc exploratory analysis of RESPONSE indicated that patients receiving ruxolitinib showed a rapid normalization of abnormal iron indices at baseline, compared with those receiving BAT.⁵⁰

Treatment safety and tolerability are particularly important considerations for patients with polycythemia vera, given the long natural history of the disease. In a preplanned analysis of RESPONSE at 80 weeks, 83% of patients randomized to receive treatment with ruxolitinib remained on treatment (median exposure, 111 weeks).⁴⁹ Most adverse events reported in both treatment arms were grade 1/2.^16,49 The most frequent nonhematologic adverse events (per 100 patient-years of exposure) in the ruxolitinib arm were headache (10.5%), diarrhea (9.7%), pruritus (9.7%), and fatigue (8.3%). The most common grade 3/4 nonhematologic adverse events (occurring at a rate of ≥0.9 per 100 patient-years of exposure) were limited to dyspnea (1.3%), abdominal pain (0.9%), headache (0.9%), and herpes zoster (0.9%).⁴⁹ Hematologic adverse event rates in the ruxolitinib and BAT arms included anemia (any grade, 27.2% vs 47.6%, respectively; grade 3/4, 0.9% vs 0%), lymphopenia (27.2% vs 78.8%; 9.7% vs 27.2%), and thrombocytopenia (14.9% vs 29.9%; 2.6% vs 5.4%).⁴⁹ Herpes zoster infections occurred more frequently in the ruxolitinib arm (any grade, 5.3%; grade 3/4, 0.9%) compared with the BAT arm (no herpes zoster events).⁴⁹ There was a higher rate of nonmelanoma skin cancer (NMSC) in the ruxolitinib arm (4.4%), compared with the BAT arm (2.7%),⁴⁹ most of which occurred in patients with a history of NMSC or precancerous skin lesions.¹⁶ Grade 1 or 2 elevations in serum lipids and cholesterol were observed with ruxolitinib but not BAT; however, subsequent effects on patient outcomes have not been determined.^8,16 The rates of MF and AML transformations were 1.3% and 0.4%, respectively, in patients randomized to receive ruxolitinib,⁴⁹ similar to previously published reports for patients with polycythemia vera.⁴⁴

Additional insight regarding the effect of ruxolitinib on polycythemia vera–related symptoms is available from the RELIEF trial, a randomized, multicenter, double-blind, double-dummy, phase 3b clinical trial. In RELIEF, 110 patients were randomized to receive ruxolitinib or a stable dose of hydroxyurea and were then asked to record disease-related symptoms.⁵¹ Although the study failed to meet its primary endpoint (a ≥50% improvement by week 16 in MPN-SAF total symptom score for the cytokine symptom cluster [sum of individual scores for tiredness, itching, muscle aches, night sweats, and sweats while awake]), a numerically greater proportion of patients receiving ruxolitinib achieved the primary endpoint compared with those receiving hydroxyurea (43.4% and 29.6%, respectively; P = .139; odds ratio, 1.82; 95% confidence interval, 0.82-4.04). Similarly, the proportion of patients reporting a ≥50% improvement in pruritus and fatigue favored ruxolitinib over hydroxyurea (itching, 40.0% vs 26.4%; tiredness, 54.2% vs 32.0%). The safety profile for ruxolitinib was similar to that reported in the RESPONSE trial.

Possible future treatment options

Other possible treatment options for patients with polycythemia vera that are currently in clinical development include three pegylated IFN-α (PEG-IFN-α) variants and the telomerase inhibitor, imetelstat.

Pegylated interferon-α. PEG–IFN-α has the advantage of a longer plasma half-life compared with conventional IFN-α, permitting administration once per week or less often.⁴⁶ Currently, three variants are under active investigation in phase 3 clinical trials: PEG–IFN-α2a (NCT01259856 and NCT01387763), PEG–IFN-α2b (NCT01387763), and AOP2014/P1101 (NCT02218047, NCT02523638, and NCT01949805).

Imetelstat. The telomerase inhibitor imetelstat is in clinical development for patients with MPNs. Clinical benefit was previously observed in patients with primary MF as well as post-polycythemia vera and post-ET MF.⁵² Imetelstat was evaluated in a phase 2 trial in patients with polycythemia vera or ET who required cytoreductive therapy and were resistant to or intolerant of ≥1 previous line of therapy or who refused standard therapy (NCT01243073). Results in patients with ET were published,⁵³ however, findings from the polycythemia vera cohort have not been reported.

Community oncologist role in managing disease burden

Most patients with polycythemia vera are managed in the community setting. Consequently, the community oncologist plays a critical role in the initial diagnosis, risk stratification, patient education, and disease management.

Early disease recognition allows prompt therapeutic intervention with low-dose aspirin and phlebotomy, interventions shown to reduce the risk of cardiovascular events based on the ECLAP³² and CYTO-PV trials,¹² respectively. The diagnosis of polycythemia vera is facilitated by applying the WHO diagnostic criteria (Figure 2);¹ however, one should be aware of atypical presentations, including “masked” polycythemia vera,³⁰ as well as the development of thrombosis at atypical sites.²⁶

Optimal management strategies must include the frequent assessment of symptom burden and its effect on a patient’s QoL, with a keen awareness of the nonspecific nature of polycythemia vera–related symptoms, and the potential for patients and clinicians to minimize that effect.²⁰ Patient-reported symptom severity and QoL should be assessed at each office visit with validated instruments, such as the MPN-SAF 10-item questionnaire.²²It is important for the community oncologist to define treatment goals and implement a plan that reduces disease-associated morbidity and mortality. A critical treatment goal is to maintain hematocrit <45% by the appropriate use of phlebotomy¹² and/or cytoreductive agents.^12,16,46 Continued reassessment is important to identify patients with progressive disease and those who fail to achieve stated treatment goals or require an adjustment in cytoreductive therapy. Oncologists should be familiar with the concept of hydroxyurea resistance/intolerance as defined by the ELN (Table)^31,45 to allow early identification of those patients who are most likely to benefit from a treatment change for continued optimal outcome.

Conclusions

Polycythemia vera is a clonal myeloproliferative neoplasm associated with significant disease-related morbidity and mortality. Appropriate management includes early diagnosis and implementation of appropriate therapy according to patient risk and therapeutic tolerance. Patients should initially receive aspirin³² and phlebotomy,¹² with the goal of maintaining hematocrit <45%. Higher-risk patients and those who had inadequate disease control with phlebotomy alone require cytoreduction, typically with hydroxyurea. Although most patients will achieve adequate disease control with hydroxyurea,^33,43 one in four patients will develop drug resistance or intolerance.⁴⁴ Ruxolitinib is approved by the FDA and the EMA for the treatment of patients with polycythemia vera who are resistant to or intolerant of hydroxyurea. Compared with BAT, ruxolitinib is associated with improved hematocrit control, reductions in spleen size, a greater probability of blood count normalization, and improvement in polycythemia vera–related symptoms.¹⁶

Acknowledgments
Writing assistance was provided by Cory Pfeiffenberger, PhD, of Complete Healthcare Communications LLC, and was funded by Incyte Corporation, the maker of ruxolitinib.

Polycythemia vera, classified as a myeloproliferative neoplasm (MPN) and characterized by uncontrolled, clonal, myeloid expansion with predominant erythrocytosis,¹ affects about 100,000 individuals in the United States.² It is a chronic and burdensome disease associated with shortened survival.³ Patients are at an increased risk of cardiovascular events, solid tumors, and transformation to myelofibrosis (MF) and/or acute myeloid leukemia (AML).^4,5 Furthermore, patients generally have a reduced quality of life (QoL) stemming from prevalent and occasionally severe polycythemia vera–related signs and symptoms, including fatigue, pruritus, and splenomegaly.⁶ In general, the classical Philadelphia chromosome-negative MPNs are associated with driver mutations in the following three genes: Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL).⁷ Almost all patients with polycythemia vera have an activating mutation in the cytoplasmic signal transduction protein JAK2.⁴ Patients with essential thrombocythemia (ET) or MF can have mutations in JAK2, CALR, or MPL. However, CALR and MPL mutations are absent or exceedingly rare in patients with polycythemia vera.⁷ Diagnosis can be challenging and is currently based on 2016 World Health Organization (WHO) diagnostic criteria.¹

Management strategies include the use of aspirin, phlebotomy, and cytoreductive therapy. Ruxolitinib is a newer treatment option available for patients with polycythemia vera who are either resistant to or intolerant of hydroxyurea^8,9— a population that previously had few treatment options. It is important for community oncologists and other treating clinicians to understand current diagnostic strategy and management options based on established guidelines, recent clinical evidence, and regulatory updates.

Search and selection process for research sources

In September 2016, we searched PubMed for articles published since 2006 with polycythemia vera included in the abstract or title. The initial 1,730 publications were screened by eye to select 46 key articles that guide current management of polycythemia vera. Four studies published before 2006 were also included based on their continued relevance.

Epidemiology and pathophysiology

Based on a meta-analysis of patients from Europe and the United States, the annual incidence of polycythemia vera estimated to be between 0.7 and 2.6 per 100,000 people.¹⁰ The age-adjusted prevalence of polycythemia vera in the United States is about 45-57 per 100,000 people,² however, the true prevalence might be considerably greater.

Patients with polycythemia vera are at increased risk of cardiovascular events, thrombosis, and death.^3-5 Risk is highest among patients older than 60 years or with a history of thrombosis.¹¹ Uncontrolled myeloproliferation has also been identified as a risk factor for cardiovascular mortality and thrombosis. This was demonstrated in the prospective Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial, which reported more cardiovascular events in patients with hematocrit levels of 45%-50%, compared with those whose hematocrit levels were <45%.¹² In addition, retrospective data suggest leukocytosis is a potential risk factor for thromboembolic events and poor outcomes.¹³

Dysregulated JAK2 signaling is the principal driver of polycythemia vera pathophysiology. About 95% of patients with polycythemia vera will have an identifiable JAK2 V617F exon 14 mutation, with an additional 3%-5% demonstrating a JAK2 exon 12 mutation.^4,14 Under physiologic conditions, JAK2 interacts with the STAT family of signal transduction proteins and serves as an important regulator of normal hematopoiesis.¹⁵ Mutated, constitutively activated JAK2 signaling promotes the various polycythemia vera disease manifestations, including excessive myeloproliferation, splenomegaly,¹⁵ and constitutional symptoms.^14,16,17

Burden of disease for the individual

Mortality

Patients with polycythemia vera have an increased risk of mortality compared with an unaffected, age- and gender-matched cohort of the general population.³ A retrospective study of Medicare patients with polycythemia vera (mean age at diagnosis, 76.1 years) reported a median survival of 5.4 years, compared with 8.7 years for a matched cohort.³ A second retrospective study reported a median survival of 13.5 years (median age at diagnosis, 64 years; median follow-up time, 11.8 years).¹⁸

Leading causes of death for patients with polycythemia vera include cardiovascular and thrombotic events, the development of secondary solid tumors, and disease transformation to MF and/or AML. In the prospective European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study of 1,638 patients, 45% of deaths (74/164) resulted from cardiovascular causes (1.7 per 100 patient-years).⁵ Thirteen percent of deaths were related to either leukemic or myelofibrotic transformation, and 20% of deaths were attributed to secondary solid tumors.⁵ In a retrospective analysis of 1,545 patients with polycythemia vera followed for a median of 6.9 years after diagnosis, 347 had died, primarily from acute leukemia (10%), secondary malignancies (10%), and thrombotic events (9%).⁴ Arterial and venous thrombotic events occurred in 12% and 9% of patients, respectively, with disease transformation to MF and AML occurring in 9% and 3% of patients. Further support of an increased risk of secondary malignancies comes from a retrospective analysis of a large Swedish cancer registry (1958–2006) that found an increased risk of secondary endocrine, renal, and skin malignancies; MF; and leukemia among patients with polycythemia vera.¹⁹

Symptoms and quality of life

Symptoms of polycythemia vera vary in severity, and patients often fail to attribute symptoms to the disease.²⁰ Moreover, clinicians may underestimate a patient’s true disease burden or the effect it has on QoL.²⁰ Point-of-care metrics, such as the MPN Symptom Assessment Form (MPN-SAF), were developed to aid in identifying and grading symptom burden. Studies using this metric have reported fatigue as the most common and most severe symptom (incidence, 73%-92%), with a variety of other symptoms also affecting a majority of patients (Figure 1).^6,21-24 Although fatigue, pruritus, and a higher MPN-SAF total symptom score are significantly correlated with reduced QoL,^22,25 the recent MPN Landmark survey suggests that even patients with low symptom severity scores have a reduction in their QoL.⁶ This study also highlighted that polycythemia vera can adversely affect multiple aspects of daily living: 48% of patients reported disease interfering with daily activities; 63% with family or social life; and 37% with employment, feeling compelled to work reduced hours.⁶

Splenomegaly is a common feature of polycythemia vera, affecting an estimated one in three patients, which may result in discomfort and early satiety.⁴

Identification and diagnosis

Most patients diagnosed with polycythemia vera are between the ages of 60 and 76 years,^3-5 although about 25% are diagnosed before age 50.⁴ Tefferi and colleagues reported in a retrospective study that common features at presentation include JAK2 mutations (98%), elevated hemoglobin (73%), endogenous erythroid colony growth (73%), white blood cell count of >10.5 × 10⁹/L (49%), and platelet count of ≥450 × 10⁹/L (53%).⁴ In that same study, about a third of patients presented with a palpable spleen or polycythemia vera–related symptoms, including pruritus and vasomotor symptoms. However, many patients were asymptomatic at presentation, diagnosed incidentally by abnormal laboratory values.⁴ Patients can present with vascular thrombosis, occasionally involving atypical sites (eg, Budd-Chiari syndrome, other abdominal blood clots),²⁶ thus, a heightened awareness and testing for JAK2 mutations may be appropriate in the evaluation of such individuals.

Evidence suggests many clinicians may not rigidly apply the WHO diagnostic criteria to establish a diagnosis.^1,27,28 A recent retrospective claims analysis showed that only 40% of 121 patients diagnosed with polycythemia vera met the 2008 WHO diagnostic criteria, and for some patients, the diagnosis was based solely on the presence of the JAK2 V617F mutation.²⁹ One should be aware of individuals with “masked” polycythemia vera, who may present with characteristic polycythemia vera features but have hemoglobin levels below those established by the WHO in 2008, typically owing to iron deficiency and/or a disproportionate expansion of plasma volume.³⁰ To improve polycythemia vera diagnosis, the WHO diagnostic criteria were updated in 2016 with reduced hemoglobin diagnostic thresholds (Figure 2).¹

Management strategy

Treatment goals

The primary polycythemia vera–treatment goals are to reduce the risk of cardiovascular, thrombotic, and hemorrhagic events; reduce the risk of fibrotic and/or leukemic transformation; and alleviate polycythemia vera–related symptoms.^11,31

Traditional treatment options

Aspirin. To reduce the risk of death from cardiovascular events, patients with polycythemia vera should receive low-dose aspirin³² and undergo phlebotomy to maintain a target hematocrit <45%, as established by the ECLAP and CYTO-PV trials (Figure 3).^{4,5,12,13,16,32-36} Higher doses of aspirin (ie, 325 mg 2 or more times a week) are associated with a dose-dependent increased risk of gastrointestinal bleeding.³⁷ Low-dose aspirin is generally well tolerated; however, patients with extreme thrombocytosis may develop bleeding as a consequence of a well-described, thrombocytosis-associated acquired von Willebrand disease.^11,38

Most patients benefit from long-term treatment with hydroxyurea; however, 25% develop resistance to or intolerance of hydroxyurea therapy.⁴⁴ Intolerance typically manifests as leg ulcers or other mucocutaneous toxicity, gastrointestinal side effects, or fever.⁴⁴ Resistance to hydroxyurea is defined as failure to achieve phlebotomy independence, persistent leukothrombocytosis or splenomegaly despite adequate doses of hydroxyurea, or inability to deliver the drug owing to dose-limiting cytopenias. The European LeukemiaNet (ELN) formally codified and published a definition of hydroxyurea resistance/intolerance⁴⁵ (Table), which can be used to identify patients at high risk of poor outcomes.⁴⁴ In a retrospective chart review of 261 patients with polycythemia vera, those meeting the ELN definition of hydroxyurea resistance had a 5.6-fold greater risk of mortality and a 6.8-fold increased risk of fibrotic and/or leukemic disease transformation.⁴⁴

Allogenic transplantation. Although allogeneic transplantation is a potentially curative treatment option, it has been reserved primarily for younger patients with MPNs (age <60 years³¹). Furthermore, a recent systematic review concluded that overall survival was worse following allogeneic transplantation compared with a nontransplant approach (ie, phlebotomy and aspirin).⁴⁸

Ruxolitinib. The oral JAK1/JAK2 inhibitor ruxolitinib has been approved by the US Food and Drug Administration (FDA) for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea,⁸ and by the European Medicines Agency (EMA) for adult patients with polycythemia vera who are resistant to or intolerant of hydroxyurea.⁹ Ruxolitinib is also approved by the FDA for patients with intermediate- or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF,⁸ and for similar patient populations by the EMA.⁹

Approval of ruxolitinib for the treatment of patients with polycythemia vera was based on the phase 3 randomized, open-label, multicenter RESPONSE trial in which 222 patients with polycythemia vera who met the modified ELN criteria for hydroxyurea resistance or intolerance (Table)^16,31 were randomized to ruxolitinib or best available therapy (BAT). Compared with BAT, a greater proportion of patients treated with ruxolitinib achieved the primary composite endpoint of hematocrit control without the need for phlebotomy and ≥35% reduction in spleen volume by week 32 (22.7% vs 0.9%; P < .001).^16,49 When looked at individually, hematocrit control and reduction in spleen size favored ruxolitinib over BAT (hematocrit control, 60.0% vs 18.8%, ruxolitinib and BAT, respectively; ≥35% reduction in spleen volume, 40.0% vs 0.9%). Furthermore, more patients receiving ruxolitinib achieved the key secondary endpoint of complete hematologic remission than did those receiving BAT (ie, normalization of blood counts; 23.6% vs 8.0%; P = .0016).^16,49 Of note is that most patients who achieved primary treatment responses maintained disease control for ≥80 weeks.⁴⁹

Results from RESPONSE indicate that ruxolitinib may substantially improve polycythemia vera–related symptoms. Treatment with ruxolitinib was associated with a greater improvement in nearly all symptoms evaluated by the MPN-SAF as well as greater improvements in QoL and functional measures with the EORTC QLQ-C30 trial metric compared with BAT (Figure 1).¹⁶ In addition, a post hoc exploratory analysis of RESPONSE indicated that patients receiving ruxolitinib showed a rapid normalization of abnormal iron indices at baseline, compared with those receiving BAT.⁵⁰

Treatment safety and tolerability are particularly important considerations for patients with polycythemia vera, given the long natural history of the disease. In a preplanned analysis of RESPONSE at 80 weeks, 83% of patients randomized to receive treatment with ruxolitinib remained on treatment (median exposure, 111 weeks).⁴⁹ Most adverse events reported in both treatment arms were grade 1/2.^16,49 The most frequent nonhematologic adverse events (per 100 patient-years of exposure) in the ruxolitinib arm were headache (10.5%), diarrhea (9.7%), pruritus (9.7%), and fatigue (8.3%). The most common grade 3/4 nonhematologic adverse events (occurring at a rate of ≥0.9 per 100 patient-years of exposure) were limited to dyspnea (1.3%), abdominal pain (0.9%), headache (0.9%), and herpes zoster (0.9%).⁴⁹ Hematologic adverse event rates in the ruxolitinib and BAT arms included anemia (any grade, 27.2% vs 47.6%, respectively; grade 3/4, 0.9% vs 0%), lymphopenia (27.2% vs 78.8%; 9.7% vs 27.2%), and thrombocytopenia (14.9% vs 29.9%; 2.6% vs 5.4%).⁴⁹ Herpes zoster infections occurred more frequently in the ruxolitinib arm (any grade, 5.3%; grade 3/4, 0.9%) compared with the BAT arm (no herpes zoster events).⁴⁹ There was a higher rate of nonmelanoma skin cancer (NMSC) in the ruxolitinib arm (4.4%), compared with the BAT arm (2.7%),⁴⁹ most of which occurred in patients with a history of NMSC or precancerous skin lesions.¹⁶ Grade 1 or 2 elevations in serum lipids and cholesterol were observed with ruxolitinib but not BAT; however, subsequent effects on patient outcomes have not been determined.^8,16 The rates of MF and AML transformations were 1.3% and 0.4%, respectively, in patients randomized to receive ruxolitinib,⁴⁹ similar to previously published reports for patients with polycythemia vera.⁴⁴

Additional insight regarding the effect of ruxolitinib on polycythemia vera–related symptoms is available from the RELIEF trial, a randomized, multicenter, double-blind, double-dummy, phase 3b clinical trial. In RELIEF, 110 patients were randomized to receive ruxolitinib or a stable dose of hydroxyurea and were then asked to record disease-related symptoms.⁵¹ Although the study failed to meet its primary endpoint (a ≥50% improvement by week 16 in MPN-SAF total symptom score for the cytokine symptom cluster [sum of individual scores for tiredness, itching, muscle aches, night sweats, and sweats while awake]), a numerically greater proportion of patients receiving ruxolitinib achieved the primary endpoint compared with those receiving hydroxyurea (43.4% and 29.6%, respectively; P = .139; odds ratio, 1.82; 95% confidence interval, 0.82-4.04). Similarly, the proportion of patients reporting a ≥50% improvement in pruritus and fatigue favored ruxolitinib over hydroxyurea (itching, 40.0% vs 26.4%; tiredness, 54.2% vs 32.0%). The safety profile for ruxolitinib was similar to that reported in the RESPONSE trial.

Possible future treatment options

Other possible treatment options for patients with polycythemia vera that are currently in clinical development include three pegylated IFN-α (PEG-IFN-α) variants and the telomerase inhibitor, imetelstat.

Pegylated interferon-α. PEG–IFN-α has the advantage of a longer plasma half-life compared with conventional IFN-α, permitting administration once per week or less often.⁴⁶ Currently, three variants are under active investigation in phase 3 clinical trials: PEG–IFN-α2a (NCT01259856 and NCT01387763), PEG–IFN-α2b (NCT01387763), and AOP2014/P1101 (NCT02218047, NCT02523638, and NCT01949805).

Imetelstat. The telomerase inhibitor imetelstat is in clinical development for patients with MPNs. Clinical benefit was previously observed in patients with primary MF as well as post-polycythemia vera and post-ET MF.⁵² Imetelstat was evaluated in a phase 2 trial in patients with polycythemia vera or ET who required cytoreductive therapy and were resistant to or intolerant of ≥1 previous line of therapy or who refused standard therapy (NCT01243073). Results in patients with ET were published,⁵³ however, findings from the polycythemia vera cohort have not been reported.

Community oncologist role in managing disease burden

Most patients with polycythemia vera are managed in the community setting. Consequently, the community oncologist plays a critical role in the initial diagnosis, risk stratification, patient education, and disease management.

Early disease recognition allows prompt therapeutic intervention with low-dose aspirin and phlebotomy, interventions shown to reduce the risk of cardiovascular events based on the ECLAP³² and CYTO-PV trials,¹² respectively. The diagnosis of polycythemia vera is facilitated by applying the WHO diagnostic criteria (Figure 2);¹ however, one should be aware of atypical presentations, including “masked” polycythemia vera,³⁰ as well as the development of thrombosis at atypical sites.²⁶

Optimal management strategies must include the frequent assessment of symptom burden and its effect on a patient’s QoL, with a keen awareness of the nonspecific nature of polycythemia vera–related symptoms, and the potential for patients and clinicians to minimize that effect.²⁰ Patient-reported symptom severity and QoL should be assessed at each office visit with validated instruments, such as the MPN-SAF 10-item questionnaire.²²It is important for the community oncologist to define treatment goals and implement a plan that reduces disease-associated morbidity and mortality. A critical treatment goal is to maintain hematocrit <45% by the appropriate use of phlebotomy¹² and/or cytoreductive agents.^12,16,46 Continued reassessment is important to identify patients with progressive disease and those who fail to achieve stated treatment goals or require an adjustment in cytoreductive therapy. Oncologists should be familiar with the concept of hydroxyurea resistance/intolerance as defined by the ELN (Table)^31,45 to allow early identification of those patients who are most likely to benefit from a treatment change for continued optimal outcome.

Conclusions

Polycythemia vera is a clonal myeloproliferative neoplasm associated with significant disease-related morbidity and mortality. Appropriate management includes early diagnosis and implementation of appropriate therapy according to patient risk and therapeutic tolerance. Patients should initially receive aspirin³² and phlebotomy,¹² with the goal of maintaining hematocrit <45%. Higher-risk patients and those who had inadequate disease control with phlebotomy alone require cytoreduction, typically with hydroxyurea. Although most patients will achieve adequate disease control with hydroxyurea,^33,43 one in four patients will develop drug resistance or intolerance.⁴⁴ Ruxolitinib is approved by the FDA and the EMA for the treatment of patients with polycythemia vera who are resistant to or intolerant of hydroxyurea. Compared with BAT, ruxolitinib is associated with improved hematocrit control, reductions in spleen size, a greater probability of blood count normalization, and improvement in polycythemia vera–related symptoms.¹⁶

Acknowledgments
Writing assistance was provided by Cory Pfeiffenberger, PhD, of Complete Healthcare Communications LLC, and was funded by Incyte Corporation, the maker of ruxolitinib.

Polycythemia vera, classified as a myeloproliferative neoplasm (MPN) and characterized by uncontrolled, clonal, myeloid expansion with predominant erythrocytosis,¹ affects about 100,000 individuals in the United States.² It is a chronic and burdensome disease associated with shortened survival.³ Patients are at an increased risk of cardiovascular events, solid tumors, and transformation to myelofibrosis (MF) and/or acute myeloid leukemia (AML).^4,5 Furthermore, patients generally have a reduced quality of life (QoL) stemming from prevalent and occasionally severe polycythemia vera–related signs and symptoms, including fatigue, pruritus, and splenomegaly.⁶ In general, the classical Philadelphia chromosome-negative MPNs are associated with driver mutations in the following three genes: Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL).⁷ Almost all patients with polycythemia vera have an activating mutation in the cytoplasmic signal transduction protein JAK2.⁴ Patients with essential thrombocythemia (ET) or MF can have mutations in JAK2, CALR, or MPL. However, CALR and MPL mutations are absent or exceedingly rare in patients with polycythemia vera.⁷ Diagnosis can be challenging and is currently based on 2016 World Health Organization (WHO) diagnostic criteria.¹

Management strategies include the use of aspirin, phlebotomy, and cytoreductive therapy. Ruxolitinib is a newer treatment option available for patients with polycythemia vera who are either resistant to or intolerant of hydroxyurea^8,9— a population that previously had few treatment options. It is important for community oncologists and other treating clinicians to understand current diagnostic strategy and management options based on established guidelines, recent clinical evidence, and regulatory updates.

Search and selection process for research sources

In September 2016, we searched PubMed for articles published since 2006 with polycythemia vera included in the abstract or title. The initial 1,730 publications were screened by eye to select 46 key articles that guide current management of polycythemia vera. Four studies published before 2006 were also included based on their continued relevance.

Epidemiology and pathophysiology

Based on a meta-analysis of patients from Europe and the United States, the annual incidence of polycythemia vera estimated to be between 0.7 and 2.6 per 100,000 people.¹⁰ The age-adjusted prevalence of polycythemia vera in the United States is about 45-57 per 100,000 people,² however, the true prevalence might be considerably greater.

Patients with polycythemia vera are at increased risk of cardiovascular events, thrombosis, and death.^3-5 Risk is highest among patients older than 60 years or with a history of thrombosis.¹¹ Uncontrolled myeloproliferation has also been identified as a risk factor for cardiovascular mortality and thrombosis. This was demonstrated in the prospective Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial, which reported more cardiovascular events in patients with hematocrit levels of 45%-50%, compared with those whose hematocrit levels were <45%.¹² In addition, retrospective data suggest leukocytosis is a potential risk factor for thromboembolic events and poor outcomes.¹³

Dysregulated JAK2 signaling is the principal driver of polycythemia vera pathophysiology. About 95% of patients with polycythemia vera will have an identifiable JAK2 V617F exon 14 mutation, with an additional 3%-5% demonstrating a JAK2 exon 12 mutation.^4,14 Under physiologic conditions, JAK2 interacts with the STAT family of signal transduction proteins and serves as an important regulator of normal hematopoiesis.¹⁵ Mutated, constitutively activated JAK2 signaling promotes the various polycythemia vera disease manifestations, including excessive myeloproliferation, splenomegaly,¹⁵ and constitutional symptoms.^14,16,17

Burden of disease for the individual

Mortality

Patients with polycythemia vera have an increased risk of mortality compared with an unaffected, age- and gender-matched cohort of the general population.³ A retrospective study of Medicare patients with polycythemia vera (mean age at diagnosis, 76.1 years) reported a median survival of 5.4 years, compared with 8.7 years for a matched cohort.³ A second retrospective study reported a median survival of 13.5 years (median age at diagnosis, 64 years; median follow-up time, 11.8 years).¹⁸

Leading causes of death for patients with polycythemia vera include cardiovascular and thrombotic events, the development of secondary solid tumors, and disease transformation to MF and/or AML. In the prospective European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study of 1,638 patients, 45% of deaths (74/164) resulted from cardiovascular causes (1.7 per 100 patient-years).⁵ Thirteen percent of deaths were related to either leukemic or myelofibrotic transformation, and 20% of deaths were attributed to secondary solid tumors.⁵ In a retrospective analysis of 1,545 patients with polycythemia vera followed for a median of 6.9 years after diagnosis, 347 had died, primarily from acute leukemia (10%), secondary malignancies (10%), and thrombotic events (9%).⁴ Arterial and venous thrombotic events occurred in 12% and 9% of patients, respectively, with disease transformation to MF and AML occurring in 9% and 3% of patients. Further support of an increased risk of secondary malignancies comes from a retrospective analysis of a large Swedish cancer registry (1958–2006) that found an increased risk of secondary endocrine, renal, and skin malignancies; MF; and leukemia among patients with polycythemia vera.¹⁹

Symptoms and quality of life

Symptoms of polycythemia vera vary in severity, and patients often fail to attribute symptoms to the disease.²⁰ Moreover, clinicians may underestimate a patient’s true disease burden or the effect it has on QoL.²⁰ Point-of-care metrics, such as the MPN Symptom Assessment Form (MPN-SAF), were developed to aid in identifying and grading symptom burden. Studies using this metric have reported fatigue as the most common and most severe symptom (incidence, 73%-92%), with a variety of other symptoms also affecting a majority of patients (Figure 1).^6,21-24 Although fatigue, pruritus, and a higher MPN-SAF total symptom score are significantly correlated with reduced QoL,^22,25 the recent MPN Landmark survey suggests that even patients with low symptom severity scores have a reduction in their QoL.⁶ This study also highlighted that polycythemia vera can adversely affect multiple aspects of daily living: 48% of patients reported disease interfering with daily activities; 63% with family or social life; and 37% with employment, feeling compelled to work reduced hours.⁶

Splenomegaly is a common feature of polycythemia vera, affecting an estimated one in three patients, which may result in discomfort and early satiety.⁴

Identification and diagnosis

Most patients diagnosed with polycythemia vera are between the ages of 60 and 76 years,^3-5 although about 25% are diagnosed before age 50.⁴ Tefferi and colleagues reported in a retrospective study that common features at presentation include JAK2 mutations (98%), elevated hemoglobin (73%), endogenous erythroid colony growth (73%), white blood cell count of >10.5 × 10⁹/L (49%), and platelet count of ≥450 × 10⁹/L (53%).⁴ In that same study, about a third of patients presented with a palpable spleen or polycythemia vera–related symptoms, including pruritus and vasomotor symptoms. However, many patients were asymptomatic at presentation, diagnosed incidentally by abnormal laboratory values.⁴ Patients can present with vascular thrombosis, occasionally involving atypical sites (eg, Budd-Chiari syndrome, other abdominal blood clots),²⁶ thus, a heightened awareness and testing for JAK2 mutations may be appropriate in the evaluation of such individuals.

Evidence suggests many clinicians may not rigidly apply the WHO diagnostic criteria to establish a diagnosis.^1,27,28 A recent retrospective claims analysis showed that only 40% of 121 patients diagnosed with polycythemia vera met the 2008 WHO diagnostic criteria, and for some patients, the diagnosis was based solely on the presence of the JAK2 V617F mutation.²⁹ One should be aware of individuals with “masked” polycythemia vera, who may present with characteristic polycythemia vera features but have hemoglobin levels below those established by the WHO in 2008, typically owing to iron deficiency and/or a disproportionate expansion of plasma volume.³⁰ To improve polycythemia vera diagnosis, the WHO diagnostic criteria were updated in 2016 with reduced hemoglobin diagnostic thresholds (Figure 2).¹

Management strategy

Treatment goals

The primary polycythemia vera–treatment goals are to reduce the risk of cardiovascular, thrombotic, and hemorrhagic events; reduce the risk of fibrotic and/or leukemic transformation; and alleviate polycythemia vera–related symptoms.^11,31

Traditional treatment options

Aspirin. To reduce the risk of death from cardiovascular events, patients with polycythemia vera should receive low-dose aspirin³² and undergo phlebotomy to maintain a target hematocrit <45%, as established by the ECLAP and CYTO-PV trials (Figure 3).^{4,5,12,13,16,32-36} Higher doses of aspirin (ie, 325 mg 2 or more times a week) are associated with a dose-dependent increased risk of gastrointestinal bleeding.³⁷ Low-dose aspirin is generally well tolerated; however, patients with extreme thrombocytosis may develop bleeding as a consequence of a well-described, thrombocytosis-associated acquired von Willebrand disease.^11,38

Most patients benefit from long-term treatment with hydroxyurea; however, 25% develop resistance to or intolerance of hydroxyurea therapy.⁴⁴ Intolerance typically manifests as leg ulcers or other mucocutaneous toxicity, gastrointestinal side effects, or fever.⁴⁴ Resistance to hydroxyurea is defined as failure to achieve phlebotomy independence, persistent leukothrombocytosis or splenomegaly despite adequate doses of hydroxyurea, or inability to deliver the drug owing to dose-limiting cytopenias. The European LeukemiaNet (ELN) formally codified and published a definition of hydroxyurea resistance/intolerance⁴⁵ (Table), which can be used to identify patients at high risk of poor outcomes.⁴⁴ In a retrospective chart review of 261 patients with polycythemia vera, those meeting the ELN definition of hydroxyurea resistance had a 5.6-fold greater risk of mortality and a 6.8-fold increased risk of fibrotic and/or leukemic disease transformation.⁴⁴

Allogenic transplantation. Although allogeneic transplantation is a potentially curative treatment option, it has been reserved primarily for younger patients with MPNs (age <60 years³¹). Furthermore, a recent systematic review concluded that overall survival was worse following allogeneic transplantation compared with a nontransplant approach (ie, phlebotomy and aspirin).⁴⁸

Ruxolitinib. The oral JAK1/JAK2 inhibitor ruxolitinib has been approved by the US Food and Drug Administration (FDA) for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea,⁸ and by the European Medicines Agency (EMA) for adult patients with polycythemia vera who are resistant to or intolerant of hydroxyurea.⁹ Ruxolitinib is also approved by the FDA for patients with intermediate- or high-risk MF, including primary MF, post-polycythemia vera MF, and post-essential thrombocythemia MF,⁸ and for similar patient populations by the EMA.⁹

Approval of ruxolitinib for the treatment of patients with polycythemia vera was based on the phase 3 randomized, open-label, multicenter RESPONSE trial in which 222 patients with polycythemia vera who met the modified ELN criteria for hydroxyurea resistance or intolerance (Table)^16,31 were randomized to ruxolitinib or best available therapy (BAT). Compared with BAT, a greater proportion of patients treated with ruxolitinib achieved the primary composite endpoint of hematocrit control without the need for phlebotomy and ≥35% reduction in spleen volume by week 32 (22.7% vs 0.9%; P < .001).^16,49 When looked at individually, hematocrit control and reduction in spleen size favored ruxolitinib over BAT (hematocrit control, 60.0% vs 18.8%, ruxolitinib and BAT, respectively; ≥35% reduction in spleen volume, 40.0% vs 0.9%). Furthermore, more patients receiving ruxolitinib achieved the key secondary endpoint of complete hematologic remission than did those receiving BAT (ie, normalization of blood counts; 23.6% vs 8.0%; P = .0016).^16,49 Of note is that most patients who achieved primary treatment responses maintained disease control for ≥80 weeks.⁴⁹

Results from RESPONSE indicate that ruxolitinib may substantially improve polycythemia vera–related symptoms. Treatment with ruxolitinib was associated with a greater improvement in nearly all symptoms evaluated by the MPN-SAF as well as greater improvements in QoL and functional measures with the EORTC QLQ-C30 trial metric compared with BAT (Figure 1).¹⁶ In addition, a post hoc exploratory analysis of RESPONSE indicated that patients receiving ruxolitinib showed a rapid normalization of abnormal iron indices at baseline, compared with those receiving BAT.⁵⁰

Treatment safety and tolerability are particularly important considerations for patients with polycythemia vera, given the long natural history of the disease. In a preplanned analysis of RESPONSE at 80 weeks, 83% of patients randomized to receive treatment with ruxolitinib remained on treatment (median exposure, 111 weeks).⁴⁹ Most adverse events reported in both treatment arms were grade 1/2.^16,49 The most frequent nonhematologic adverse events (per 100 patient-years of exposure) in the ruxolitinib arm were headache (10.5%), diarrhea (9.7%), pruritus (9.7%), and fatigue (8.3%). The most common grade 3/4 nonhematologic adverse events (occurring at a rate of ≥0.9 per 100 patient-years of exposure) were limited to dyspnea (1.3%), abdominal pain (0.9%), headache (0.9%), and herpes zoster (0.9%).⁴⁹ Hematologic adverse event rates in the ruxolitinib and BAT arms included anemia (any grade, 27.2% vs 47.6%, respectively; grade 3/4, 0.9% vs 0%), lymphopenia (27.2% vs 78.8%; 9.7% vs 27.2%), and thrombocytopenia (14.9% vs 29.9%; 2.6% vs 5.4%).⁴⁹ Herpes zoster infections occurred more frequently in the ruxolitinib arm (any grade, 5.3%; grade 3/4, 0.9%) compared with the BAT arm (no herpes zoster events).⁴⁹ There was a higher rate of nonmelanoma skin cancer (NMSC) in the ruxolitinib arm (4.4%), compared with the BAT arm (2.7%),⁴⁹ most of which occurred in patients with a history of NMSC or precancerous skin lesions.¹⁶ Grade 1 or 2 elevations in serum lipids and cholesterol were observed with ruxolitinib but not BAT; however, subsequent effects on patient outcomes have not been determined.^8,16 The rates of MF and AML transformations were 1.3% and 0.4%, respectively, in patients randomized to receive ruxolitinib,⁴⁹ similar to previously published reports for patients with polycythemia vera.⁴⁴

Additional insight regarding the effect of ruxolitinib on polycythemia vera–related symptoms is available from the RELIEF trial, a randomized, multicenter, double-blind, double-dummy, phase 3b clinical trial. In RELIEF, 110 patients were randomized to receive ruxolitinib or a stable dose of hydroxyurea and were then asked to record disease-related symptoms.⁵¹ Although the study failed to meet its primary endpoint (a ≥50% improvement by week 16 in MPN-SAF total symptom score for the cytokine symptom cluster [sum of individual scores for tiredness, itching, muscle aches, night sweats, and sweats while awake]), a numerically greater proportion of patients receiving ruxolitinib achieved the primary endpoint compared with those receiving hydroxyurea (43.4% and 29.6%, respectively; P = .139; odds ratio, 1.82; 95% confidence interval, 0.82-4.04). Similarly, the proportion of patients reporting a ≥50% improvement in pruritus and fatigue favored ruxolitinib over hydroxyurea (itching, 40.0% vs 26.4%; tiredness, 54.2% vs 32.0%). The safety profile for ruxolitinib was similar to that reported in the RESPONSE trial.

Possible future treatment options

Other possible treatment options for patients with polycythemia vera that are currently in clinical development include three pegylated IFN-α (PEG-IFN-α) variants and the telomerase inhibitor, imetelstat.

Pegylated interferon-α. PEG–IFN-α has the advantage of a longer plasma half-life compared with conventional IFN-α, permitting administration once per week or less often.⁴⁶ Currently, three variants are under active investigation in phase 3 clinical trials: PEG–IFN-α2a (NCT01259856 and NCT01387763), PEG–IFN-α2b (NCT01387763), and AOP2014/P1101 (NCT02218047, NCT02523638, and NCT01949805).

Imetelstat. The telomerase inhibitor imetelstat is in clinical development for patients with MPNs. Clinical benefit was previously observed in patients with primary MF as well as post-polycythemia vera and post-ET MF.⁵² Imetelstat was evaluated in a phase 2 trial in patients with polycythemia vera or ET who required cytoreductive therapy and were resistant to or intolerant of ≥1 previous line of therapy or who refused standard therapy (NCT01243073). Results in patients with ET were published,⁵³ however, findings from the polycythemia vera cohort have not been reported.

Community oncologist role in managing disease burden

Most patients with polycythemia vera are managed in the community setting. Consequently, the community oncologist plays a critical role in the initial diagnosis, risk stratification, patient education, and disease management.

Early disease recognition allows prompt therapeutic intervention with low-dose aspirin and phlebotomy, interventions shown to reduce the risk of cardiovascular events based on the ECLAP³² and CYTO-PV trials,¹² respectively. The diagnosis of polycythemia vera is facilitated by applying the WHO diagnostic criteria (Figure 2);¹ however, one should be aware of atypical presentations, including “masked” polycythemia vera,³⁰ as well as the development of thrombosis at atypical sites.²⁶

Optimal management strategies must include the frequent assessment of symptom burden and its effect on a patient’s QoL, with a keen awareness of the nonspecific nature of polycythemia vera–related symptoms, and the potential for patients and clinicians to minimize that effect.²⁰ Patient-reported symptom severity and QoL should be assessed at each office visit with validated instruments, such as the MPN-SAF 10-item questionnaire.²²It is important for the community oncologist to define treatment goals and implement a plan that reduces disease-associated morbidity and mortality. A critical treatment goal is to maintain hematocrit <45% by the appropriate use of phlebotomy¹² and/or cytoreductive agents.^12,16,46 Continued reassessment is important to identify patients with progressive disease and those who fail to achieve stated treatment goals or require an adjustment in cytoreductive therapy. Oncologists should be familiar with the concept of hydroxyurea resistance/intolerance as defined by the ELN (Table)^31,45 to allow early identification of those patients who are most likely to benefit from a treatment change for continued optimal outcome.

Conclusions

Polycythemia vera is a clonal myeloproliferative neoplasm associated with significant disease-related morbidity and mortality. Appropriate management includes early diagnosis and implementation of appropriate therapy according to patient risk and therapeutic tolerance. Patients should initially receive aspirin³² and phlebotomy,¹² with the goal of maintaining hematocrit <45%. Higher-risk patients and those who had inadequate disease control with phlebotomy alone require cytoreduction, typically with hydroxyurea. Although most patients will achieve adequate disease control with hydroxyurea,^33,43 one in four patients will develop drug resistance or intolerance.⁴⁴ Ruxolitinib is approved by the FDA and the EMA for the treatment of patients with polycythemia vera who are resistant to or intolerant of hydroxyurea. Compared with BAT, ruxolitinib is associated with improved hematocrit control, reductions in spleen size, a greater probability of blood count normalization, and improvement in polycythemia vera–related symptoms.¹⁶

Acknowledgments
Writing assistance was provided by Cory Pfeiffenberger, PhD, of Complete Healthcare Communications LLC, and was funded by Incyte Corporation, the maker of ruxolitinib.

Breast cancer survivors comprise the most prevalent cancer survivor population in the United States.¹ The number of breast cancer survivors is increasing because of early detection and diagnosis, and advances in treatment have resulted in increased life expectancy. Therefore, greater attention is needed to improve the long-term quality of life of these survivors and to help them re-adjust to normal life. For many women, although the medical treatment may have been completed, the recovery process may have not.² The prevalence of long-term mental and physical illness is significant among many breast cancer survivors. Long-term mental consequences may include memory problems, anxiety, depression, and fear of recurrence³, and long-term physical consequences may include pain, fatigue, and lymphedema, among others.⁴

El Paso, Texas, is the fourth most populous city in Texas and has a Hispanic majority. This provides an opportunity to conduct clinical research targeting participants of Hispanic descent. Several studies have noted the influence of race/ethnicity on the psychosocial function of breast cancer survivors.^5,6 We have previously reported that Hispanic breast cancer survivors might experience decreased mental and physical health-related quality of life (QoL) which limit their normal social functioning.⁶Other studies have similarly reported poor outcomes of breast cancer survivors and higher rates of fatigue and depression among Hispanic patients.⁷ However, there is a paucity of research addressing specific interventions needed to improve these outcomes and provide better QoL for breast cancer survivors.^8,9 In addition, a few survivorship care interventions have focused on minorities. We sought to assess whether a multidisciplinary cancer survivorship program in a primarily Hispanic populated area would lead to improved QoL and reduce anxiety and depressive symptoms among breast cancer survivors.

Methods

After obtaining Institutional Review Board approval, we recruited consecutive patients who were treated at our institution during October 2013-October 2014 and obtained informed consent from them. The participants were within the first 5 years after diagnosis with stages I-III breast cancer and had completed surgery, chemotherapy, and/or radiation therapy. We sought to determine whether breast cancer survivors would benefit from this intervention as determined by improvement of performance at 12 months compared with baseline based on the following self-reported validated questionnaires: Patient Health Questionnaire-9 (PHQ-9) for depression; General Anxiety Disorder-7 (GAD-7); and Short-Form Health Survey-36 (SF-36, version 2) for patient quality of life. The participants were enrolled in a comprehensive survivorship program staffed by an oncologist, an oncology nurse practitioner, a nutritionist, and a certified clinical psychologist who had trained in mindfulness-based stress reduction (MBSR).

Interventions

The participants received a one-on-one individual psychological consultation visit every 3 months for 20-45 minutes during which the psychologist addressed each patient’s emotional and psychological issues in depth, discussed relaxation techniques, and provided psychosocial counselling. In addition, all participants were asked to attend an 8-week-course (in Spanish or English) using MBSR, an interventional program in which participants receive training to promote reduction of stress by self-regulating mindfulness practice.^3,10 Our institution’s MBSR program consists of a weekly 2-hour class for 8 sessions or more. The program is provided 3 times a year, in English and Spanish. It includes the following components:

• Learning various mindfulness meditation techniques (eg, body scans, awareness of breathing, sitting/walking meditations);
• Practicing the mindfulness techniques in class; and
• Practicing techniques at home through audiorecordings of mindfulness meditation exercises and daily diary writing.

Participants were provided with a workbook on MBSR in their preferred language.¹¹ In addition to the psychological component, they were also provided with oncologic evaluations by an oncology nurse practitioner. The nurse practitioner met with participants every 3 months and provided each one with a personalized summary of all the treatments received and routine oncology follow-up care in consultation with the patients’ regular oncologists. This care also addresses the long-term sequelae of treatment, including arthritis and osteoporosis, referrals to receive screening for other cancers (eg, cervical and colon cancer), and genetic counselling as appropriate. In addition, a nutritionist provided general dietary advice in individual and group sessions every 3 months.

The self-administered questionnaires, PHQ-9, GAD-7, and SF-36, were completed at baseline, and every 3 months for 12 months. The scores were reviewed by the psychologist and the oncologist. The PHQ-9 was used to initially screen survivors for depression and monitor their improvement after the intervention. The PHQ-9 is a reliable and validated self-administered depression module.¹² The PQH-9 exclusively focuses on the 9 diagnostic criteria for DSM-IV depression disorder and it can be used as a useful measure for monitoring outcomes of depression therapy. A score of 5-14 suggests mild-moderate depression, and a score of >15 suggests severe depression

The survivors were screened for anxiety using the GAD-7, a brief 7-item self-report scale to identify probable cases of anxiety disorder that has been shown to be an efficient tool for screening and assessing the severity of anxiety.¹³ For GAD-7, a score of 5 or higher is suggestive of anxiety. Scores of 5, 10, and 15 represent cut-off points for mild, moderate, and severe anxiety, respectively.

Survivor QoL was evaluated using the SF-36 questionnaire, a multipurpose survey containing 36 questions. It ranges from 0-100 and a score that is <50.0 is considered low. The lower the score, the worse the mental or physical function.¹⁴ The SF-36 yields a patient profile of 8 health domains – vitality, physical functioning, bodily pain, general health perceptions, physical, emotional, and social role functioning; and mental health.^15,16 A score of 50.0 on either the Physical Component Summary (PCS – vitality, physical functioning, bodily pain, general health perceptions, physical role functioning) or Mental Component Summary (MCS – emotional and social role functioning, and mental health) is consistent with the US norm.

Statistical analysis

In this study, the primary objective was to use the MBSR survivorship program to improve the survivors’ outcomes at 12 months compared with baseline using the following measures: PHQ-9 for depression, GAD-7 for anxiety, and SF-36 for QoL using the PCS and MCS. Quantitative data were described using the mean and standard deviation, and categorical data were described using frequency and percentage. The outcome measures were compared between patients who completed 12-month follow-up and those who did not, using unpaired t test. The change in outcome measures at 12 months from baseline was evaluated using paired t test. The effect of intervention was summarized using relative percentage change. The “dose” of the intervention was categorized the number of MBSR sessions – ≤4 sessions, 5-7 sessions, or ≤8 sessions. The change in outcome measures were compared among three groups using 1-way analysis of variance (ANOVA) followed by post hoc multiple comparison using the Bonferroni adjustment. In addition, the effect of intervention on each outcome was evaluated by important baseline characteristics of patients. In each subgroup, the changes were compared with baseline measures using the paired t test, whereas changes in outcome between groups were compared using the unpaired t test. Statistical analyses were conducted using SAS 9.3. P-values less than 5% were considered to be significant.

Results

A total of 94 survivors of breast cancer were included in this study and 60 (63.8%) completed the 12 months of follow-up. The average age of the participants was 54.4 years (SD, 8.7), and 90.4% were Hispanic (Table 1). Tumor characteristics were as follows: invasive ductal carcinoma (84.04%), estrogen receptor–positive (ER-, 71.28%), progesterone receptor–positive (PR-, 58.51%), and HER2-neu–positive (20%). In regard to therapy received, 48% of the participants had received anthracycline- and taxane-based adjuvant chemotherapy and 23%, nonanthracycline-based chemotherapy; 71% had received anti-estrogen (hormonal) therapy and 80%, radiation therapy. In regard to surgery, half of the participants had a lumpectomy, and half, a mastectomy. The trends in the outcome measures over the follow-up period are show in the Figure 1.

The effect of the number of MBSR sessions attended on the outcome measures is summarized in Table 3. There were significant improvements in the 12-month MCS scores for patients who completed 5-7 sessions of MBSR or ≥8 sessions, compared with patients who completed ≤4 sessions of MBSR. There was an improvement observed in PCS scores only among patients who received at least 8 sessions of MBSR. There was a marked improvement observed in GAD-7 and PHQ-9 among patients who received ≥8 sessions. There was no statistically significant change in the GAD-7 or PHQ-9 scores between patients who received ≤4 sessions and 5-7 sessions. No significant association was obtained between number of MBSR sessions attended and BMI.

Discussion

In this study, we showed that a group of predominately Hispanic breast cancer survivors benefited from participating in a multidisciplinary cancer survivorship program that emphasized in-depth psychological care and MBSR. They also benefited from an education effort that included providing survivors with personalized summaries of their treatment and oncology survivorship care, addressing potential long-term side effects of treatment, referral for genetic counselling and screening for other cancers as appropriate, as well dietary advice. We found significant improvement compared with baseline in both mental and physical determinants of the patient-reported outcomes, including anxiety (GAD-7), depression (PHQ-9), and HR-QoL (PCS) and (MCS). Survivors demonstrated significant improvement on the MCS and PHQ-9 if they attended 5 or more sessions of the 8-week MBSR course, and attending 8 sessions was associated with significant improvement in GAD-7 and PCS. This might suggest that survivors who are more motivated do benefit the most from such program.

To our knowledge, this study is the first to address the benefit of the MBSR intervention in Hispanic breast cancer survivors. In a randomized controlled trial that included breast cancer survivors with stages 0-III breast cancer who completed surgery, adjunctive radiation, and/or chemotherapy, MBSR was shown to reduce the symptoms of depression and anxiety and increase energy and physical functioning compared with participants who received “usual care”.³ Furthermore, Bower and colleagues have reported improvements in sleep, fatigue, and pro-inflammatory signaling in younger survivors of breast cancer.¹⁷ A similar standardized MBSR program was tested on Danish women who had been treated for stage I-III breast cancer¹⁸ and the results showed reduced levels of anxiety and depression at the 12-month follow-up. A similar study by Hoffman and colleagues¹⁹ reported improved mood, breast- and endocrine-related quality of life, and well-being with MBSR compared with standard care in women with stage 0-III breast cancer.

Several theories have been suggested to explain how MBSR reduces symptoms of depression, anxiety, and fear of recurrence in breast cancer survivors, one of which is that it provides supportive interaction between group members to practice meditation and apply mindfulness in daily situations.³ In addition, evidence is beginning to emerge that stress-reducing interventions such as MBSR may improve telomere length (TL) and telomerase activity (TA), the markers for cellular aging, psychological stress, and disease risk.^20-24 Lengacher and colleagues conducted a randomized controlled study to investigate the effects of MBSR on TL and TA in women with breast cancer, and suggested that MBSR increases telomere length and telomerase activity.²⁵ The 142 patients with stages 0-III breast cancer had completed adjuvant treatment with radiation and/or chemotherapy at least 2 weeks before enrollment and within 2 years of completion of treatment with lumpectomy and/or mastectomy. They were randomly assigned to either a 6-week MBSR for breast cancer program or usual care.²⁵ Assessments of TA and TL were obtained along with psychological measurements at baseline, 6 weeks, and 12 weeks after the patients had completed the MBSR program. The mean age of the participants was 55.3 years; 72% were non-Hispanic white; 78% had stage I or II cancer; and 36% received both chemotherapy and radiation. In analyses adjusted for baseline TA and psychological status, TA increased steadily by about 17% over 12 weeks in the MBSR group, compared with about 3% (P < .01) in the control group. No difference was observed for TL (P = .92). The authors concluded that the data provide preliminary evidence that MBSR increases TA in peripheral blood mononuclear cells from breast cancer patients and have implications for understanding how MBSR may extend cell longevity at the cellular level.

In another study among healthy volunteers who were randomly assigned to a 3-month meditation retreat or a control group, the 30 participants in the meditation group had higher TA compared with controls.²⁰ In a nonrandomized study among prostate cancer patients, TA increased and psychological stress decreased following a stress-reducing, lifestyle-modification program.²¹ The results of another intervention study among overweight women showed improvement in distress, eating behavior, and metabolic health in women participating in a MBSR program, all of which correlated with increases in TA.²² Most recently, researchers explored the impact on TA of a Kirtan Kriya yogic meditation intervention compared with exposure to relaxing music in 39 dementia family caregivers. The yogic-meditation intervention group had a 43% increase in TA after the 8-week intervention period compared with 3.7% the music group (P < .05).²³ Finally, among 22 patients with cervical cancer who were randomized to a psychosocial telephone counseling intervention,²⁴ investigators found a significant association between increased TL and changes in psychological distress.²⁰ Findings from other studies have assessed interventions to improve outcome of breast cancer survivors, such as the Taking CHARGE self-management intervention that is designed to facilitate the transition to survivorship after breast cancer treatment.⁸ Another intervention using home-based physical activity was shown in a randomized controlled trial to improve self-reported physical activity, body-mass index, and health-related QoL.⁹ Findings from another study suggested that a combined exercise and psychological counselling program might improve QoL more than a single entity intervention.²⁶ As noted previously, these studies did not focus on minority breast cancer survivors’ population, and it is not clear if they are generalizable to Hispanics.

In addition to the MBSR component, our program has also included one-on-one psychological assessment for long-term treatment complications and provided participants with appropriate care and follow-up plans, adding the benefits of self-awareness and self-attention for the survivors, which can effectively reduce the fear of recurrence.³ Furthermore, we included dietary consults based on general cancer survivor guidelines recommending a high fruit and vegetable diet that is low in fat and sugar.²⁷ Healthier dietary lifestyle has been reported to improve breast cancer prognosis, metabolic disease, and cardiovascular outcomes among Hispanic breast cancer survivors.²⁸

Our study has some limitations, including a relatively small sample size. It did not include an exercise program, which would have been helpful in addressing the issue of overweight and obesity we encountered in the most of the Hispanic breast cancer survivors (baseline average BMI, 31.32 kg/m²; obesity range, >30 kg/m²). Because of the small sample size and nonrandomized design of the study, it is hard to evaluate the confounding effect of time on intervention effect. However, a subgroup analysis by MBSR number of sessions showed that the survivors who completed the full course of MBSR sessions (8 sessions) achieved superior benefit, compared with those who did not complete the full course, which indicates that the intervention did weigh in regardless of time. Despite these limitations, the participants in this interventional program showed improved outcomes, including less anxiety and depression and improved MCS score of the SF-36. A larger and longer follow-up prospective, randomized study is needed to validate the findings of this study. Implementing cancer survivorship as an integral component of cancer care during and after treatment is essential to improve the quality of life of cancer survivors and empower them in their transition from cancer treatment to survivorship.

Breast cancer survivors comprise the most prevalent cancer survivor population in the United States.¹ The number of breast cancer survivors is increasing because of early detection and diagnosis, and advances in treatment have resulted in increased life expectancy. Therefore, greater attention is needed to improve the long-term quality of life of these survivors and to help them re-adjust to normal life. For many women, although the medical treatment may have been completed, the recovery process may have not.² The prevalence of long-term mental and physical illness is significant among many breast cancer survivors. Long-term mental consequences may include memory problems, anxiety, depression, and fear of recurrence³, and long-term physical consequences may include pain, fatigue, and lymphedema, among others.⁴

El Paso, Texas, is the fourth most populous city in Texas and has a Hispanic majority. This provides an opportunity to conduct clinical research targeting participants of Hispanic descent. Several studies have noted the influence of race/ethnicity on the psychosocial function of breast cancer survivors.^5,6 We have previously reported that Hispanic breast cancer survivors might experience decreased mental and physical health-related quality of life (QoL) which limit their normal social functioning.⁶Other studies have similarly reported poor outcomes of breast cancer survivors and higher rates of fatigue and depression among Hispanic patients.⁷ However, there is a paucity of research addressing specific interventions needed to improve these outcomes and provide better QoL for breast cancer survivors.^8,9 In addition, a few survivorship care interventions have focused on minorities. We sought to assess whether a multidisciplinary cancer survivorship program in a primarily Hispanic populated area would lead to improved QoL and reduce anxiety and depressive symptoms among breast cancer survivors.

Methods

After obtaining Institutional Review Board approval, we recruited consecutive patients who were treated at our institution during October 2013-October 2014 and obtained informed consent from them. The participants were within the first 5 years after diagnosis with stages I-III breast cancer and had completed surgery, chemotherapy, and/or radiation therapy. We sought to determine whether breast cancer survivors would benefit from this intervention as determined by improvement of performance at 12 months compared with baseline based on the following self-reported validated questionnaires: Patient Health Questionnaire-9 (PHQ-9) for depression; General Anxiety Disorder-7 (GAD-7); and Short-Form Health Survey-36 (SF-36, version 2) for patient quality of life. The participants were enrolled in a comprehensive survivorship program staffed by an oncologist, an oncology nurse practitioner, a nutritionist, and a certified clinical psychologist who had trained in mindfulness-based stress reduction (MBSR).

Interventions

The participants received a one-on-one individual psychological consultation visit every 3 months for 20-45 minutes during which the psychologist addressed each patient’s emotional and psychological issues in depth, discussed relaxation techniques, and provided psychosocial counselling. In addition, all participants were asked to attend an 8-week-course (in Spanish or English) using MBSR, an interventional program in which participants receive training to promote reduction of stress by self-regulating mindfulness practice.^3,10 Our institution’s MBSR program consists of a weekly 2-hour class for 8 sessions or more. The program is provided 3 times a year, in English and Spanish. It includes the following components:

• Learning various mindfulness meditation techniques (eg, body scans, awareness of breathing, sitting/walking meditations);
• Practicing the mindfulness techniques in class; and
• Practicing techniques at home through audiorecordings of mindfulness meditation exercises and daily diary writing.

Participants were provided with a workbook on MBSR in their preferred language.¹¹ In addition to the psychological component, they were also provided with oncologic evaluations by an oncology nurse practitioner. The nurse practitioner met with participants every 3 months and provided each one with a personalized summary of all the treatments received and routine oncology follow-up care in consultation with the patients’ regular oncologists. This care also addresses the long-term sequelae of treatment, including arthritis and osteoporosis, referrals to receive screening for other cancers (eg, cervical and colon cancer), and genetic counselling as appropriate. In addition, a nutritionist provided general dietary advice in individual and group sessions every 3 months.

The self-administered questionnaires, PHQ-9, GAD-7, and SF-36, were completed at baseline, and every 3 months for 12 months. The scores were reviewed by the psychologist and the oncologist. The PHQ-9 was used to initially screen survivors for depression and monitor their improvement after the intervention. The PHQ-9 is a reliable and validated self-administered depression module.¹² The PQH-9 exclusively focuses on the 9 diagnostic criteria for DSM-IV depression disorder and it can be used as a useful measure for monitoring outcomes of depression therapy. A score of 5-14 suggests mild-moderate depression, and a score of >15 suggests severe depression

The survivors were screened for anxiety using the GAD-7, a brief 7-item self-report scale to identify probable cases of anxiety disorder that has been shown to be an efficient tool for screening and assessing the severity of anxiety.¹³ For GAD-7, a score of 5 or higher is suggestive of anxiety. Scores of 5, 10, and 15 represent cut-off points for mild, moderate, and severe anxiety, respectively.

Survivor QoL was evaluated using the SF-36 questionnaire, a multipurpose survey containing 36 questions. It ranges from 0-100 and a score that is <50.0 is considered low. The lower the score, the worse the mental or physical function.¹⁴ The SF-36 yields a patient profile of 8 health domains – vitality, physical functioning, bodily pain, general health perceptions, physical, emotional, and social role functioning; and mental health.^15,16 A score of 50.0 on either the Physical Component Summary (PCS – vitality, physical functioning, bodily pain, general health perceptions, physical role functioning) or Mental Component Summary (MCS – emotional and social role functioning, and mental health) is consistent with the US norm.

Statistical analysis

In this study, the primary objective was to use the MBSR survivorship program to improve the survivors’ outcomes at 12 months compared with baseline using the following measures: PHQ-9 for depression, GAD-7 for anxiety, and SF-36 for QoL using the PCS and MCS. Quantitative data were described using the mean and standard deviation, and categorical data were described using frequency and percentage. The outcome measures were compared between patients who completed 12-month follow-up and those who did not, using unpaired t test. The change in outcome measures at 12 months from baseline was evaluated using paired t test. The effect of intervention was summarized using relative percentage change. The “dose” of the intervention was categorized the number of MBSR sessions – ≤4 sessions, 5-7 sessions, or ≤8 sessions. The change in outcome measures were compared among three groups using 1-way analysis of variance (ANOVA) followed by post hoc multiple comparison using the Bonferroni adjustment. In addition, the effect of intervention on each outcome was evaluated by important baseline characteristics of patients. In each subgroup, the changes were compared with baseline measures using the paired t test, whereas changes in outcome between groups were compared using the unpaired t test. Statistical analyses were conducted using SAS 9.3. P-values less than 5% were considered to be significant.

Results

A total of 94 survivors of breast cancer were included in this study and 60 (63.8%) completed the 12 months of follow-up. The average age of the participants was 54.4 years (SD, 8.7), and 90.4% were Hispanic (Table 1). Tumor characteristics were as follows: invasive ductal carcinoma (84.04%), estrogen receptor–positive (ER-, 71.28%), progesterone receptor–positive (PR-, 58.51%), and HER2-neu–positive (20%). In regard to therapy received, 48% of the participants had received anthracycline- and taxane-based adjuvant chemotherapy and 23%, nonanthracycline-based chemotherapy; 71% had received anti-estrogen (hormonal) therapy and 80%, radiation therapy. In regard to surgery, half of the participants had a lumpectomy, and half, a mastectomy. The trends in the outcome measures over the follow-up period are show in the Figure 1.

The effect of the number of MBSR sessions attended on the outcome measures is summarized in Table 3. There were significant improvements in the 12-month MCS scores for patients who completed 5-7 sessions of MBSR or ≥8 sessions, compared with patients who completed ≤4 sessions of MBSR. There was an improvement observed in PCS scores only among patients who received at least 8 sessions of MBSR. There was a marked improvement observed in GAD-7 and PHQ-9 among patients who received ≥8 sessions. There was no statistically significant change in the GAD-7 or PHQ-9 scores between patients who received ≤4 sessions and 5-7 sessions. No significant association was obtained between number of MBSR sessions attended and BMI.

Discussion

In this study, we showed that a group of predominately Hispanic breast cancer survivors benefited from participating in a multidisciplinary cancer survivorship program that emphasized in-depth psychological care and MBSR. They also benefited from an education effort that included providing survivors with personalized summaries of their treatment and oncology survivorship care, addressing potential long-term side effects of treatment, referral for genetic counselling and screening for other cancers as appropriate, as well dietary advice. We found significant improvement compared with baseline in both mental and physical determinants of the patient-reported outcomes, including anxiety (GAD-7), depression (PHQ-9), and HR-QoL (PCS) and (MCS). Survivors demonstrated significant improvement on the MCS and PHQ-9 if they attended 5 or more sessions of the 8-week MBSR course, and attending 8 sessions was associated with significant improvement in GAD-7 and PCS. This might suggest that survivors who are more motivated do benefit the most from such program.

To our knowledge, this study is the first to address the benefit of the MBSR intervention in Hispanic breast cancer survivors. In a randomized controlled trial that included breast cancer survivors with stages 0-III breast cancer who completed surgery, adjunctive radiation, and/or chemotherapy, MBSR was shown to reduce the symptoms of depression and anxiety and increase energy and physical functioning compared with participants who received “usual care”.³ Furthermore, Bower and colleagues have reported improvements in sleep, fatigue, and pro-inflammatory signaling in younger survivors of breast cancer.¹⁷ A similar standardized MBSR program was tested on Danish women who had been treated for stage I-III breast cancer¹⁸ and the results showed reduced levels of anxiety and depression at the 12-month follow-up. A similar study by Hoffman and colleagues¹⁹ reported improved mood, breast- and endocrine-related quality of life, and well-being with MBSR compared with standard care in women with stage 0-III breast cancer.

Several theories have been suggested to explain how MBSR reduces symptoms of depression, anxiety, and fear of recurrence in breast cancer survivors, one of which is that it provides supportive interaction between group members to practice meditation and apply mindfulness in daily situations.³ In addition, evidence is beginning to emerge that stress-reducing interventions such as MBSR may improve telomere length (TL) and telomerase activity (TA), the markers for cellular aging, psychological stress, and disease risk.^20-24 Lengacher and colleagues conducted a randomized controlled study to investigate the effects of MBSR on TL and TA in women with breast cancer, and suggested that MBSR increases telomere length and telomerase activity.²⁵ The 142 patients with stages 0-III breast cancer had completed adjuvant treatment with radiation and/or chemotherapy at least 2 weeks before enrollment and within 2 years of completion of treatment with lumpectomy and/or mastectomy. They were randomly assigned to either a 6-week MBSR for breast cancer program or usual care.²⁵ Assessments of TA and TL were obtained along with psychological measurements at baseline, 6 weeks, and 12 weeks after the patients had completed the MBSR program. The mean age of the participants was 55.3 years; 72% were non-Hispanic white; 78% had stage I or II cancer; and 36% received both chemotherapy and radiation. In analyses adjusted for baseline TA and psychological status, TA increased steadily by about 17% over 12 weeks in the MBSR group, compared with about 3% (P < .01) in the control group. No difference was observed for TL (P = .92). The authors concluded that the data provide preliminary evidence that MBSR increases TA in peripheral blood mononuclear cells from breast cancer patients and have implications for understanding how MBSR may extend cell longevity at the cellular level.

In another study among healthy volunteers who were randomly assigned to a 3-month meditation retreat or a control group, the 30 participants in the meditation group had higher TA compared with controls.²⁰ In a nonrandomized study among prostate cancer patients, TA increased and psychological stress decreased following a stress-reducing, lifestyle-modification program.²¹ The results of another intervention study among overweight women showed improvement in distress, eating behavior, and metabolic health in women participating in a MBSR program, all of which correlated with increases in TA.²² Most recently, researchers explored the impact on TA of a Kirtan Kriya yogic meditation intervention compared with exposure to relaxing music in 39 dementia family caregivers. The yogic-meditation intervention group had a 43% increase in TA after the 8-week intervention period compared with 3.7% the music group (P < .05).²³ Finally, among 22 patients with cervical cancer who were randomized to a psychosocial telephone counseling intervention,²⁴ investigators found a significant association between increased TL and changes in psychological distress.²⁰ Findings from other studies have assessed interventions to improve outcome of breast cancer survivors, such as the Taking CHARGE self-management intervention that is designed to facilitate the transition to survivorship after breast cancer treatment.⁸ Another intervention using home-based physical activity was shown in a randomized controlled trial to improve self-reported physical activity, body-mass index, and health-related QoL.⁹ Findings from another study suggested that a combined exercise and psychological counselling program might improve QoL more than a single entity intervention.²⁶ As noted previously, these studies did not focus on minority breast cancer survivors’ population, and it is not clear if they are generalizable to Hispanics.

In addition to the MBSR component, our program has also included one-on-one psychological assessment for long-term treatment complications and provided participants with appropriate care and follow-up plans, adding the benefits of self-awareness and self-attention for the survivors, which can effectively reduce the fear of recurrence.³ Furthermore, we included dietary consults based on general cancer survivor guidelines recommending a high fruit and vegetable diet that is low in fat and sugar.²⁷ Healthier dietary lifestyle has been reported to improve breast cancer prognosis, metabolic disease, and cardiovascular outcomes among Hispanic breast cancer survivors.²⁸

Our study has some limitations, including a relatively small sample size. It did not include an exercise program, which would have been helpful in addressing the issue of overweight and obesity we encountered in the most of the Hispanic breast cancer survivors (baseline average BMI, 31.32 kg/m²; obesity range, >30 kg/m²). Because of the small sample size and nonrandomized design of the study, it is hard to evaluate the confounding effect of time on intervention effect. However, a subgroup analysis by MBSR number of sessions showed that the survivors who completed the full course of MBSR sessions (8 sessions) achieved superior benefit, compared with those who did not complete the full course, which indicates that the intervention did weigh in regardless of time. Despite these limitations, the participants in this interventional program showed improved outcomes, including less anxiety and depression and improved MCS score of the SF-36. A larger and longer follow-up prospective, randomized study is needed to validate the findings of this study. Implementing cancer survivorship as an integral component of cancer care during and after treatment is essential to improve the quality of life of cancer survivors and empower them in their transition from cancer treatment to survivorship.

Breast cancer survivors comprise the most prevalent cancer survivor population in the United States.¹ The number of breast cancer survivors is increasing because of early detection and diagnosis, and advances in treatment have resulted in increased life expectancy. Therefore, greater attention is needed to improve the long-term quality of life of these survivors and to help them re-adjust to normal life. For many women, although the medical treatment may have been completed, the recovery process may have not.² The prevalence of long-term mental and physical illness is significant among many breast cancer survivors. Long-term mental consequences may include memory problems, anxiety, depression, and fear of recurrence³, and long-term physical consequences may include pain, fatigue, and lymphedema, among others.⁴

El Paso, Texas, is the fourth most populous city in Texas and has a Hispanic majority. This provides an opportunity to conduct clinical research targeting participants of Hispanic descent. Several studies have noted the influence of race/ethnicity on the psychosocial function of breast cancer survivors.^5,6 We have previously reported that Hispanic breast cancer survivors might experience decreased mental and physical health-related quality of life (QoL) which limit their normal social functioning.⁶Other studies have similarly reported poor outcomes of breast cancer survivors and higher rates of fatigue and depression among Hispanic patients.⁷ However, there is a paucity of research addressing specific interventions needed to improve these outcomes and provide better QoL for breast cancer survivors.^8,9 In addition, a few survivorship care interventions have focused on minorities. We sought to assess whether a multidisciplinary cancer survivorship program in a primarily Hispanic populated area would lead to improved QoL and reduce anxiety and depressive symptoms among breast cancer survivors.

Methods

After obtaining Institutional Review Board approval, we recruited consecutive patients who were treated at our institution during October 2013-October 2014 and obtained informed consent from them. The participants were within the first 5 years after diagnosis with stages I-III breast cancer and had completed surgery, chemotherapy, and/or radiation therapy. We sought to determine whether breast cancer survivors would benefit from this intervention as determined by improvement of performance at 12 months compared with baseline based on the following self-reported validated questionnaires: Patient Health Questionnaire-9 (PHQ-9) for depression; General Anxiety Disorder-7 (GAD-7); and Short-Form Health Survey-36 (SF-36, version 2) for patient quality of life. The participants were enrolled in a comprehensive survivorship program staffed by an oncologist, an oncology nurse practitioner, a nutritionist, and a certified clinical psychologist who had trained in mindfulness-based stress reduction (MBSR).

Interventions

The participants received a one-on-one individual psychological consultation visit every 3 months for 20-45 minutes during which the psychologist addressed each patient’s emotional and psychological issues in depth, discussed relaxation techniques, and provided psychosocial counselling. In addition, all participants were asked to attend an 8-week-course (in Spanish or English) using MBSR, an interventional program in which participants receive training to promote reduction of stress by self-regulating mindfulness practice.^3,10 Our institution’s MBSR program consists of a weekly 2-hour class for 8 sessions or more. The program is provided 3 times a year, in English and Spanish. It includes the following components:

• Learning various mindfulness meditation techniques (eg, body scans, awareness of breathing, sitting/walking meditations);
• Practicing the mindfulness techniques in class; and
• Practicing techniques at home through audiorecordings of mindfulness meditation exercises and daily diary writing.

Participants were provided with a workbook on MBSR in their preferred language.¹¹ In addition to the psychological component, they were also provided with oncologic evaluations by an oncology nurse practitioner. The nurse practitioner met with participants every 3 months and provided each one with a personalized summary of all the treatments received and routine oncology follow-up care in consultation with the patients’ regular oncologists. This care also addresses the long-term sequelae of treatment, including arthritis and osteoporosis, referrals to receive screening for other cancers (eg, cervical and colon cancer), and genetic counselling as appropriate. In addition, a nutritionist provided general dietary advice in individual and group sessions every 3 months.

The self-administered questionnaires, PHQ-9, GAD-7, and SF-36, were completed at baseline, and every 3 months for 12 months. The scores were reviewed by the psychologist and the oncologist. The PHQ-9 was used to initially screen survivors for depression and monitor their improvement after the intervention. The PHQ-9 is a reliable and validated self-administered depression module.¹² The PQH-9 exclusively focuses on the 9 diagnostic criteria for DSM-IV depression disorder and it can be used as a useful measure for monitoring outcomes of depression therapy. A score of 5-14 suggests mild-moderate depression, and a score of >15 suggests severe depression

The survivors were screened for anxiety using the GAD-7, a brief 7-item self-report scale to identify probable cases of anxiety disorder that has been shown to be an efficient tool for screening and assessing the severity of anxiety.¹³ For GAD-7, a score of 5 or higher is suggestive of anxiety. Scores of 5, 10, and 15 represent cut-off points for mild, moderate, and severe anxiety, respectively.

Survivor QoL was evaluated using the SF-36 questionnaire, a multipurpose survey containing 36 questions. It ranges from 0-100 and a score that is <50.0 is considered low. The lower the score, the worse the mental or physical function.¹⁴ The SF-36 yields a patient profile of 8 health domains – vitality, physical functioning, bodily pain, general health perceptions, physical, emotional, and social role functioning; and mental health.^15,16 A score of 50.0 on either the Physical Component Summary (PCS – vitality, physical functioning, bodily pain, general health perceptions, physical role functioning) or Mental Component Summary (MCS – emotional and social role functioning, and mental health) is consistent with the US norm.

Statistical analysis

In this study, the primary objective was to use the MBSR survivorship program to improve the survivors’ outcomes at 12 months compared with baseline using the following measures: PHQ-9 for depression, GAD-7 for anxiety, and SF-36 for QoL using the PCS and MCS. Quantitative data were described using the mean and standard deviation, and categorical data were described using frequency and percentage. The outcome measures were compared between patients who completed 12-month follow-up and those who did not, using unpaired t test. The change in outcome measures at 12 months from baseline was evaluated using paired t test. The effect of intervention was summarized using relative percentage change. The “dose” of the intervention was categorized the number of MBSR sessions – ≤4 sessions, 5-7 sessions, or ≤8 sessions. The change in outcome measures were compared among three groups using 1-way analysis of variance (ANOVA) followed by post hoc multiple comparison using the Bonferroni adjustment. In addition, the effect of intervention on each outcome was evaluated by important baseline characteristics of patients. In each subgroup, the changes were compared with baseline measures using the paired t test, whereas changes in outcome between groups were compared using the unpaired t test. Statistical analyses were conducted using SAS 9.3. P-values less than 5% were considered to be significant.

Results

A total of 94 survivors of breast cancer were included in this study and 60 (63.8%) completed the 12 months of follow-up. The average age of the participants was 54.4 years (SD, 8.7), and 90.4% were Hispanic (Table 1). Tumor characteristics were as follows: invasive ductal carcinoma (84.04%), estrogen receptor–positive (ER-, 71.28%), progesterone receptor–positive (PR-, 58.51%), and HER2-neu–positive (20%). In regard to therapy received, 48% of the participants had received anthracycline- and taxane-based adjuvant chemotherapy and 23%, nonanthracycline-based chemotherapy; 71% had received anti-estrogen (hormonal) therapy and 80%, radiation therapy. In regard to surgery, half of the participants had a lumpectomy, and half, a mastectomy. The trends in the outcome measures over the follow-up period are show in the Figure 1.

The effect of the number of MBSR sessions attended on the outcome measures is summarized in Table 3. There were significant improvements in the 12-month MCS scores for patients who completed 5-7 sessions of MBSR or ≥8 sessions, compared with patients who completed ≤4 sessions of MBSR. There was an improvement observed in PCS scores only among patients who received at least 8 sessions of MBSR. There was a marked improvement observed in GAD-7 and PHQ-9 among patients who received ≥8 sessions. There was no statistically significant change in the GAD-7 or PHQ-9 scores between patients who received ≤4 sessions and 5-7 sessions. No significant association was obtained between number of MBSR sessions attended and BMI.

Discussion

In this study, we showed that a group of predominately Hispanic breast cancer survivors benefited from participating in a multidisciplinary cancer survivorship program that emphasized in-depth psychological care and MBSR. They also benefited from an education effort that included providing survivors with personalized summaries of their treatment and oncology survivorship care, addressing potential long-term side effects of treatment, referral for genetic counselling and screening for other cancers as appropriate, as well dietary advice. We found significant improvement compared with baseline in both mental and physical determinants of the patient-reported outcomes, including anxiety (GAD-7), depression (PHQ-9), and HR-QoL (PCS) and (MCS). Survivors demonstrated significant improvement on the MCS and PHQ-9 if they attended 5 or more sessions of the 8-week MBSR course, and attending 8 sessions was associated with significant improvement in GAD-7 and PCS. This might suggest that survivors who are more motivated do benefit the most from such program.

To our knowledge, this study is the first to address the benefit of the MBSR intervention in Hispanic breast cancer survivors. In a randomized controlled trial that included breast cancer survivors with stages 0-III breast cancer who completed surgery, adjunctive radiation, and/or chemotherapy, MBSR was shown to reduce the symptoms of depression and anxiety and increase energy and physical functioning compared with participants who received “usual care”.³ Furthermore, Bower and colleagues have reported improvements in sleep, fatigue, and pro-inflammatory signaling in younger survivors of breast cancer.¹⁷ A similar standardized MBSR program was tested on Danish women who had been treated for stage I-III breast cancer¹⁸ and the results showed reduced levels of anxiety and depression at the 12-month follow-up. A similar study by Hoffman and colleagues¹⁹ reported improved mood, breast- and endocrine-related quality of life, and well-being with MBSR compared with standard care in women with stage 0-III breast cancer.

Several theories have been suggested to explain how MBSR reduces symptoms of depression, anxiety, and fear of recurrence in breast cancer survivors, one of which is that it provides supportive interaction between group members to practice meditation and apply mindfulness in daily situations.³ In addition, evidence is beginning to emerge that stress-reducing interventions such as MBSR may improve telomere length (TL) and telomerase activity (TA), the markers for cellular aging, psychological stress, and disease risk.^20-24 Lengacher and colleagues conducted a randomized controlled study to investigate the effects of MBSR on TL and TA in women with breast cancer, and suggested that MBSR increases telomere length and telomerase activity.²⁵ The 142 patients with stages 0-III breast cancer had completed adjuvant treatment with radiation and/or chemotherapy at least 2 weeks before enrollment and within 2 years of completion of treatment with lumpectomy and/or mastectomy. They were randomly assigned to either a 6-week MBSR for breast cancer program or usual care.²⁵ Assessments of TA and TL were obtained along with psychological measurements at baseline, 6 weeks, and 12 weeks after the patients had completed the MBSR program. The mean age of the participants was 55.3 years; 72% were non-Hispanic white; 78% had stage I or II cancer; and 36% received both chemotherapy and radiation. In analyses adjusted for baseline TA and psychological status, TA increased steadily by about 17% over 12 weeks in the MBSR group, compared with about 3% (P < .01) in the control group. No difference was observed for TL (P = .92). The authors concluded that the data provide preliminary evidence that MBSR increases TA in peripheral blood mononuclear cells from breast cancer patients and have implications for understanding how MBSR may extend cell longevity at the cellular level.

In another study among healthy volunteers who were randomly assigned to a 3-month meditation retreat or a control group, the 30 participants in the meditation group had higher TA compared with controls.²⁰ In a nonrandomized study among prostate cancer patients, TA increased and psychological stress decreased following a stress-reducing, lifestyle-modification program.²¹ The results of another intervention study among overweight women showed improvement in distress, eating behavior, and metabolic health in women participating in a MBSR program, all of which correlated with increases in TA.²² Most recently, researchers explored the impact on TA of a Kirtan Kriya yogic meditation intervention compared with exposure to relaxing music in 39 dementia family caregivers. The yogic-meditation intervention group had a 43% increase in TA after the 8-week intervention period compared with 3.7% the music group (P < .05).²³ Finally, among 22 patients with cervical cancer who were randomized to a psychosocial telephone counseling intervention,²⁴ investigators found a significant association between increased TL and changes in psychological distress.²⁰ Findings from other studies have assessed interventions to improve outcome of breast cancer survivors, such as the Taking CHARGE self-management intervention that is designed to facilitate the transition to survivorship after breast cancer treatment.⁸ Another intervention using home-based physical activity was shown in a randomized controlled trial to improve self-reported physical activity, body-mass index, and health-related QoL.⁹ Findings from another study suggested that a combined exercise and psychological counselling program might improve QoL more than a single entity intervention.²⁶ As noted previously, these studies did not focus on minority breast cancer survivors’ population, and it is not clear if they are generalizable to Hispanics.

In addition to the MBSR component, our program has also included one-on-one psychological assessment for long-term treatment complications and provided participants with appropriate care and follow-up plans, adding the benefits of self-awareness and self-attention for the survivors, which can effectively reduce the fear of recurrence.³ Furthermore, we included dietary consults based on general cancer survivor guidelines recommending a high fruit and vegetable diet that is low in fat and sugar.²⁷ Healthier dietary lifestyle has been reported to improve breast cancer prognosis, metabolic disease, and cardiovascular outcomes among Hispanic breast cancer survivors.²⁸

Our study has some limitations, including a relatively small sample size. It did not include an exercise program, which would have been helpful in addressing the issue of overweight and obesity we encountered in the most of the Hispanic breast cancer survivors (baseline average BMI, 31.32 kg/m²; obesity range, >30 kg/m²). Because of the small sample size and nonrandomized design of the study, it is hard to evaluate the confounding effect of time on intervention effect. However, a subgroup analysis by MBSR number of sessions showed that the survivors who completed the full course of MBSR sessions (8 sessions) achieved superior benefit, compared with those who did not complete the full course, which indicates that the intervention did weigh in regardless of time. Despite these limitations, the participants in this interventional program showed improved outcomes, including less anxiety and depression and improved MCS score of the SF-36. A larger and longer follow-up prospective, randomized study is needed to validate the findings of this study. Implementing cancer survivorship as an integral component of cancer care during and after treatment is essential to improve the quality of life of cancer survivors and empower them in their transition from cancer treatment to survivorship.

Goals-of-care conversations led by the oncologist are a key opportunity to improve advance care planning and end-of-life care,¹ but our patients are not understanding the essentials. Findings from a study of patients’ expectations about chemotherapy showed that more than two-thirds of patients with lung or colorectal cancers thought their palliative chemotherapy,² radiation, ³ and/or surgery⁴ could cure them. Failure to effectively educate patients can lead to end-of-life care associated with poor quality of care, including over-aggressive care, poor quality of life with suboptimal symptom management, caregiver distress, and other potentially preventable problems.⁵

Palliative care routinely includes goals-of-care (GoC) discussions as part of the standard note. At one large urban hospital, the 30-day readmission rate was 10% if palliative care consultation was done, compared with 15% if no consultation was obtained.⁶ Patients who had consultations that included GoC discussions in addition to a symptom management consultation had a lower hospital readmission rate of 5%, compared with 15% in patients who received symptom management consultations alone (adjusted odds ratio [AOR], 0.36; confidence interval [CI], 0.27-0.48; P < .001). ⁶ Findings from another study showed that the use of aggressive end-of-life care was reduced by one-third when the patient and provider had a GoC planning session close to the time of diagnosis, instead of at the end of life.⁷

We prepared a template to be incorporated into the electronic medical record (EMR) to facilitate GoC discussions between the oncologist and patient as part of a randomized phase 3 trial of early versus delayed palliative care for phase 1 clinical trial patients. Documentation is one of the most important elements of efforts to improve end-of-life care, along with advance care planning, GoC discussions, and understanding the system of care.⁸ Because we have found this approach useful in our everyday oncology practice, we are sharing this simple, doable template in the hope that others will find it effective.

The GoC template

What does it look like?

We developed a document for oncology GoC discussions that was incorporated into the EMR (Table). We use the GoC document in much the same way we’d review a computed-tomography scan with our patients and their families: we bring it up on the computer screen, show them the categories, and type in responses on the allotted spaces on the right-hand side of the document. The input can be done in real time or after the conversation, or even after the patient has left. In our practice, we access the Patient Instructions part of the EMR, use a SmartPhrase to copy the Word template into the chart, and start typing.

How do you use template?

It is critically important to make sure that the patient and family are ready for this discussion. To further facilitate the discussion, we have devised a temporary palliative care tattoo with a script, or prompts, for what questions to ask and in what order they should be asked (Figure). The easy-to-read tattoo is worn on the inner forearm so that it is readily visible to the oncologist or advanced practice nurse.¹²

We always start by asking, “How do you like to get medical information?” (Table, question 1) and follow up with something like, “Are you the sort of person who wants all the details, or not?” (Table). If the response is yes, they want all the details, then we follow up with another question, “Does that include talking about prognosis and what might happen?” (Table). Most patients will want full disclosure of their circumstances and prognosis, but some will not, and will feel overwhelmed and disempowered if you proceed.

After reviewing the answers to question 1 and any follow-up questions you may have asked, you will be able to gauge whether you should continue with questions 2-4 in the template. Once you know more about the patient and the family’s understanding of the situation (Table, question 2), what is important to them (question 3), what they are hoping for (question 4), and have spoken to them about disease progression, recapped their treatment to date, and checked to see if they might be eligible for any clinical trials (question 5), it will be easier to move on to the next questions, about progressive disease and advance care planning: “You are doing OK now, but have you thought about a time when you could be sicker [and need] a living will or advance directive [question 6, see next section of this article]?” For people unwilling to have this discussion, or have it at that moment, there is an excellent article that outlines the process to help practitioners increase prognostic awareness.¹⁴ Patient readiness will change over time as they adjust to the life changes forced by serious illness, and one can put off the discussion until they are more accepting. Just remember that patients are not likely to broach the subject themselves, and part of our job is to offer guidance.

As Singh and colleagues have noted, many patients with incurable disease have poor “prognosis awareness,” ¹⁵ so it is important for the oncologist to have a GoC conversation with the patient to be able to guage the patient’s understanding of the prognosis after a scan that shows progressive disease. Singh and his colleagues reported that of 64 taped oncologist-patient conversations about scan results, only 4 included frank discussions about prognosis. The authors suggested asking the question, “Would you like to talk about what this means?” after showing the patient the scan to allow the patient some control and to get permission to disclose crucial information based on the reading of the scan.¹⁵

Getting started on the GoC discussions may be the hardest part. Some useful introductory lines might include: “In my experience, it is easier to talk about our goals of care while people are still doing well. I know the future can be more uncertain. That’s why I want us to discuss these things now,” or “I am worried about you, after looking at these scans. I think it is time to have another discussion about what the future holds.”

Starting the hospice information visit

For patients with progressive disease, how do you know when to initiate a discussion about hospice and specifically, the hospice information visit, in a timely manner? It turns out oncologists are fairly adept at sensing when the prognosis has changed, but one useful tip is to routinely ask yourself the “surprise” question: “Would you be surprised if this patient were to die within the next 6 months?”.¹⁶ We have developed this hospice information visit practice to ensure that hospice is brought up as part of a natural transition to end-of-life care. We have not formally tested the tool, but every oncologist we know who has adopted the practice has continued it.

If the answer to the “surprise” question is, “No, I would not be surprised if the patient were to die within 6 months,” then we will make a referral to hospice for a hospice information visit. This allows for a timely, carefully planned transition to a known team, working with the oncologist, at some reasonably predictable point on the illness trajectory, usually while the patient is still on treatment. This transition can be difficult for patients and their families, and often they will voice concerns about feeling abandoned by the treating oncologist: “Dr Smith took care of us for seven years, and now – when Mom is the sickest and likely dying – he is sending us to someone whom we have never met before.” The timing of this transition is important, because the tendency is to delay for as long as possible, as demonstrated in a study by O’Connor and colleagues of admissions to hospice, which found that 16% of cancer patients were on hospice for 3 days or less.¹⁷

After we have discussed hospice care with the patient, we ask the hospice team to call the patient to set up the hospice information visit. We have been surprised to see that most patients, after the initial shock of talking about hospice care, have indicated that they found this planned transition visit with the hospice team informative and helpful.

One way in which you could broach the topic of hospice care with a patient to avoid the feelings of abandonment, is to say, “I want you to meet the people who will be helping me take care of you if and when we need them.” This emphasizes the continuity of care and the desire for a smooth, planned transition. We try to do this when we think the patient has about 6 months to live. Then, when the patient’s performance status changes or the disease progresses, we will activate the referral and will say, “Remember nurse Bob and the social worker Clare who came out to your house 3 months ago? I think it’s time we touch base with them again. It’s time to change goals from fighting the cancer to maintaining your quality of life. In my experience, hospice support will help us do just that.”

Adelson and colleagues developed standardized criteria (triggers or prompts) for use in palliative care consultation to help improve overall quality of care.¹⁸ The criteria included any solid tumor patient with: stage IV solid malignancy or stage III lung or pancreatic cancer; a hospitalization of >7 days; hospitalized in the last 30 days (not including routine chemotherapy); and uncontrolled symptoms (pain, nausea/vomiting, dyspnea, delirium, psychological distress). The investigators showed that use of the standardized criteria for palliative care consultation was associated with a decline in 30-day readmission rates (35% for the intervention group, 13% for the control group), the use of chemotherapy after discharge (18% and 44%, respectively), and use of support services after discharge.

Discussion

We see this approach with GoC discussions as part of our TEAM approach (Time, Education, Assessment, and Management) to care¹⁹ that is patient and family centered, education centered, and symptom centered. Other institutions where similar prompt systems have been used have also shown improvements in advance care planning. Temel and colleagues found in a 2010 retrospective review of the EMRs and longitudinal medical records of 2,498 patients with metastatic cancer that only 20% patients had a documented code status, despite their advanced disease state.²⁰ A second study at the same institution, also by Temel and colleagues, showed that during 2009-2011, e-mail prompts encouraging physicians to document their patients’ code status resulted in a doubling of the rate of code status documentation, from 14.5% for historical controls to 33.7% after introducing the prompt system.²¹

In a study of a disease-management pilot program in Medicare patients with cancer, US Oncology adopted the best practice model of appointing someone in the practice, usually a nurse, to review advance care planning within the first visits of diagnosis of a life-limiting illness, and increased advance care planning to more than 80%.²² In another US Oncology study, Neubauer and colleagues reported that the implementation of an ACP process at 38 member sites resulted in a 15.6% increase in the incidence of code status documentation, and although the incidence of documentation varied considerably, it was as high as 89% at some sites.²³

For how long should a terminally ill cancer patient be enrolled in hospice? Von Gunten has suggested increasing length of stay (LoS) in hospice as a quality improvement task. He reported on a study in which oncologists in Ohio were given the LoS recommendations from the state’s Oncology Clinical Guidance Council (LoS, 45-90 days), the national LoS average (43 days), and their peers (19.7 days) at baseline, including a chart showing the median LoS by oncologist. Follow-up with the medical oncologist after a year, showed that there was a doubling of hospice LoS, from the baseline 19.7 days to 39.6 days.²⁴

Patients who have timely end-of-life discussions addressing GoC and understanding of their illness, are more likely to be satisfied with their quality of care, receive care that is closer to their stated preferences, and die at the place of their choosing, and their family members will be less distressed.²⁵ In addition, Enzinger and colleagues have shown that patients who had prognostic discussions with their oncologists revised their self-reported estimates of their survival downward by 17.2 months, which brought them closer to a more realistic expectation of life expectancy, without having a negative impact on their emotional well-being (sadness, anxiety) or relationship with the physician.²⁶ However, it is important to remember, that we, as the oncologist, have to start the GoC, hospice, and EoL conversations, because patients understandably rarely bring it up of their own free will.

Goals-of-care conversations led by the oncologist are a key opportunity to improve advance care planning and end-of-life care,¹ but our patients are not understanding the essentials. Findings from a study of patients’ expectations about chemotherapy showed that more than two-thirds of patients with lung or colorectal cancers thought their palliative chemotherapy,² radiation, ³ and/or surgery⁴ could cure them. Failure to effectively educate patients can lead to end-of-life care associated with poor quality of care, including over-aggressive care, poor quality of life with suboptimal symptom management, caregiver distress, and other potentially preventable problems.⁵

Palliative care routinely includes goals-of-care (GoC) discussions as part of the standard note. At one large urban hospital, the 30-day readmission rate was 10% if palliative care consultation was done, compared with 15% if no consultation was obtained.⁶ Patients who had consultations that included GoC discussions in addition to a symptom management consultation had a lower hospital readmission rate of 5%, compared with 15% in patients who received symptom management consultations alone (adjusted odds ratio [AOR], 0.36; confidence interval [CI], 0.27-0.48; P < .001). ⁶ Findings from another study showed that the use of aggressive end-of-life care was reduced by one-third when the patient and provider had a GoC planning session close to the time of diagnosis, instead of at the end of life.⁷

We prepared a template to be incorporated into the electronic medical record (EMR) to facilitate GoC discussions between the oncologist and patient as part of a randomized phase 3 trial of early versus delayed palliative care for phase 1 clinical trial patients. Documentation is one of the most important elements of efforts to improve end-of-life care, along with advance care planning, GoC discussions, and understanding the system of care.⁸ Because we have found this approach useful in our everyday oncology practice, we are sharing this simple, doable template in the hope that others will find it effective.

The GoC template

What does it look like?

We developed a document for oncology GoC discussions that was incorporated into the EMR (Table). We use the GoC document in much the same way we’d review a computed-tomography scan with our patients and their families: we bring it up on the computer screen, show them the categories, and type in responses on the allotted spaces on the right-hand side of the document. The input can be done in real time or after the conversation, or even after the patient has left. In our practice, we access the Patient Instructions part of the EMR, use a SmartPhrase to copy the Word template into the chart, and start typing.

How do you use template?

It is critically important to make sure that the patient and family are ready for this discussion. To further facilitate the discussion, we have devised a temporary palliative care tattoo with a script, or prompts, for what questions to ask and in what order they should be asked (Figure). The easy-to-read tattoo is worn on the inner forearm so that it is readily visible to the oncologist or advanced practice nurse.¹²

We always start by asking, “How do you like to get medical information?” (Table, question 1) and follow up with something like, “Are you the sort of person who wants all the details, or not?” (Table). If the response is yes, they want all the details, then we follow up with another question, “Does that include talking about prognosis and what might happen?” (Table). Most patients will want full disclosure of their circumstances and prognosis, but some will not, and will feel overwhelmed and disempowered if you proceed.

After reviewing the answers to question 1 and any follow-up questions you may have asked, you will be able to gauge whether you should continue with questions 2-4 in the template. Once you know more about the patient and the family’s understanding of the situation (Table, question 2), what is important to them (question 3), what they are hoping for (question 4), and have spoken to them about disease progression, recapped their treatment to date, and checked to see if they might be eligible for any clinical trials (question 5), it will be easier to move on to the next questions, about progressive disease and advance care planning: “You are doing OK now, but have you thought about a time when you could be sicker [and need] a living will or advance directive [question 6, see next section of this article]?” For people unwilling to have this discussion, or have it at that moment, there is an excellent article that outlines the process to help practitioners increase prognostic awareness.¹⁴ Patient readiness will change over time as they adjust to the life changes forced by serious illness, and one can put off the discussion until they are more accepting. Just remember that patients are not likely to broach the subject themselves, and part of our job is to offer guidance.

As Singh and colleagues have noted, many patients with incurable disease have poor “prognosis awareness,” ¹⁵ so it is important for the oncologist to have a GoC conversation with the patient to be able to guage the patient’s understanding of the prognosis after a scan that shows progressive disease. Singh and his colleagues reported that of 64 taped oncologist-patient conversations about scan results, only 4 included frank discussions about prognosis. The authors suggested asking the question, “Would you like to talk about what this means?” after showing the patient the scan to allow the patient some control and to get permission to disclose crucial information based on the reading of the scan.¹⁵

Getting started on the GoC discussions may be the hardest part. Some useful introductory lines might include: “In my experience, it is easier to talk about our goals of care while people are still doing well. I know the future can be more uncertain. That’s why I want us to discuss these things now,” or “I am worried about you, after looking at these scans. I think it is time to have another discussion about what the future holds.”

Starting the hospice information visit

For patients with progressive disease, how do you know when to initiate a discussion about hospice and specifically, the hospice information visit, in a timely manner? It turns out oncologists are fairly adept at sensing when the prognosis has changed, but one useful tip is to routinely ask yourself the “surprise” question: “Would you be surprised if this patient were to die within the next 6 months?”.¹⁶ We have developed this hospice information visit practice to ensure that hospice is brought up as part of a natural transition to end-of-life care. We have not formally tested the tool, but every oncologist we know who has adopted the practice has continued it.

If the answer to the “surprise” question is, “No, I would not be surprised if the patient were to die within 6 months,” then we will make a referral to hospice for a hospice information visit. This allows for a timely, carefully planned transition to a known team, working with the oncologist, at some reasonably predictable point on the illness trajectory, usually while the patient is still on treatment. This transition can be difficult for patients and their families, and often they will voice concerns about feeling abandoned by the treating oncologist: “Dr Smith took care of us for seven years, and now – when Mom is the sickest and likely dying – he is sending us to someone whom we have never met before.” The timing of this transition is important, because the tendency is to delay for as long as possible, as demonstrated in a study by O’Connor and colleagues of admissions to hospice, which found that 16% of cancer patients were on hospice for 3 days or less.¹⁷

After we have discussed hospice care with the patient, we ask the hospice team to call the patient to set up the hospice information visit. We have been surprised to see that most patients, after the initial shock of talking about hospice care, have indicated that they found this planned transition visit with the hospice team informative and helpful.

One way in which you could broach the topic of hospice care with a patient to avoid the feelings of abandonment, is to say, “I want you to meet the people who will be helping me take care of you if and when we need them.” This emphasizes the continuity of care and the desire for a smooth, planned transition. We try to do this when we think the patient has about 6 months to live. Then, when the patient’s performance status changes or the disease progresses, we will activate the referral and will say, “Remember nurse Bob and the social worker Clare who came out to your house 3 months ago? I think it’s time we touch base with them again. It’s time to change goals from fighting the cancer to maintaining your quality of life. In my experience, hospice support will help us do just that.”

Adelson and colleagues developed standardized criteria (triggers or prompts) for use in palliative care consultation to help improve overall quality of care.¹⁸ The criteria included any solid tumor patient with: stage IV solid malignancy or stage III lung or pancreatic cancer; a hospitalization of >7 days; hospitalized in the last 30 days (not including routine chemotherapy); and uncontrolled symptoms (pain, nausea/vomiting, dyspnea, delirium, psychological distress). The investigators showed that use of the standardized criteria for palliative care consultation was associated with a decline in 30-day readmission rates (35% for the intervention group, 13% for the control group), the use of chemotherapy after discharge (18% and 44%, respectively), and use of support services after discharge.

Discussion

We see this approach with GoC discussions as part of our TEAM approach (Time, Education, Assessment, and Management) to care¹⁹ that is patient and family centered, education centered, and symptom centered. Other institutions where similar prompt systems have been used have also shown improvements in advance care planning. Temel and colleagues found in a 2010 retrospective review of the EMRs and longitudinal medical records of 2,498 patients with metastatic cancer that only 20% patients had a documented code status, despite their advanced disease state.²⁰ A second study at the same institution, also by Temel and colleagues, showed that during 2009-2011, e-mail prompts encouraging physicians to document their patients’ code status resulted in a doubling of the rate of code status documentation, from 14.5% for historical controls to 33.7% after introducing the prompt system.²¹

In a study of a disease-management pilot program in Medicare patients with cancer, US Oncology adopted the best practice model of appointing someone in the practice, usually a nurse, to review advance care planning within the first visits of diagnosis of a life-limiting illness, and increased advance care planning to more than 80%.²² In another US Oncology study, Neubauer and colleagues reported that the implementation of an ACP process at 38 member sites resulted in a 15.6% increase in the incidence of code status documentation, and although the incidence of documentation varied considerably, it was as high as 89% at some sites.²³

For how long should a terminally ill cancer patient be enrolled in hospice? Von Gunten has suggested increasing length of stay (LoS) in hospice as a quality improvement task. He reported on a study in which oncologists in Ohio were given the LoS recommendations from the state’s Oncology Clinical Guidance Council (LoS, 45-90 days), the national LoS average (43 days), and their peers (19.7 days) at baseline, including a chart showing the median LoS by oncologist. Follow-up with the medical oncologist after a year, showed that there was a doubling of hospice LoS, from the baseline 19.7 days to 39.6 days.²⁴

Patients who have timely end-of-life discussions addressing GoC and understanding of their illness, are more likely to be satisfied with their quality of care, receive care that is closer to their stated preferences, and die at the place of their choosing, and their family members will be less distressed.²⁵ In addition, Enzinger and colleagues have shown that patients who had prognostic discussions with their oncologists revised their self-reported estimates of their survival downward by 17.2 months, which brought them closer to a more realistic expectation of life expectancy, without having a negative impact on their emotional well-being (sadness, anxiety) or relationship with the physician.²⁶ However, it is important to remember, that we, as the oncologist, have to start the GoC, hospice, and EoL conversations, because patients understandably rarely bring it up of their own free will.

Goals-of-care conversations led by the oncologist are a key opportunity to improve advance care planning and end-of-life care,¹ but our patients are not understanding the essentials. Findings from a study of patients’ expectations about chemotherapy showed that more than two-thirds of patients with lung or colorectal cancers thought their palliative chemotherapy,² radiation, ³ and/or surgery⁴ could cure them. Failure to effectively educate patients can lead to end-of-life care associated with poor quality of care, including over-aggressive care, poor quality of life with suboptimal symptom management, caregiver distress, and other potentially preventable problems.⁵

Palliative care routinely includes goals-of-care (GoC) discussions as part of the standard note. At one large urban hospital, the 30-day readmission rate was 10% if palliative care consultation was done, compared with 15% if no consultation was obtained.⁶ Patients who had consultations that included GoC discussions in addition to a symptom management consultation had a lower hospital readmission rate of 5%, compared with 15% in patients who received symptom management consultations alone (adjusted odds ratio [AOR], 0.36; confidence interval [CI], 0.27-0.48; P < .001). ⁶ Findings from another study showed that the use of aggressive end-of-life care was reduced by one-third when the patient and provider had a GoC planning session close to the time of diagnosis, instead of at the end of life.⁷

We prepared a template to be incorporated into the electronic medical record (EMR) to facilitate GoC discussions between the oncologist and patient as part of a randomized phase 3 trial of early versus delayed palliative care for phase 1 clinical trial patients. Documentation is one of the most important elements of efforts to improve end-of-life care, along with advance care planning, GoC discussions, and understanding the system of care.⁸ Because we have found this approach useful in our everyday oncology practice, we are sharing this simple, doable template in the hope that others will find it effective.

The GoC template

What does it look like?

We developed a document for oncology GoC discussions that was incorporated into the EMR (Table). We use the GoC document in much the same way we’d review a computed-tomography scan with our patients and their families: we bring it up on the computer screen, show them the categories, and type in responses on the allotted spaces on the right-hand side of the document. The input can be done in real time or after the conversation, or even after the patient has left. In our practice, we access the Patient Instructions part of the EMR, use a SmartPhrase to copy the Word template into the chart, and start typing.

How do you use template?

It is critically important to make sure that the patient and family are ready for this discussion. To further facilitate the discussion, we have devised a temporary palliative care tattoo with a script, or prompts, for what questions to ask and in what order they should be asked (Figure). The easy-to-read tattoo is worn on the inner forearm so that it is readily visible to the oncologist or advanced practice nurse.¹²

We always start by asking, “How do you like to get medical information?” (Table, question 1) and follow up with something like, “Are you the sort of person who wants all the details, or not?” (Table). If the response is yes, they want all the details, then we follow up with another question, “Does that include talking about prognosis and what might happen?” (Table). Most patients will want full disclosure of their circumstances and prognosis, but some will not, and will feel overwhelmed and disempowered if you proceed.

After reviewing the answers to question 1 and any follow-up questions you may have asked, you will be able to gauge whether you should continue with questions 2-4 in the template. Once you know more about the patient and the family’s understanding of the situation (Table, question 2), what is important to them (question 3), what they are hoping for (question 4), and have spoken to them about disease progression, recapped their treatment to date, and checked to see if they might be eligible for any clinical trials (question 5), it will be easier to move on to the next questions, about progressive disease and advance care planning: “You are doing OK now, but have you thought about a time when you could be sicker [and need] a living will or advance directive [question 6, see next section of this article]?” For people unwilling to have this discussion, or have it at that moment, there is an excellent article that outlines the process to help practitioners increase prognostic awareness.¹⁴ Patient readiness will change over time as they adjust to the life changes forced by serious illness, and one can put off the discussion until they are more accepting. Just remember that patients are not likely to broach the subject themselves, and part of our job is to offer guidance.

As Singh and colleagues have noted, many patients with incurable disease have poor “prognosis awareness,” ¹⁵ so it is important for the oncologist to have a GoC conversation with the patient to be able to guage the patient’s understanding of the prognosis after a scan that shows progressive disease. Singh and his colleagues reported that of 64 taped oncologist-patient conversations about scan results, only 4 included frank discussions about prognosis. The authors suggested asking the question, “Would you like to talk about what this means?” after showing the patient the scan to allow the patient some control and to get permission to disclose crucial information based on the reading of the scan.¹⁵

Getting started on the GoC discussions may be the hardest part. Some useful introductory lines might include: “In my experience, it is easier to talk about our goals of care while people are still doing well. I know the future can be more uncertain. That’s why I want us to discuss these things now,” or “I am worried about you, after looking at these scans. I think it is time to have another discussion about what the future holds.”

Starting the hospice information visit

For patients with progressive disease, how do you know when to initiate a discussion about hospice and specifically, the hospice information visit, in a timely manner? It turns out oncologists are fairly adept at sensing when the prognosis has changed, but one useful tip is to routinely ask yourself the “surprise” question: “Would you be surprised if this patient were to die within the next 6 months?”.¹⁶ We have developed this hospice information visit practice to ensure that hospice is brought up as part of a natural transition to end-of-life care. We have not formally tested the tool, but every oncologist we know who has adopted the practice has continued it.

If the answer to the “surprise” question is, “No, I would not be surprised if the patient were to die within 6 months,” then we will make a referral to hospice for a hospice information visit. This allows for a timely, carefully planned transition to a known team, working with the oncologist, at some reasonably predictable point on the illness trajectory, usually while the patient is still on treatment. This transition can be difficult for patients and their families, and often they will voice concerns about feeling abandoned by the treating oncologist: “Dr Smith took care of us for seven years, and now – when Mom is the sickest and likely dying – he is sending us to someone whom we have never met before.” The timing of this transition is important, because the tendency is to delay for as long as possible, as demonstrated in a study by O’Connor and colleagues of admissions to hospice, which found that 16% of cancer patients were on hospice for 3 days or less.¹⁷

After we have discussed hospice care with the patient, we ask the hospice team to call the patient to set up the hospice information visit. We have been surprised to see that most patients, after the initial shock of talking about hospice care, have indicated that they found this planned transition visit with the hospice team informative and helpful.

One way in which you could broach the topic of hospice care with a patient to avoid the feelings of abandonment, is to say, “I want you to meet the people who will be helping me take care of you if and when we need them.” This emphasizes the continuity of care and the desire for a smooth, planned transition. We try to do this when we think the patient has about 6 months to live. Then, when the patient’s performance status changes or the disease progresses, we will activate the referral and will say, “Remember nurse Bob and the social worker Clare who came out to your house 3 months ago? I think it’s time we touch base with them again. It’s time to change goals from fighting the cancer to maintaining your quality of life. In my experience, hospice support will help us do just that.”

Adelson and colleagues developed standardized criteria (triggers or prompts) for use in palliative care consultation to help improve overall quality of care.¹⁸ The criteria included any solid tumor patient with: stage IV solid malignancy or stage III lung or pancreatic cancer; a hospitalization of >7 days; hospitalized in the last 30 days (not including routine chemotherapy); and uncontrolled symptoms (pain, nausea/vomiting, dyspnea, delirium, psychological distress). The investigators showed that use of the standardized criteria for palliative care consultation was associated with a decline in 30-day readmission rates (35% for the intervention group, 13% for the control group), the use of chemotherapy after discharge (18% and 44%, respectively), and use of support services after discharge.

Discussion

We see this approach with GoC discussions as part of our TEAM approach (Time, Education, Assessment, and Management) to care¹⁹ that is patient and family centered, education centered, and symptom centered. Other institutions where similar prompt systems have been used have also shown improvements in advance care planning. Temel and colleagues found in a 2010 retrospective review of the EMRs and longitudinal medical records of 2,498 patients with metastatic cancer that only 20% patients had a documented code status, despite their advanced disease state.²⁰ A second study at the same institution, also by Temel and colleagues, showed that during 2009-2011, e-mail prompts encouraging physicians to document their patients’ code status resulted in a doubling of the rate of code status documentation, from 14.5% for historical controls to 33.7% after introducing the prompt system.²¹

In a study of a disease-management pilot program in Medicare patients with cancer, US Oncology adopted the best practice model of appointing someone in the practice, usually a nurse, to review advance care planning within the first visits of diagnosis of a life-limiting illness, and increased advance care planning to more than 80%.²² In another US Oncology study, Neubauer and colleagues reported that the implementation of an ACP process at 38 member sites resulted in a 15.6% increase in the incidence of code status documentation, and although the incidence of documentation varied considerably, it was as high as 89% at some sites.²³

For how long should a terminally ill cancer patient be enrolled in hospice? Von Gunten has suggested increasing length of stay (LoS) in hospice as a quality improvement task. He reported on a study in which oncologists in Ohio were given the LoS recommendations from the state’s Oncology Clinical Guidance Council (LoS, 45-90 days), the national LoS average (43 days), and their peers (19.7 days) at baseline, including a chart showing the median LoS by oncologist. Follow-up with the medical oncologist after a year, showed that there was a doubling of hospice LoS, from the baseline 19.7 days to 39.6 days.²⁴

Patients who have timely end-of-life discussions addressing GoC and understanding of their illness, are more likely to be satisfied with their quality of care, receive care that is closer to their stated preferences, and die at the place of their choosing, and their family members will be less distressed.²⁵ In addition, Enzinger and colleagues have shown that patients who had prognostic discussions with their oncologists revised their self-reported estimates of their survival downward by 17.2 months, which brought them closer to a more realistic expectation of life expectancy, without having a negative impact on their emotional well-being (sadness, anxiety) or relationship with the physician.²⁶ However, it is important to remember, that we, as the oncologist, have to start the GoC, hospice, and EoL conversations, because patients understandably rarely bring it up of their own free will.

As we head into vacation season and the dog days of summer, let’s reflect for a few minutes on some of the very important advances we heard about at this year’s annual meeting of the American Society of Clinical Oncology in Chicago. Nearly 40,000 individuals registered for the conference, an indication of both the interest and the excitement around the new agents and the emerging clinical trial data. Scientific sessions dedicated to the use of combination immunotherapy, the role of antibody drug conjugates, and targeting molecular aberrations with small molecules were among the most popular (p. e236).

As we head into vacation season and the dog days of summer, let’s reflect for a few minutes on some of the very important advances we heard about at this year’s annual meeting of the American Society of Clinical Oncology in Chicago. Nearly 40,000 individuals registered for the conference, an indication of both the interest and the excitement around the new agents and the emerging clinical trial data. Scientific sessions dedicated to the use of combination immunotherapy, the role of antibody drug conjugates, and targeting molecular aberrations with small molecules were among the most popular (p. e236).

As we head into vacation season and the dog days of summer, let’s reflect for a few minutes on some of the very important advances we heard about at this year’s annual meeting of the American Society of Clinical Oncology in Chicago. Nearly 40,000 individuals registered for the conference, an indication of both the interest and the excitement around the new agents and the emerging clinical trial data. Scientific sessions dedicated to the use of combination immunotherapy, the role of antibody drug conjugates, and targeting molecular aberrations with small molecules were among the most popular (p. e236).

Photo from AstraZeneca

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial of the anti-PD-L1 antibody durvalumab (Imfinzi™).

In these trials, researchers are testing durvalumab in combination with immunomodulatory and chemotherapy agents in patients with multiple myeloma (MM) and lymphomas.

At present, no new patients can be enrolled in any of the 6 trials.

Patients enrolled in the trials on partial clinical hold can remain on treatment if they are receiving clinical benefit.

Patients enrolled in the trial on full clinical hold will discontinue the study treatment.

The FDA’s decision to place these trials on hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the MEDI4736-MM-002 trial on full clinical hold.

MEDI4736-MM-002 is a phase 1b study designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, in patients with newly diagnosed MM.

The FDA also placed the following trials on partial clinical hold:

• MEDI4736-MM-001: A phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide, with or without low-dose dexamethasone, in patients with relapsed and refractory MM
• MEDI4736-MM-003: A phase 2 study to determine the safety and efficacy of the combination of durvalumab and daratumumab in patients with relapsed and refractory MM
• MEDI4736-MM-005: A phase 2 study to determine the efficacy of the combination of durvalumab plus daratumumab in patients with relapsed and refractory MM who have progressed while on a current treatment regimen containing daratumumab
• MEDI4736-NHL-001: A phase 1/2 study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphomas, including chronic lymphocytic leukemia. The only arm in this trial for which enrollment is suspended is the arm with the durvalumab, lenalidomide, and rituximab combination.
• MEDI4736-DLBCL-001: A phase 2 study to evaluate the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma.

The trials that will continue to enroll are:

• MEDI4736-MDS-001: A phase 2 study evaluating the efficacy and safety of subcutaneous azacitidine in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥65 years) acute myeloid leukemia patients not eligible for hematopoietic stem cell transplant
• CC-486-MDS-006: A phase 2 study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with myelodysplastic syndromes who fail to achieve an objective response to treatment with azacitidine for injection or decitabine.

Durvalumab is being developed by Celgene Corporation and MedImmune, the global biologics research and development arm of AstraZeneca.

The use of durvalumab in combination with other agents for the treatment of patients with hematologic malignancies is not approved by the FDA, and the safety and efficacy of those combinations has not been established.

Durvalumab has accelerated approval from the FDA to treat patients with locally advanced or metastatic urothelial carcinoma.

Photo from AstraZeneca

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial of the anti-PD-L1 antibody durvalumab (Imfinzi™).

In these trials, researchers are testing durvalumab in combination with immunomodulatory and chemotherapy agents in patients with multiple myeloma (MM) and lymphomas.

At present, no new patients can be enrolled in any of the 6 trials.

Patients enrolled in the trials on partial clinical hold can remain on treatment if they are receiving clinical benefit.

Patients enrolled in the trial on full clinical hold will discontinue the study treatment.

The FDA’s decision to place these trials on hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the MEDI4736-MM-002 trial on full clinical hold.

MEDI4736-MM-002 is a phase 1b study designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, in patients with newly diagnosed MM.

The FDA also placed the following trials on partial clinical hold:

• MEDI4736-MM-001: A phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide, with or without low-dose dexamethasone, in patients with relapsed and refractory MM
• MEDI4736-MM-003: A phase 2 study to determine the safety and efficacy of the combination of durvalumab and daratumumab in patients with relapsed and refractory MM
• MEDI4736-MM-005: A phase 2 study to determine the efficacy of the combination of durvalumab plus daratumumab in patients with relapsed and refractory MM who have progressed while on a current treatment regimen containing daratumumab
• MEDI4736-NHL-001: A phase 1/2 study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphomas, including chronic lymphocytic leukemia. The only arm in this trial for which enrollment is suspended is the arm with the durvalumab, lenalidomide, and rituximab combination.
• MEDI4736-DLBCL-001: A phase 2 study to evaluate the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma.

The trials that will continue to enroll are:

• MEDI4736-MDS-001: A phase 2 study evaluating the efficacy and safety of subcutaneous azacitidine in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥65 years) acute myeloid leukemia patients not eligible for hematopoietic stem cell transplant
• CC-486-MDS-006: A phase 2 study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with myelodysplastic syndromes who fail to achieve an objective response to treatment with azacitidine for injection or decitabine.

Durvalumab is being developed by Celgene Corporation and MedImmune, the global biologics research and development arm of AstraZeneca.

The use of durvalumab in combination with other agents for the treatment of patients with hematologic malignancies is not approved by the FDA, and the safety and efficacy of those combinations has not been established.

Durvalumab has accelerated approval from the FDA to treat patients with locally advanced or metastatic urothelial carcinoma.

Photo from AstraZeneca

The US Food and Drug Administration (FDA) has placed a partial clinical hold on 5 trials and a full clinical hold on 1 trial of the anti-PD-L1 antibody durvalumab (Imfinzi™).

In these trials, researchers are testing durvalumab in combination with immunomodulatory and chemotherapy agents in patients with multiple myeloma (MM) and lymphomas.

At present, no new patients can be enrolled in any of the 6 trials.

Patients enrolled in the trials on partial clinical hold can remain on treatment if they are receiving clinical benefit.

Patients enrolled in the trial on full clinical hold will discontinue the study treatment.

The FDA’s decision to place these trials on hold is related to risks identified in trials studying another anti-PD-1 agent, pembrolizumab, in MM patients.

Data from the pembrolizumab trials indicate the risks outweigh the benefits when PD-1/PD-L1 treatment is given to MM patients in combination with dexamethasone and pomalidomide or lenalidomide.

In addition, there may be an unfavorable risk-benefit ratio for MM patients receiving PD-1/PD-L1 treatments alone or in other combinations.

With this in mind, the FDA placed the MEDI4736-MM-002 trial on full clinical hold.

MEDI4736-MM-002 is a phase 1b study designed to determine the recommended dose and regimen of durvalumab in combination with lenalidomide, with and without low-dose dexamethasone, in patients with newly diagnosed MM.

The FDA also placed the following trials on partial clinical hold:

• MEDI4736-MM-001: A phase 1b study to determine the recommended dose and regimen of durvalumab either as monotherapy or in combination with pomalidomide, with or without low-dose dexamethasone, in patients with relapsed and refractory MM
• MEDI4736-MM-003: A phase 2 study to determine the safety and efficacy of the combination of durvalumab and daratumumab in patients with relapsed and refractory MM
• MEDI4736-MM-005: A phase 2 study to determine the efficacy of the combination of durvalumab plus daratumumab in patients with relapsed and refractory MM who have progressed while on a current treatment regimen containing daratumumab
• MEDI4736-NHL-001: A phase 1/2 study to assess the safety and tolerability of durvalumab as monotherapy and in combination therapy in patients with lymphomas, including chronic lymphocytic leukemia. The only arm in this trial for which enrollment is suspended is the arm with the durvalumab, lenalidomide, and rituximab combination.
• MEDI4736-DLBCL-001: A phase 2 study to evaluate the safety and clinical activity of durvalumab in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or with lenalidomide plus R-CHOP in patients with previously untreated, high-risk diffuse large B-cell lymphoma.

The trials that will continue to enroll are:

• MEDI4736-MDS-001: A phase 2 study evaluating the efficacy and safety of subcutaneous azacitidine in combination with durvalumab in previously untreated patients with higher-risk myelodysplastic syndromes or in elderly (≥65 years) acute myeloid leukemia patients not eligible for hematopoietic stem cell transplant
• CC-486-MDS-006: A phase 2 study to evaluate the efficacy and safety of CC-486 alone or in combination with durvalumab in patients with myelodysplastic syndromes who fail to achieve an objective response to treatment with azacitidine for injection or decitabine.

Durvalumab is being developed by Celgene Corporation and MedImmune, the global biologics research and development arm of AstraZeneca.

The use of durvalumab in combination with other agents for the treatment of patients with hematologic malignancies is not approved by the FDA, and the safety and efficacy of those combinations has not been established.

Durvalumab has accelerated approval from the FDA to treat patients with locally advanced or metastatic urothelial carcinoma.

Structure of RNA

Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.

As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.

Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.

Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.

“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.

“We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”

About the patient

Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.

Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.

Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.

The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.

All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.

As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.

The company also notified study investigators and global regulatory authorities.

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.

Structure of RNA

Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.

As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.

Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.

Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.

“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.

“We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”

About the patient

Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.

Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.

Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.

The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.

All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.

As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.

The company also notified study investigators and global regulatory authorities.

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.

Structure of RNA

Alnylam Pharmaceuticals, Inc. has announced suspension of dosing in all trials of fitusiran, an RNAi therapeutic being developed to treat patients with hemophilia A and B, with and without inhibitors.

Alnylam reported a fatal thrombotic event in a patient with hemophilia A without inhibitors in the phase 2 open-label extension study of fitusiran.

As a result, the company has suspended dosing in all ongoing fitusiran studies pending further review of the event and development of a risk mitigation strategy.

Fitusiran trials include the trial in which the death was reported—a phase 2 open-label extension study of hemophilia A and B patients with and without inhibitors—and the ATLAS phase 3 program, in which patient dosing has not yet begun.

Based on an overall consideration of fitusiran’s benefit-risk profile, Alnylam said it aims to resume or begin dosing in these trials as soon as possible, upon agreement with global regulatory authorities and with appropriate protocol amendments in place for enhanced patient safety monitoring.

“We are deeply saddened to learn of this patient’s death, and we extend our sympathies to his family,” said Akshay Vaishnaw, MD, PhD, executive vice president of research and development at Alnylam.

“We believe that fitusiran holds great promise as a potential treatment option for patients with hemophilia, and we remain fully committed to its ongoing development. Following further investigation of this safety finding, implementation of a risk mitigation strategy, and alignment with global regulatory authorities, we expect to resume fitusiran dosing in our clinical studies as soon as possible, potentially as early as late 2017, with a goal of advancing this innovative investigational medicine to hemophilia patients in need.”

About the patient

Alnylam recently became aware of a fatal serious adverse event in a patient with hemophilia A who was receiving fitusiran in the phase 2 open-label extension study.

Approximately 9 days prior to hospital admission, the patient developed exercise-induced right hip pain that was treated with a total of 3 doses of factor VIII concentrate (31-46 IU/kg) on 3 separate days.

Four days prior to admission, when the patient received his third dose of factor, he developed a severe headache.

While he was initially suspected of having viral meningitis, the patient was diagnosed with subarachnoid hemorrhage on the basis of CT imaging, and he was treated with factor VIII concentrate administered 2 to 3 times daily.

Over a 14-day hospitalization, his medical condition worsened, and the patient died from subsequent cerebral edema.

The initial diagnosis of subarachnoid hemorrhage was reported by the investigator as not related to fitusiran.

For a more complete understanding, Alnylam initiated further investigation of the event, including review of the patient’s CT scans by 3 independent neuro-radiologists.

All 3 neuro-radiologists confirmed that the initiating event was a cerebral venous sinus thrombosis and not a subarachnoid hemorrhage.

As a result of this new information, Alnylam suspended dosing in fitusiran studies in order to further investigate the safety event, now considered to be possibly related to fitusiran, and to develop a risk mitigation plan.

The company also notified study investigators and global regulatory authorities.

About fitusiran

Fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. Fitusiran also has the potential to be used for rare bleeding disorders.

Fitusiran is designed to lower levels of antithrombin with the goal of promoting sufficient thrombin generation to restore hemostasis and prevent bleeding.

The safety and efficacy of fitusiran have not been evaluated by the FDA or any other health authority.