Pfizer has recalled four more lots of the smoking cessation drug varenicline (Chantix), according to an Aug. 16 update on the U.S. Food and Drug Administration website.

In a new FDA MedWatch, the agency notes that these 0.5 mg/1 mg tablets are being recalled because of the presence of N-nitroso-varenicline, a nitrosamine impurity, at a level higher than Pfizer’s acceptable intake limit.

On July 2, the FDA reported that Pfizer had voluntarily recalled nine lots of the drug for this reason. As reported by this news organization, the company added three more lots to the recall a few weeks later. The new recall now brings to 16 the number of lots that have been recalled.

In the update, the FDA noted that, although long-term ingestion of the impurity “may be associated with a theoretical potential increased cancer risk in humans,” there is no immediate risk in taking this medication. The agency added that no related adverse events (AEs) have been reported.

The four additional lots included in the newest recall are as follows:

• 00018522 (expiration date: August 2021).
• 00018523 (expiration date: August 2021).
• 00018739 (expiration date: August 2021).
• 00018740 (expiration date: August 2021).

The recalled lots were distributed in the United States and Puerto Rico from June 2019 to June 2021.

As before, the FDA noted that the benefits of stopping smoking “outweigh the theoretical potential cancer risk” from varenicline’s impurity.

It added that, although the impurities may increase risk for cancer if a high level of exposure continues over a long period, the drug is intended as a short-term treatment to aid in smoking cessation.

For now, clinicians should report any AEs from varenicline to the FDA’s MedWatch program, and patients taking this treatment should consult with their health care practitioner or pharmacy, the update notes.

A version of this article first appeared on Medscape.com.

Pfizer has recalled four more lots of the smoking cessation drug varenicline (Chantix), according to an Aug. 16 update on the U.S. Food and Drug Administration website.

In a new FDA MedWatch, the agency notes that these 0.5 mg/1 mg tablets are being recalled because of the presence of N-nitroso-varenicline, a nitrosamine impurity, at a level higher than Pfizer’s acceptable intake limit.

On July 2, the FDA reported that Pfizer had voluntarily recalled nine lots of the drug for this reason. As reported by this news organization, the company added three more lots to the recall a few weeks later. The new recall now brings to 16 the number of lots that have been recalled.

In the update, the FDA noted that, although long-term ingestion of the impurity “may be associated with a theoretical potential increased cancer risk in humans,” there is no immediate risk in taking this medication. The agency added that no related adverse events (AEs) have been reported.

The four additional lots included in the newest recall are as follows:

• 00018522 (expiration date: August 2021).
• 00018523 (expiration date: August 2021).
• 00018739 (expiration date: August 2021).
• 00018740 (expiration date: August 2021).

The recalled lots were distributed in the United States and Puerto Rico from June 2019 to June 2021.

As before, the FDA noted that the benefits of stopping smoking “outweigh the theoretical potential cancer risk” from varenicline’s impurity.

It added that, although the impurities may increase risk for cancer if a high level of exposure continues over a long period, the drug is intended as a short-term treatment to aid in smoking cessation.

For now, clinicians should report any AEs from varenicline to the FDA’s MedWatch program, and patients taking this treatment should consult with their health care practitioner or pharmacy, the update notes.

A version of this article first appeared on Medscape.com.

Pfizer has recalled four more lots of the smoking cessation drug varenicline (Chantix), according to an Aug. 16 update on the U.S. Food and Drug Administration website.

In a new FDA MedWatch, the agency notes that these 0.5 mg/1 mg tablets are being recalled because of the presence of N-nitroso-varenicline, a nitrosamine impurity, at a level higher than Pfizer’s acceptable intake limit.

On July 2, the FDA reported that Pfizer had voluntarily recalled nine lots of the drug for this reason. As reported by this news organization, the company added three more lots to the recall a few weeks later. The new recall now brings to 16 the number of lots that have been recalled.

In the update, the FDA noted that, although long-term ingestion of the impurity “may be associated with a theoretical potential increased cancer risk in humans,” there is no immediate risk in taking this medication. The agency added that no related adverse events (AEs) have been reported.

The four additional lots included in the newest recall are as follows:

• 00018522 (expiration date: August 2021).
• 00018523 (expiration date: August 2021).
• 00018739 (expiration date: August 2021).
• 00018740 (expiration date: August 2021).

The recalled lots were distributed in the United States and Puerto Rico from June 2019 to June 2021.

As before, the FDA noted that the benefits of stopping smoking “outweigh the theoretical potential cancer risk” from varenicline’s impurity.

It added that, although the impurities may increase risk for cancer if a high level of exposure continues over a long period, the drug is intended as a short-term treatment to aid in smoking cessation.

For now, clinicians should report any AEs from varenicline to the FDA’s MedWatch program, and patients taking this treatment should consult with their health care practitioner or pharmacy, the update notes.

A version of this article first appeared on Medscape.com.

Preliminary data from seven states suggests that breakthrough COVID-19 infections among vaccinated people may be on the rise because of the more contagious Delta variant.

Breakthrough cases accounted for about one in five newly diagnosed cases in six of the states, according to the New York Times. Hospitalizations and deaths among vaccinated people may be higher than previously thought as well.

“Remember when the early vaccine studies came out, it was like nobody gets hospitalized, nobody dies,” Robert Wachter, MD, chairman of the department of medicine at the University of California, San Francisco, said in an interview. “That clearly is not true.”

The New York Times analyzed data in seven states – California, Colorado, Massachusetts, Oregon, Utah, Vermont, and Virginia – that are tracking the most detailed information. The trends in these states may not reflect the numbers throughout the country, the newspaper reported.

Even still, the numbers back up the idea that vaccinated people may need booster shots this fall to support their earlier vaccine doses. Federal health officials are scheduled to approve the extra shots in coming weeks, potentially in September. The first people to receive booster shots will likely be health care workers and nursing home residents who took the first vaccines in December and January.

“If the chances of a breakthrough infection have gone up considerably, and I think the evidence is clear that they have, and the level of protection against severe illness is no longer as robust as it was, I think the case for boosters goes up pretty quickly,” Dr. Wachter said.

Previous analyses of breakthrough cases included data from June and earlier, the newspaper reported. But since July, COVID-19 cases have soared again because of the Delta variant, and the most recent numbers show an uptick among vaccinated people. In Los Angeles County, for instance, fully vaccinated people account for 20% of new COVID-19 cases, which is up from 11% in May, 5% in April, and 2% in March, according to a late July report from the Los Angeles County Department of Public Health.

What’s more, breakthrough infections in the seven states accounted for 12%-24% of COVID-19 hospitalizations in those states. About 8,000 breakthrough hospitalizations have been reported to the CDC. Still, the overall numbers remain low – in California, for instance, about 1,615 people have been hospitalized with breakthrough infections, which accounts for 0.007% of the state’s 22 million vaccinated people, the Times reported.

The breakthrough infections appear to be more severe among vaccinated people who are older or have weakened immune systems. About 74% of breakthrough cases are among adults 65 or older, the CDC reported.

The increase may shift how vaccinated people see their risks for infection and interact with loved ones. Public health officials have suggested that people follow some COVID-19 safety protocols again, such as wearing masks in public indoor spaces regardless of vaccination status.

As the Delta variant continues to circulate this fall, public health researchers will be researching more about breakthrough cases among vaccinated people, including whether they have prolonged symptoms and how easily they may pass the virus to others.

“I think some of us have been challenged by the numbers of clusters that we’ve seen,” Michael Osterholm, PhD, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, told this news organization.

“I think that really needs to be examined more,” he said.

A version of this article first appeared on WebMD.com.

Preliminary data from seven states suggests that breakthrough COVID-19 infections among vaccinated people may be on the rise because of the more contagious Delta variant.

Breakthrough cases accounted for about one in five newly diagnosed cases in six of the states, according to the New York Times. Hospitalizations and deaths among vaccinated people may be higher than previously thought as well.

“Remember when the early vaccine studies came out, it was like nobody gets hospitalized, nobody dies,” Robert Wachter, MD, chairman of the department of medicine at the University of California, San Francisco, said in an interview. “That clearly is not true.”

The New York Times analyzed data in seven states – California, Colorado, Massachusetts, Oregon, Utah, Vermont, and Virginia – that are tracking the most detailed information. The trends in these states may not reflect the numbers throughout the country, the newspaper reported.

Even still, the numbers back up the idea that vaccinated people may need booster shots this fall to support their earlier vaccine doses. Federal health officials are scheduled to approve the extra shots in coming weeks, potentially in September. The first people to receive booster shots will likely be health care workers and nursing home residents who took the first vaccines in December and January.

“If the chances of a breakthrough infection have gone up considerably, and I think the evidence is clear that they have, and the level of protection against severe illness is no longer as robust as it was, I think the case for boosters goes up pretty quickly,” Dr. Wachter said.

Previous analyses of breakthrough cases included data from June and earlier, the newspaper reported. But since July, COVID-19 cases have soared again because of the Delta variant, and the most recent numbers show an uptick among vaccinated people. In Los Angeles County, for instance, fully vaccinated people account for 20% of new COVID-19 cases, which is up from 11% in May, 5% in April, and 2% in March, according to a late July report from the Los Angeles County Department of Public Health.

What’s more, breakthrough infections in the seven states accounted for 12%-24% of COVID-19 hospitalizations in those states. About 8,000 breakthrough hospitalizations have been reported to the CDC. Still, the overall numbers remain low – in California, for instance, about 1,615 people have been hospitalized with breakthrough infections, which accounts for 0.007% of the state’s 22 million vaccinated people, the Times reported.

The breakthrough infections appear to be more severe among vaccinated people who are older or have weakened immune systems. About 74% of breakthrough cases are among adults 65 or older, the CDC reported.

The increase may shift how vaccinated people see their risks for infection and interact with loved ones. Public health officials have suggested that people follow some COVID-19 safety protocols again, such as wearing masks in public indoor spaces regardless of vaccination status.

As the Delta variant continues to circulate this fall, public health researchers will be researching more about breakthrough cases among vaccinated people, including whether they have prolonged symptoms and how easily they may pass the virus to others.

“I think some of us have been challenged by the numbers of clusters that we’ve seen,” Michael Osterholm, PhD, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, told this news organization.

“I think that really needs to be examined more,” he said.

A version of this article first appeared on WebMD.com.

Preliminary data from seven states suggests that breakthrough COVID-19 infections among vaccinated people may be on the rise because of the more contagious Delta variant.

Breakthrough cases accounted for about one in five newly diagnosed cases in six of the states, according to the New York Times. Hospitalizations and deaths among vaccinated people may be higher than previously thought as well.

“Remember when the early vaccine studies came out, it was like nobody gets hospitalized, nobody dies,” Robert Wachter, MD, chairman of the department of medicine at the University of California, San Francisco, said in an interview. “That clearly is not true.”

The New York Times analyzed data in seven states – California, Colorado, Massachusetts, Oregon, Utah, Vermont, and Virginia – that are tracking the most detailed information. The trends in these states may not reflect the numbers throughout the country, the newspaper reported.

Even still, the numbers back up the idea that vaccinated people may need booster shots this fall to support their earlier vaccine doses. Federal health officials are scheduled to approve the extra shots in coming weeks, potentially in September. The first people to receive booster shots will likely be health care workers and nursing home residents who took the first vaccines in December and January.

“If the chances of a breakthrough infection have gone up considerably, and I think the evidence is clear that they have, and the level of protection against severe illness is no longer as robust as it was, I think the case for boosters goes up pretty quickly,” Dr. Wachter said.

Previous analyses of breakthrough cases included data from June and earlier, the newspaper reported. But since July, COVID-19 cases have soared again because of the Delta variant, and the most recent numbers show an uptick among vaccinated people. In Los Angeles County, for instance, fully vaccinated people account for 20% of new COVID-19 cases, which is up from 11% in May, 5% in April, and 2% in March, according to a late July report from the Los Angeles County Department of Public Health.

What’s more, breakthrough infections in the seven states accounted for 12%-24% of COVID-19 hospitalizations in those states. About 8,000 breakthrough hospitalizations have been reported to the CDC. Still, the overall numbers remain low – in California, for instance, about 1,615 people have been hospitalized with breakthrough infections, which accounts for 0.007% of the state’s 22 million vaccinated people, the Times reported.

The breakthrough infections appear to be more severe among vaccinated people who are older or have weakened immune systems. About 74% of breakthrough cases are among adults 65 or older, the CDC reported.

The increase may shift how vaccinated people see their risks for infection and interact with loved ones. Public health officials have suggested that people follow some COVID-19 safety protocols again, such as wearing masks in public indoor spaces regardless of vaccination status.

As the Delta variant continues to circulate this fall, public health researchers will be researching more about breakthrough cases among vaccinated people, including whether they have prolonged symptoms and how easily they may pass the virus to others.

“I think some of us have been challenged by the numbers of clusters that we’ve seen,” Michael Osterholm, PhD, director of the Center for Infectious Disease Research and Policy at the University of Minnesota, told this news organization.

“I think that really needs to be examined more,” he said.

A version of this article first appeared on WebMD.com.

It is well known that survivors of critical care are at heightened risk of mental health disorders even months afterward they are discharged, but it’s less clear what factors might contribute to those outcomes. A new attempt to identify risk factors for post-ICU depression, anxiety, or posttraumatic stress disorder, as well as worse quality of life, paints a complex picture.

Age, mental preexisting mental health concerns, acute emotional stress at the time of critical care, and post-care physical impairment all may play a role, according to the multicenter, prospective cohort study conducted in Brazil, which was published in CHEST .

Previous systematic reviews have shown raised frequencies mental health disorders following ICU discharge, including anxiety (32%-40%), depression (29%-34%), and PTSD (16%-23%). Few studies have looked at the potential impact of preexisting conditions or post-ICU disability on these outcomes, yet that information is critical to key to designing effective prevention and rehabilitation interventions.

The results suggest that preexisting mental health and factors associated with the critical illness, which have gained attention as potential factors, aren’t sufficient to explain these outcomes. “Our data suggest that the network of potential risk factors for mental illness among patients who have been discharged from the ICU is much more complex and may involve risk factors from multiple domains. ... Long-term mental health disorders after critical illness may be the result of the interaction among stressors before ICU stay, during ICU stay, and after ICU stay, calling attention to the need for interdisciplinary and multifaceted strategies aimed at preventing and screening for mental health disorders after ICU discharge,” Cassiano Teixeira, MD, PhD, of the Postgraduation of Pulmonology–Federal University of Rio Grande do Sul, Brazil, and colleagues wrote.

The researchers also noted that some risk factors could be screened and may be modifiable, including anxiety and depression symptoms at ICU discharge, as well as reduced physical function status.
 

Complications or risk factors?

The findings are significant, though they may represent complications of emotional distress following ICU stays, rather than risk factors that predict it, according to an accompanying editorial. The author, O. Joseph Bienvenu III, MD, PhD, who is a professor of psychiatry and behavioral sciences at Johns Hopkins Medicine, Baltimore. He called for prospective studies to determine the predictive value of these factors. “If we are to improve long-term mental health after critical illnesses, this predictive information will be vital to selective prevention efforts.”

Dr. O. Joseph Bienvenu

Potential interventions could include psychological treatment in the ICU, ICU follow-up clinics, support groups, and cognitive-behavioral therapy, among others. Whichever approach is used, it should be targeted, according to Dr. Bienvenu, since patients who have greater emotional distress seem to gain the most benefit from such interventions.

The researchers examined outcomes among 579 adults who had spent at least 72 hours in the ICU. The median age was 61 years, and 47% were women.

Six months after release from the ICU, telephone assessments by trained researchers revealed that 48% had impairment in physical function, compared with the time preceding ICU admission. 36.2% of participants had a mental health disorder: 24.2% reported anxiety, 20.9% had depression, and 15.4% had PTSD.

Increasing numbers of psychiatric syndromes, from 0 to 3, was associated with worse scores on the mental dimension on the health-related quality of life (HRQoL) score, but there was no relationship with scores on the physical dimension.
 

Risks to mental health

Clinical characteristics associated with risk of anxiety at 6 months post discharge included being 65 years or older (prevalence ratio, 0.63; P = .009), a history of depression (PR, 1.52; P = .009), anxiety at discharge (PR, 1.65; P = .003), depression at discharge (HR, 1.44; P = .02), physical dependence (PR, 1.48; P = .01), and reduced physical functional status at 6 months post discharge (PR, 1.38; P = .04).

Characteristics associated with depression at 6 months post discharge included a history of depression (PR, 1.78; P = .001), symptoms of depression at discharge (PR, 3.04; P < .001), and reduced physical functional status at 6 months (PR, 1.53; P = .01).

Characteristics associated with PTSD at 6 months post discharge were depression symptoms at discharge (PR, 1.70; P = .01), physical dependence (PR, 1.79; P = .01), and reduced physical status at 6 months (PR, 1.62; P = .02).

Characteristics associated with any mental health disorder included higher education (PR, 0.74; P = .04), a history of depression (PR, 1.32; P = .02), anxiety symptoms at discharge (PR, 1.55; P = .001), depression symptoms at discharge (PR, 1.50; P = .001), and physical dependence at 6 months following discharge (PR, 1.66; P < .001).

“The lower HRQoL found in ICU survivors with mental health disorders in comparison with those without is a reason for concern. This finding, in association with the higher prevalence of psychiatric syndromes among ICU survivors, reinforces the importance of assessing anxiety, depression, and PTSD symptoms among ICU survivors, because these syndromes typically are long lasting and underdiagnosed, and their occurrence may affect quality of life, survival, and costs in the context of care after ICU discharge,” according to the researchers.

The authors of the study and Dr. Bienvenu have no relevant financial disclosures.

It is well known that survivors of critical care are at heightened risk of mental health disorders even months afterward they are discharged, but it’s less clear what factors might contribute to those outcomes. A new attempt to identify risk factors for post-ICU depression, anxiety, or posttraumatic stress disorder, as well as worse quality of life, paints a complex picture.

Age, mental preexisting mental health concerns, acute emotional stress at the time of critical care, and post-care physical impairment all may play a role, according to the multicenter, prospective cohort study conducted in Brazil, which was published in CHEST .

Previous systematic reviews have shown raised frequencies mental health disorders following ICU discharge, including anxiety (32%-40%), depression (29%-34%), and PTSD (16%-23%). Few studies have looked at the potential impact of preexisting conditions or post-ICU disability on these outcomes, yet that information is critical to key to designing effective prevention and rehabilitation interventions.

The results suggest that preexisting mental health and factors associated with the critical illness, which have gained attention as potential factors, aren’t sufficient to explain these outcomes. “Our data suggest that the network of potential risk factors for mental illness among patients who have been discharged from the ICU is much more complex and may involve risk factors from multiple domains. ... Long-term mental health disorders after critical illness may be the result of the interaction among stressors before ICU stay, during ICU stay, and after ICU stay, calling attention to the need for interdisciplinary and multifaceted strategies aimed at preventing and screening for mental health disorders after ICU discharge,” Cassiano Teixeira, MD, PhD, of the Postgraduation of Pulmonology–Federal University of Rio Grande do Sul, Brazil, and colleagues wrote.

The researchers also noted that some risk factors could be screened and may be modifiable, including anxiety and depression symptoms at ICU discharge, as well as reduced physical function status.
 

Complications or risk factors?

The findings are significant, though they may represent complications of emotional distress following ICU stays, rather than risk factors that predict it, according to an accompanying editorial. The author, O. Joseph Bienvenu III, MD, PhD, who is a professor of psychiatry and behavioral sciences at Johns Hopkins Medicine, Baltimore. He called for prospective studies to determine the predictive value of these factors. “If we are to improve long-term mental health after critical illnesses, this predictive information will be vital to selective prevention efforts.”

Dr. O. Joseph Bienvenu

Potential interventions could include psychological treatment in the ICU, ICU follow-up clinics, support groups, and cognitive-behavioral therapy, among others. Whichever approach is used, it should be targeted, according to Dr. Bienvenu, since patients who have greater emotional distress seem to gain the most benefit from such interventions.

The researchers examined outcomes among 579 adults who had spent at least 72 hours in the ICU. The median age was 61 years, and 47% were women.

Six months after release from the ICU, telephone assessments by trained researchers revealed that 48% had impairment in physical function, compared with the time preceding ICU admission. 36.2% of participants had a mental health disorder: 24.2% reported anxiety, 20.9% had depression, and 15.4% had PTSD.

Increasing numbers of psychiatric syndromes, from 0 to 3, was associated with worse scores on the mental dimension on the health-related quality of life (HRQoL) score, but there was no relationship with scores on the physical dimension.
 

Risks to mental health

Clinical characteristics associated with risk of anxiety at 6 months post discharge included being 65 years or older (prevalence ratio, 0.63; P = .009), a history of depression (PR, 1.52; P = .009), anxiety at discharge (PR, 1.65; P = .003), depression at discharge (HR, 1.44; P = .02), physical dependence (PR, 1.48; P = .01), and reduced physical functional status at 6 months post discharge (PR, 1.38; P = .04).

Characteristics associated with depression at 6 months post discharge included a history of depression (PR, 1.78; P = .001), symptoms of depression at discharge (PR, 3.04; P < .001), and reduced physical functional status at 6 months (PR, 1.53; P = .01).

Characteristics associated with PTSD at 6 months post discharge were depression symptoms at discharge (PR, 1.70; P = .01), physical dependence (PR, 1.79; P = .01), and reduced physical status at 6 months (PR, 1.62; P = .02).

Characteristics associated with any mental health disorder included higher education (PR, 0.74; P = .04), a history of depression (PR, 1.32; P = .02), anxiety symptoms at discharge (PR, 1.55; P = .001), depression symptoms at discharge (PR, 1.50; P = .001), and physical dependence at 6 months following discharge (PR, 1.66; P < .001).

“The lower HRQoL found in ICU survivors with mental health disorders in comparison with those without is a reason for concern. This finding, in association with the higher prevalence of psychiatric syndromes among ICU survivors, reinforces the importance of assessing anxiety, depression, and PTSD symptoms among ICU survivors, because these syndromes typically are long lasting and underdiagnosed, and their occurrence may affect quality of life, survival, and costs in the context of care after ICU discharge,” according to the researchers.

The authors of the study and Dr. Bienvenu have no relevant financial disclosures.

It is well known that survivors of critical care are at heightened risk of mental health disorders even months afterward they are discharged, but it’s less clear what factors might contribute to those outcomes. A new attempt to identify risk factors for post-ICU depression, anxiety, or posttraumatic stress disorder, as well as worse quality of life, paints a complex picture.

Age, mental preexisting mental health concerns, acute emotional stress at the time of critical care, and post-care physical impairment all may play a role, according to the multicenter, prospective cohort study conducted in Brazil, which was published in CHEST .

Previous systematic reviews have shown raised frequencies mental health disorders following ICU discharge, including anxiety (32%-40%), depression (29%-34%), and PTSD (16%-23%). Few studies have looked at the potential impact of preexisting conditions or post-ICU disability on these outcomes, yet that information is critical to key to designing effective prevention and rehabilitation interventions.

The results suggest that preexisting mental health and factors associated with the critical illness, which have gained attention as potential factors, aren’t sufficient to explain these outcomes. “Our data suggest that the network of potential risk factors for mental illness among patients who have been discharged from the ICU is much more complex and may involve risk factors from multiple domains. ... Long-term mental health disorders after critical illness may be the result of the interaction among stressors before ICU stay, during ICU stay, and after ICU stay, calling attention to the need for interdisciplinary and multifaceted strategies aimed at preventing and screening for mental health disorders after ICU discharge,” Cassiano Teixeira, MD, PhD, of the Postgraduation of Pulmonology–Federal University of Rio Grande do Sul, Brazil, and colleagues wrote.

The researchers also noted that some risk factors could be screened and may be modifiable, including anxiety and depression symptoms at ICU discharge, as well as reduced physical function status.
 

Complications or risk factors?

The findings are significant, though they may represent complications of emotional distress following ICU stays, rather than risk factors that predict it, according to an accompanying editorial. The author, O. Joseph Bienvenu III, MD, PhD, who is a professor of psychiatry and behavioral sciences at Johns Hopkins Medicine, Baltimore. He called for prospective studies to determine the predictive value of these factors. “If we are to improve long-term mental health after critical illnesses, this predictive information will be vital to selective prevention efforts.”

Dr. O. Joseph Bienvenu

Potential interventions could include psychological treatment in the ICU, ICU follow-up clinics, support groups, and cognitive-behavioral therapy, among others. Whichever approach is used, it should be targeted, according to Dr. Bienvenu, since patients who have greater emotional distress seem to gain the most benefit from such interventions.

The researchers examined outcomes among 579 adults who had spent at least 72 hours in the ICU. The median age was 61 years, and 47% were women.

Six months after release from the ICU, telephone assessments by trained researchers revealed that 48% had impairment in physical function, compared with the time preceding ICU admission. 36.2% of participants had a mental health disorder: 24.2% reported anxiety, 20.9% had depression, and 15.4% had PTSD.

Increasing numbers of psychiatric syndromes, from 0 to 3, was associated with worse scores on the mental dimension on the health-related quality of life (HRQoL) score, but there was no relationship with scores on the physical dimension.
 

Risks to mental health

Clinical characteristics associated with risk of anxiety at 6 months post discharge included being 65 years or older (prevalence ratio, 0.63; P = .009), a history of depression (PR, 1.52; P = .009), anxiety at discharge (PR, 1.65; P = .003), depression at discharge (HR, 1.44; P = .02), physical dependence (PR, 1.48; P = .01), and reduced physical functional status at 6 months post discharge (PR, 1.38; P = .04).

Characteristics associated with depression at 6 months post discharge included a history of depression (PR, 1.78; P = .001), symptoms of depression at discharge (PR, 3.04; P < .001), and reduced physical functional status at 6 months (PR, 1.53; P = .01).

Characteristics associated with PTSD at 6 months post discharge were depression symptoms at discharge (PR, 1.70; P = .01), physical dependence (PR, 1.79; P = .01), and reduced physical status at 6 months (PR, 1.62; P = .02).

Characteristics associated with any mental health disorder included higher education (PR, 0.74; P = .04), a history of depression (PR, 1.32; P = .02), anxiety symptoms at discharge (PR, 1.55; P = .001), depression symptoms at discharge (PR, 1.50; P = .001), and physical dependence at 6 months following discharge (PR, 1.66; P < .001).

“The lower HRQoL found in ICU survivors with mental health disorders in comparison with those without is a reason for concern. This finding, in association with the higher prevalence of psychiatric syndromes among ICU survivors, reinforces the importance of assessing anxiety, depression, and PTSD symptoms among ICU survivors, because these syndromes typically are long lasting and underdiagnosed, and their occurrence may affect quality of life, survival, and costs in the context of care after ICU discharge,” according to the researchers.

The authors of the study and Dr. Bienvenu have no relevant financial disclosures.

Preterm and early birth is associated with an increased risk of autism independent of genetic or environmental factors, according to new research published in Pediatrics.

Although previous studies have linked preterm births to an increased risk of autism – one 2017 study published in Cerebral Cortex found that 27.4% of the children born extremely preterm were diagnosed with autism – Casey Crump, MD, PhD, said potential causality, sex-specific differences, and association with early-term births were still unclear.

“Preterm birth had previously been linked with higher risk of autism; however, several important questions remained unanswered,” said Dr. Crump, professor and vice chair for research at the department of family medicine and community health and professor of epidemiology in the department of population health science and policy at Icahn School of Medicine at Mount Sinai New York. “To our knowledge, [our study] is the largest to date of gestational age at birth in relation to autism, and one of the first to investigate sex-specific differences, early term birth, or the influence of shared familial factors.”

Dr. Crump and colleagues examined data from more than 4 million infants born in Sweden between 1973 and 2013 who were followed-up for autism spectrum disorder identified from nationwide outpatient and inpatient diagnoses through December 2015. Children born between 22 and 27 weeks were considered extremely preterm, those born between 28 and 33 week were characterized as very to moderate preterm, and those born between 34 and 36 weeks were considered late preterm. Early-term births are characterized as infants born between 37 and 38 weeks and children born between 39 and 41 weeks were considered term births.

They found that 6.1% of those born extremely preterm were diagnosed with autism. Meanwhile, autism spectrum disorder prevalences were 2.6% for very to moderate preterm, 1.9% for late preterm, 2.1% for all preterm, and 1.6% for early term, compared with 1.4% for term birth.

The researchers’ analysis showed that preterm and early birth were associated with a significantly increased risk of autism in males and females. Children who were born extremely preterm had an approximately fourfold increased risk of autism. Researchers also found that each additional week of gestation was associated with a 5% lower prevalence of autism spectrum disorder (ASD) on average.

“The elevated risk even in [late preterm] infants is not completely surprising because a number of investigators have shown higher incidences of early cognitive, language motor and impairment, and school problems ... and psychiatric disorders, some of which may extend to adulthood,” Elisabeth McGowan, MD, who was not involved in the study, said in a solicited editorial commentary about the study.

Dr. Crump believes the association between preterm birth and autism may be because of increased inflammatory marker levels. A 2009 study published in Reproductive Sciences found that increased proinflammatory cytokine levels have been associated with the timing and initiation of preterm birth, and also have been detected in the brain and cerebrospinal fluid of individuals with autism “and may play a key role in its pathogenesis,” Dr. Crump said.

“Inflammatory-driven alteration of neuronal connections during critical periods of brain development may be central to the development of autism,” Dr. Crump explained.

However, Dr. Crump said that, although the relative risks of autism were higher in those born preterm, the absolute risk of the condition is low.

“The report by Crump is in many ways a definitive accounting of the elevated rates of ASD in preterm infants,” said Dr. McGowan, associate professor of pediatrics at the Women and Infants Hospital, Providence, R.I. “And although the impact of prematurity on brain development may be part of the causal chain resulting in ASD (or other neurodevelopmental outcomes), these factors are operating in a complex biological landscape, with pathways to ASD outcomes that can be expected to be heterogeneous.”

ASD is a developmental condition that affects about 1 in 54 children, according to the Centers for Disease Control and Prevention. Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the CDC.

“Children born prematurely need early evaluation and long-term follow-up to facilitate timely detection and treatment of autism, especially those born at the earliest gestational ages,” Dr. Crump said in an interview. “In patients of all ages, gestational age at birth should be routinely included in history-taking and medical records to help identify in clinical practice those born preterm or early term. Such information can provide additional valuable context for understanding patients’ health and may facilitate earlier evaluation for autism and other neurodevelopmental conditions in those born prematurely.”

Dr. Crump and colleagues said more research is needed to understand the biologic mechanisms linking preterm birth with higher risks of autism, which “may reveal new targets for intervention at critical windows of neurodevelopment to improve the disease trajectory.”

Experts interviewed did not disclose any relevant financial relationships.

Preterm and early birth is associated with an increased risk of autism independent of genetic or environmental factors, according to new research published in Pediatrics.

Although previous studies have linked preterm births to an increased risk of autism – one 2017 study published in Cerebral Cortex found that 27.4% of the children born extremely preterm were diagnosed with autism – Casey Crump, MD, PhD, said potential causality, sex-specific differences, and association with early-term births were still unclear.

“Preterm birth had previously been linked with higher risk of autism; however, several important questions remained unanswered,” said Dr. Crump, professor and vice chair for research at the department of family medicine and community health and professor of epidemiology in the department of population health science and policy at Icahn School of Medicine at Mount Sinai New York. “To our knowledge, [our study] is the largest to date of gestational age at birth in relation to autism, and one of the first to investigate sex-specific differences, early term birth, or the influence of shared familial factors.”

Dr. Crump and colleagues examined data from more than 4 million infants born in Sweden between 1973 and 2013 who were followed-up for autism spectrum disorder identified from nationwide outpatient and inpatient diagnoses through December 2015. Children born between 22 and 27 weeks were considered extremely preterm, those born between 28 and 33 week were characterized as very to moderate preterm, and those born between 34 and 36 weeks were considered late preterm. Early-term births are characterized as infants born between 37 and 38 weeks and children born between 39 and 41 weeks were considered term births.

They found that 6.1% of those born extremely preterm were diagnosed with autism. Meanwhile, autism spectrum disorder prevalences were 2.6% for very to moderate preterm, 1.9% for late preterm, 2.1% for all preterm, and 1.6% for early term, compared with 1.4% for term birth.

The researchers’ analysis showed that preterm and early birth were associated with a significantly increased risk of autism in males and females. Children who were born extremely preterm had an approximately fourfold increased risk of autism. Researchers also found that each additional week of gestation was associated with a 5% lower prevalence of autism spectrum disorder (ASD) on average.

“The elevated risk even in [late preterm] infants is not completely surprising because a number of investigators have shown higher incidences of early cognitive, language motor and impairment, and school problems ... and psychiatric disorders, some of which may extend to adulthood,” Elisabeth McGowan, MD, who was not involved in the study, said in a solicited editorial commentary about the study.

Dr. Crump believes the association between preterm birth and autism may be because of increased inflammatory marker levels. A 2009 study published in Reproductive Sciences found that increased proinflammatory cytokine levels have been associated with the timing and initiation of preterm birth, and also have been detected in the brain and cerebrospinal fluid of individuals with autism “and may play a key role in its pathogenesis,” Dr. Crump said.

“Inflammatory-driven alteration of neuronal connections during critical periods of brain development may be central to the development of autism,” Dr. Crump explained.

However, Dr. Crump said that, although the relative risks of autism were higher in those born preterm, the absolute risk of the condition is low.

“The report by Crump is in many ways a definitive accounting of the elevated rates of ASD in preterm infants,” said Dr. McGowan, associate professor of pediatrics at the Women and Infants Hospital, Providence, R.I. “And although the impact of prematurity on brain development may be part of the causal chain resulting in ASD (or other neurodevelopmental outcomes), these factors are operating in a complex biological landscape, with pathways to ASD outcomes that can be expected to be heterogeneous.”

ASD is a developmental condition that affects about 1 in 54 children, according to the Centers for Disease Control and Prevention. Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the CDC.

“Children born prematurely need early evaluation and long-term follow-up to facilitate timely detection and treatment of autism, especially those born at the earliest gestational ages,” Dr. Crump said in an interview. “In patients of all ages, gestational age at birth should be routinely included in history-taking and medical records to help identify in clinical practice those born preterm or early term. Such information can provide additional valuable context for understanding patients’ health and may facilitate earlier evaluation for autism and other neurodevelopmental conditions in those born prematurely.”

Dr. Crump and colleagues said more research is needed to understand the biologic mechanisms linking preterm birth with higher risks of autism, which “may reveal new targets for intervention at critical windows of neurodevelopment to improve the disease trajectory.”

Experts interviewed did not disclose any relevant financial relationships.

Preterm and early birth is associated with an increased risk of autism independent of genetic or environmental factors, according to new research published in Pediatrics.

Although previous studies have linked preterm births to an increased risk of autism – one 2017 study published in Cerebral Cortex found that 27.4% of the children born extremely preterm were diagnosed with autism – Casey Crump, MD, PhD, said potential causality, sex-specific differences, and association with early-term births were still unclear.

“Preterm birth had previously been linked with higher risk of autism; however, several important questions remained unanswered,” said Dr. Crump, professor and vice chair for research at the department of family medicine and community health and professor of epidemiology in the department of population health science and policy at Icahn School of Medicine at Mount Sinai New York. “To our knowledge, [our study] is the largest to date of gestational age at birth in relation to autism, and one of the first to investigate sex-specific differences, early term birth, or the influence of shared familial factors.”

Dr. Crump and colleagues examined data from more than 4 million infants born in Sweden between 1973 and 2013 who were followed-up for autism spectrum disorder identified from nationwide outpatient and inpatient diagnoses through December 2015. Children born between 22 and 27 weeks were considered extremely preterm, those born between 28 and 33 week were characterized as very to moderate preterm, and those born between 34 and 36 weeks were considered late preterm. Early-term births are characterized as infants born between 37 and 38 weeks and children born between 39 and 41 weeks were considered term births.

They found that 6.1% of those born extremely preterm were diagnosed with autism. Meanwhile, autism spectrum disorder prevalences were 2.6% for very to moderate preterm, 1.9% for late preterm, 2.1% for all preterm, and 1.6% for early term, compared with 1.4% for term birth.

The researchers’ analysis showed that preterm and early birth were associated with a significantly increased risk of autism in males and females. Children who were born extremely preterm had an approximately fourfold increased risk of autism. Researchers also found that each additional week of gestation was associated with a 5% lower prevalence of autism spectrum disorder (ASD) on average.

“The elevated risk even in [late preterm] infants is not completely surprising because a number of investigators have shown higher incidences of early cognitive, language motor and impairment, and school problems ... and psychiatric disorders, some of which may extend to adulthood,” Elisabeth McGowan, MD, who was not involved in the study, said in a solicited editorial commentary about the study.

Dr. Crump believes the association between preterm birth and autism may be because of increased inflammatory marker levels. A 2009 study published in Reproductive Sciences found that increased proinflammatory cytokine levels have been associated with the timing and initiation of preterm birth, and also have been detected in the brain and cerebrospinal fluid of individuals with autism “and may play a key role in its pathogenesis,” Dr. Crump said.

“Inflammatory-driven alteration of neuronal connections during critical periods of brain development may be central to the development of autism,” Dr. Crump explained.

However, Dr. Crump said that, although the relative risks of autism were higher in those born preterm, the absolute risk of the condition is low.

“The report by Crump is in many ways a definitive accounting of the elevated rates of ASD in preterm infants,” said Dr. McGowan, associate professor of pediatrics at the Women and Infants Hospital, Providence, R.I. “And although the impact of prematurity on brain development may be part of the causal chain resulting in ASD (or other neurodevelopmental outcomes), these factors are operating in a complex biological landscape, with pathways to ASD outcomes that can be expected to be heterogeneous.”

ASD is a developmental condition that affects about 1 in 54 children, according to the Centers for Disease Control and Prevention. Many children are not diagnosed with ASD until later in childhood, which in some cases delays treatment and early intervention. ASD may be detected as early as 18 months, but the average age of diagnosis for ASD is 4.3 years, according to the CDC.

“Children born prematurely need early evaluation and long-term follow-up to facilitate timely detection and treatment of autism, especially those born at the earliest gestational ages,” Dr. Crump said in an interview. “In patients of all ages, gestational age at birth should be routinely included in history-taking and medical records to help identify in clinical practice those born preterm or early term. Such information can provide additional valuable context for understanding patients’ health and may facilitate earlier evaluation for autism and other neurodevelopmental conditions in those born prematurely.”

Dr. Crump and colleagues said more research is needed to understand the biologic mechanisms linking preterm birth with higher risks of autism, which “may reveal new targets for intervention at critical windows of neurodevelopment to improve the disease trajectory.”

Experts interviewed did not disclose any relevant financial relationships.

Superinfected eczema is an inflammation of the skin accompanied by itchy, weeping, oozing lesions. Secondary infection of the open skin can occur as a result of scratching. In this case, the infection was a consequence of sensitivity to wearing shin pads. 

Although superinfected eczema is a complication of eczema, it can produce separate challenges. With damaged protective skin function and disturbance of quantity and quality of skin lipids, patients with eczema may have secondary bacterial infections. Staphylococcus aureus organisms are the most common etiologic agents; up to 90% of patients with eczema have staphylococcal colonization. Streptococcus is less commonly a cause. The progression from colonization to infection often is associated with a flare of eczema, and increased severity of the eczema is associated with more colonization. More erythema may be noted when the infection begins; then, the affected areas become encrusted or show a serous drainage. A clinical clue to superinfection of any kind is when patients stop responding to therapies that they are normally responsive to (eg, topical steroids). 

With the recent increase in methicillin-resistant S. aureus (MRSA), treatment of a secondary infection of eczema with these organisms can be tricky. Patients with eczema and secondary bacterial skin infections should be treated with topical steroids or other anti-inflammatory medications and moisturizers to repair the skin barrier. The level of skin colonization with S. aureus is decreased with use of these agents alone. Topical or systemic antibiotics appropriate for specific or community-based sensitivities may be needed in severe infections.

Because of the damaged protective skin function, cutaneous inoculation of herpes simplex virus (HSV) can occur. Eczema herpeticum, or HSV-associated Kaposi varicelliform eruption, describes eczema secondarily infected with HSV (type 1 or type 2). The eczema may become more erythematous; then, vesicles develop that are arranged in a grouped pattern. Accompanying symptoms include fever, malaise, and lymphadenopathy. The condition can be diagnosed by a Tzanck smear (seeking multinucleated giant cells), a fluorescent antibody smear, or culture of a vesicular lesion. Patients with eczema herpeticum should be treated with acyclovir. More severe involvement may require hospitalization and use of systemic antivirals. In addition, topical steroids and moisturizers should be continued to repair the skin barrier. 

Children with eczema are more likely than adults to acquire molluscum contagiosum infection, and the disease tends to be widespread. The lesions are generally smooth papules, sometimes with umbilicated skin. The lesions can spread by auto-inoculation to surrounding areas. Molluscum dermatitis accompanies 10% of molluscum lesions, and the dermatitis can be difficult to distinguish from eczema lesions. Untreated, molluscum lesions may resolve on their own; if necessary, the lesions can be treated with cantharidin, liquid nitrogen, or curettage. 

Molluscum dermatitis is treated with topical steroids. Early recognition of infections associated with a diagnosis of eczema is critical for timely initiation of appropriate treatment.
 

Brian S. Kim, MD, Associate Professor, Department of Medicine, Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri

Brian S. Kim, MD, has disclosed no relevant financial relationships.

Superinfected eczema is an inflammation of the skin accompanied by itchy, weeping, oozing lesions. Secondary infection of the open skin can occur as a result of scratching. In this case, the infection was a consequence of sensitivity to wearing shin pads. 

Although superinfected eczema is a complication of eczema, it can produce separate challenges. With damaged protective skin function and disturbance of quantity and quality of skin lipids, patients with eczema may have secondary bacterial infections. Staphylococcus aureus organisms are the most common etiologic agents; up to 90% of patients with eczema have staphylococcal colonization. Streptococcus is less commonly a cause. The progression from colonization to infection often is associated with a flare of eczema, and increased severity of the eczema is associated with more colonization. More erythema may be noted when the infection begins; then, the affected areas become encrusted or show a serous drainage. A clinical clue to superinfection of any kind is when patients stop responding to therapies that they are normally responsive to (eg, topical steroids). 

With the recent increase in methicillin-resistant S. aureus (MRSA), treatment of a secondary infection of eczema with these organisms can be tricky. Patients with eczema and secondary bacterial skin infections should be treated with topical steroids or other anti-inflammatory medications and moisturizers to repair the skin barrier. The level of skin colonization with S. aureus is decreased with use of these agents alone. Topical or systemic antibiotics appropriate for specific or community-based sensitivities may be needed in severe infections.

Because of the damaged protective skin function, cutaneous inoculation of herpes simplex virus (HSV) can occur. Eczema herpeticum, or HSV-associated Kaposi varicelliform eruption, describes eczema secondarily infected with HSV (type 1 or type 2). The eczema may become more erythematous; then, vesicles develop that are arranged in a grouped pattern. Accompanying symptoms include fever, malaise, and lymphadenopathy. The condition can be diagnosed by a Tzanck smear (seeking multinucleated giant cells), a fluorescent antibody smear, or culture of a vesicular lesion. Patients with eczema herpeticum should be treated with acyclovir. More severe involvement may require hospitalization and use of systemic antivirals. In addition, topical steroids and moisturizers should be continued to repair the skin barrier. 

Children with eczema are more likely than adults to acquire molluscum contagiosum infection, and the disease tends to be widespread. The lesions are generally smooth papules, sometimes with umbilicated skin. The lesions can spread by auto-inoculation to surrounding areas. Molluscum dermatitis accompanies 10% of molluscum lesions, and the dermatitis can be difficult to distinguish from eczema lesions. Untreated, molluscum lesions may resolve on their own; if necessary, the lesions can be treated with cantharidin, liquid nitrogen, or curettage. 

Molluscum dermatitis is treated with topical steroids. Early recognition of infections associated with a diagnosis of eczema is critical for timely initiation of appropriate treatment.
 

Brian S. Kim, MD, Associate Professor, Department of Medicine, Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri

Brian S. Kim, MD, has disclosed no relevant financial relationships.

Superinfected eczema is an inflammation of the skin accompanied by itchy, weeping, oozing lesions. Secondary infection of the open skin can occur as a result of scratching. In this case, the infection was a consequence of sensitivity to wearing shin pads. 

Although superinfected eczema is a complication of eczema, it can produce separate challenges. With damaged protective skin function and disturbance of quantity and quality of skin lipids, patients with eczema may have secondary bacterial infections. Staphylococcus aureus organisms are the most common etiologic agents; up to 90% of patients with eczema have staphylococcal colonization. Streptococcus is less commonly a cause. The progression from colonization to infection often is associated with a flare of eczema, and increased severity of the eczema is associated with more colonization. More erythema may be noted when the infection begins; then, the affected areas become encrusted or show a serous drainage. A clinical clue to superinfection of any kind is when patients stop responding to therapies that they are normally responsive to (eg, topical steroids). 

With the recent increase in methicillin-resistant S. aureus (MRSA), treatment of a secondary infection of eczema with these organisms can be tricky. Patients with eczema and secondary bacterial skin infections should be treated with topical steroids or other anti-inflammatory medications and moisturizers to repair the skin barrier. The level of skin colonization with S. aureus is decreased with use of these agents alone. Topical or systemic antibiotics appropriate for specific or community-based sensitivities may be needed in severe infections.

Because of the damaged protective skin function, cutaneous inoculation of herpes simplex virus (HSV) can occur. Eczema herpeticum, or HSV-associated Kaposi varicelliform eruption, describes eczema secondarily infected with HSV (type 1 or type 2). The eczema may become more erythematous; then, vesicles develop that are arranged in a grouped pattern. Accompanying symptoms include fever, malaise, and lymphadenopathy. The condition can be diagnosed by a Tzanck smear (seeking multinucleated giant cells), a fluorescent antibody smear, or culture of a vesicular lesion. Patients with eczema herpeticum should be treated with acyclovir. More severe involvement may require hospitalization and use of systemic antivirals. In addition, topical steroids and moisturizers should be continued to repair the skin barrier. 

Children with eczema are more likely than adults to acquire molluscum contagiosum infection, and the disease tends to be widespread. The lesions are generally smooth papules, sometimes with umbilicated skin. The lesions can spread by auto-inoculation to surrounding areas. Molluscum dermatitis accompanies 10% of molluscum lesions, and the dermatitis can be difficult to distinguish from eczema lesions. Untreated, molluscum lesions may resolve on their own; if necessary, the lesions can be treated with cantharidin, liquid nitrogen, or curettage. 

Molluscum dermatitis is treated with topical steroids. Early recognition of infections associated with a diagnosis of eczema is critical for timely initiation of appropriate treatment.
 

Brian S. Kim, MD, Associate Professor, Department of Medicine, Division of Dermatology, Washington University School of Medicine, St. Louis, Missouri

Brian S. Kim, MD, has disclosed no relevant financial relationships.

With the Delta variant surging across the country, already spread-thin health care workers are facing even sicker –and younger – Americans affected by COVID-19 than at the start of the pandemic.

While the exact toll the pandemic will take on essential workers will remain unknown, one thing is clear: The COVID-19 outbreak they’re experiencing right now on the front lines is a far cry from the original strain. They’re scared, exasperated, and crying out for us to pay attention and get vaccinated.

Five health care workers told this news organization about their experiences working the front lines amid the recent surge and what they think needs to happen – fast.
 

COVID-19 perspective from a paramedic in Connecticut

Michael Battistelli has been an emergency medical services worker for over 20 years and a licensed paramedic in Stratford, Conn., for a decade. He’s also the father of a 5-year-old daughter who isn’t eligible for a vaccination yet. For him, every day has been the same since the start of the pandemic: Surgical mask, N95 mask, face shield, change clothes before going home, and shower as soon as he walks in the door. He’s worried about Delta right now and wants you to be, too.

What keeps him up at night: “It seems like the last time, COVID-19 hit the Pacific Northwest and Northeast first. I hope it’s not the reverse and that it isn’t working its way back up to us here in Connecticut. I’ll add that if we start seeing young people dying, that might be it for me. That might be my final stand as an EMS.”

Why he’s frustrated: “For people to say COVID-19 isn’t real is mind-blowing. I’ve been at this for over a year, and all I think about is how to keep my daughter safe and protect my parents, especially my mom, who is a cancer survivor. When this first started, I brought people into the hospital who thought they would be fine after a day or week in the hospital. They ended up being on ventilators for months – and these were healthy people.”

What he wants to see: “I try not to judge people, but please understand how hard health care workers are working. We’re fatigued and burned out, and we are begging you: Please get vaccinated.”
 

COVID-19 perspective from an ICU director in Tennessee

Todd Rice, MD, FCCP, is an associate professor of medicine in the division of allergy, pulmonary and critical care at Vanderbilt Medical Center in Nashville, Tenn. While this father of two – ages 15 and 17 – trained for a pandemic, specifically Ebola and H1N1, the sheer volume of young COVID-19 patients in the ICU right now is taking a huge toll on him and his staff.

Why he’s frustrated: “First, there are a group of people that are adamantly against getting vaccinated. It doesn’t matter what we do or say. Second, a lot of people are confused and tell me that they don’t have somebody they trust to answer their questions about the vaccine. Third, some of this is driven by our colleagues: In the last 2 weeks, eight pregnant women with COVID-19 were admitted to our ICU. At least six said that their [obstetrician] told them not to get the vaccine while pregnant. That myth is still out there.”

What’s going on in the ICU: “I want people to know that our unvaccinated infected COVID-19 patients are the sickest patients we take care of. Their condition can change on a dime. We think they’re getting better, and suddenly we turn around and they’re near death or they die in seconds. What’s hard for our staff is that many of these patients have been with us for several weeks, and we get to know them. So when this happens, it hurts us even more because we’ve gotten to know them.”

What we need to do: “While it may take time, we have to talk to vaccine-hesitant people one by one and ask them what questions they have and then provide them with the answers they need. I think the next 6 months is going to be all about getting people who are still movable on this and get them to be comfortable that the vaccine is safe, that we didn’t cut corners. Yes, it was developed faster than anything we’ve ever done before, but that’s because it had to be.”
 

COVID-19 perspective from a cardiopulmonary doctor in Florida

Yvonne Billings, MD, director of cardiopulmonary medicine at Cleveland Clinic Martin Health in Stuart, Fla., says the “explosion” of COVID-19 cases right after July 4 has left her and her staff emotionally and physically overwhelmed.

What worries her: “We have great PPE, but we’re all worries because Delta is so contagious, and our colleagues have gotten it. We’ll eat lunch next to each other – socially distanced, of course – and we won’t know if we’ve gotten it by just sitting down to eat.”

What she wants us to do – now: “Everyone needs to listen to the real medical science and understand how much this is impacting everyone’s care. For example, if you need to come to the hospital for something other than COVID-19, you will receive slower care because everyone is so tied up caring for COVID-19 patients.”

Health care workers need to get on board, too: “I look at some of my respiratory therapists who chose not to be vaccinated until this last surge. Many told me that when the younger patients started coming in, they could relate to that. One said: ‘I see this gentleman is 27. I’m 27. I could be in the exact same position.’ I don’t want to see anyone get sick, but I’m hoping that when people see that this affects anyone at any age, they can push politics and what they thought was true about the vaccine aside, and make different choices and move forward.”
 

COVID-19 perspective from a registered nurse in Louisiana

Gina McNemar, 37, an ICU nurse at Baton Rouge General Medical Center in Baton Rouge, La., is wiped out. Her ICU unit is currently full of COVID-19 patients. This mom of 5-year-old twins is so upset about the onslaught of patients in her unit that she sent an email to the CEO of the hospital, which he then shared on Facebook with hundreds of followers. From the email: “This Covid is different. Let me repeat myself: THIS COVID IS NOT THE SAME. ... For the first time since April 2020, I kneeled on top of a patient in the middle of CPR and saw myself. She was 41 years old, no comorbidities, a full life ahead of her. The first time we fought Covid, everyone was old and sickly. They weren’t ‘me.’ This sweet woman was ‘me.’ We ran a full code on her for 1 hour and 26 minutes in front of her fiancé. He cried out to God to save her. He cried out to us to save her. We did everything in our power to save her. We weren’t able to. Three nurses, a pharmacy tech, an x-ray tech, and our HMG doctor hugged, prayed, and cried together after. She was living her life, got Covid, and died.”

Why she wants people to pay attention: “Our COVID-19 patients are young, they’re healthy, they’re able to answer our questions and immediately crash. We don’t have time to catch our breath between one code to the next. This COVID-19 is a much more violent disease, and I can no longer keep quiet. Someone has to say it. Someone has to say, ‘You can believe what you want to believe,’ but I’m seeing it with my own eyes, I’m holding their hands while they die, I’m bagging their body for the morgue. See this crisis through my eyes – please!”

What’s happening with her coworkers: “We’ve had some pretty bad days. We’re all crying and we’re afraid for each other now. We feel like it could be any of us at any point. I’m feeling that I don’t want to let it get to me, but it is. At home, we pray every night. The other night, one of my twins said: ‘I pray that you don’t get coronavirus and die.’ I can’t help but think: 5-year-olds should pray for unicorns and rainbows, not that their mom could die at work.”

Please stop playing politics: “America has become so divided and the vaccine somehow became the evil thing instead of the fact that the vaccine is the savior. I waited in line to get my vaccine because the scientists came up with something to end all this, but not everyone sees it that way. I feel like people don’t want to see and it shouldn’t matter if you’re a Republican or Democrat – after all, Biden is vaccinated [and] Trump is vaccinated.”
 

COVID-19 perspective from an ED doctor in New York City

Amanda Smith, MD, an ED doctor at Staten Island University Hospital in New York, says she’s sensing a “slow wave coming” when it comes to the Delta variant. The mom of three kids (she has 10-year-old twins and a 12-year-old) thinks often of the first signs of COVID-19 in 2020 and hopes that there won’t be a repeat surge like the initial one in New York City.

It’s hard not to feel frustrated: “I’m annoyed about the Delta variant. Of course, I’ve experienced the ‘I’m not getting the vaccine’ argument, and I’ve been at this long enough that I’m able to compartmentalize my own feelings, but I’m worn down, and I’m aware that I have compassion fatigue. When people complain about their COVID-19 symptoms and say things like ‘If I knew I would feel this horrible, I would have gotten the vaccine,’ I can’t help but feel that this was avoidable. It’s hard to talk to those people. I want to say ‘600,000 dead people weren’t enough to get vaccinated?’ ”

The people avoiding the vaccine: “There are the absolute deniers who will never get vaccinated and aren’t going to change their minds. Then there are the people who feel invincible, and then there are the folks who think that COVID-19 isn’t that bad, it’s just like the flu, it’s only old people dying and they’re not getting information from an appropriate source. It’s not the flu, it does kill you. Delta kills younger people, and it’s very easy to spread. Every one person who was infected with the original strain could infect two to three others. The Delta variant can infect 8-9, and measles, at 13, is the most contagious, so we need to keep reminding people about this.”

It’s not just about you: “Vaccination campaigns were never about the individual. We live together in a civilized society, and the vaccine is something you do for each other. People don’t understand the importance of breaking the chain of transmission and doing this to help each other and eradicate the spread. I just don’t understand what happened to us that we forgot this.”

A version of this article first appeared on WebMD.com.

With the Delta variant surging across the country, already spread-thin health care workers are facing even sicker –and younger – Americans affected by COVID-19 than at the start of the pandemic.

While the exact toll the pandemic will take on essential workers will remain unknown, one thing is clear: The COVID-19 outbreak they’re experiencing right now on the front lines is a far cry from the original strain. They’re scared, exasperated, and crying out for us to pay attention and get vaccinated.

Five health care workers told this news organization about their experiences working the front lines amid the recent surge and what they think needs to happen – fast.
 

COVID-19 perspective from a paramedic in Connecticut

Michael Battistelli has been an emergency medical services worker for over 20 years and a licensed paramedic in Stratford, Conn., for a decade. He’s also the father of a 5-year-old daughter who isn’t eligible for a vaccination yet. For him, every day has been the same since the start of the pandemic: Surgical mask, N95 mask, face shield, change clothes before going home, and shower as soon as he walks in the door. He’s worried about Delta right now and wants you to be, too.

What keeps him up at night: “It seems like the last time, COVID-19 hit the Pacific Northwest and Northeast first. I hope it’s not the reverse and that it isn’t working its way back up to us here in Connecticut. I’ll add that if we start seeing young people dying, that might be it for me. That might be my final stand as an EMS.”

Why he’s frustrated: “For people to say COVID-19 isn’t real is mind-blowing. I’ve been at this for over a year, and all I think about is how to keep my daughter safe and protect my parents, especially my mom, who is a cancer survivor. When this first started, I brought people into the hospital who thought they would be fine after a day or week in the hospital. They ended up being on ventilators for months – and these were healthy people.”

What he wants to see: “I try not to judge people, but please understand how hard health care workers are working. We’re fatigued and burned out, and we are begging you: Please get vaccinated.”
 

COVID-19 perspective from an ICU director in Tennessee

Todd Rice, MD, FCCP, is an associate professor of medicine in the division of allergy, pulmonary and critical care at Vanderbilt Medical Center in Nashville, Tenn. While this father of two – ages 15 and 17 – trained for a pandemic, specifically Ebola and H1N1, the sheer volume of young COVID-19 patients in the ICU right now is taking a huge toll on him and his staff.

Why he’s frustrated: “First, there are a group of people that are adamantly against getting vaccinated. It doesn’t matter what we do or say. Second, a lot of people are confused and tell me that they don’t have somebody they trust to answer their questions about the vaccine. Third, some of this is driven by our colleagues: In the last 2 weeks, eight pregnant women with COVID-19 were admitted to our ICU. At least six said that their [obstetrician] told them not to get the vaccine while pregnant. That myth is still out there.”

What’s going on in the ICU: “I want people to know that our unvaccinated infected COVID-19 patients are the sickest patients we take care of. Their condition can change on a dime. We think they’re getting better, and suddenly we turn around and they’re near death or they die in seconds. What’s hard for our staff is that many of these patients have been with us for several weeks, and we get to know them. So when this happens, it hurts us even more because we’ve gotten to know them.”

What we need to do: “While it may take time, we have to talk to vaccine-hesitant people one by one and ask them what questions they have and then provide them with the answers they need. I think the next 6 months is going to be all about getting people who are still movable on this and get them to be comfortable that the vaccine is safe, that we didn’t cut corners. Yes, it was developed faster than anything we’ve ever done before, but that’s because it had to be.”
 

COVID-19 perspective from a cardiopulmonary doctor in Florida

Yvonne Billings, MD, director of cardiopulmonary medicine at Cleveland Clinic Martin Health in Stuart, Fla., says the “explosion” of COVID-19 cases right after July 4 has left her and her staff emotionally and physically overwhelmed.

What worries her: “We have great PPE, but we’re all worries because Delta is so contagious, and our colleagues have gotten it. We’ll eat lunch next to each other – socially distanced, of course – and we won’t know if we’ve gotten it by just sitting down to eat.”

What she wants us to do – now: “Everyone needs to listen to the real medical science and understand how much this is impacting everyone’s care. For example, if you need to come to the hospital for something other than COVID-19, you will receive slower care because everyone is so tied up caring for COVID-19 patients.”

Health care workers need to get on board, too: “I look at some of my respiratory therapists who chose not to be vaccinated until this last surge. Many told me that when the younger patients started coming in, they could relate to that. One said: ‘I see this gentleman is 27. I’m 27. I could be in the exact same position.’ I don’t want to see anyone get sick, but I’m hoping that when people see that this affects anyone at any age, they can push politics and what they thought was true about the vaccine aside, and make different choices and move forward.”
 

COVID-19 perspective from a registered nurse in Louisiana

Gina McNemar, 37, an ICU nurse at Baton Rouge General Medical Center in Baton Rouge, La., is wiped out. Her ICU unit is currently full of COVID-19 patients. This mom of 5-year-old twins is so upset about the onslaught of patients in her unit that she sent an email to the CEO of the hospital, which he then shared on Facebook with hundreds of followers. From the email: “This Covid is different. Let me repeat myself: THIS COVID IS NOT THE SAME. ... For the first time since April 2020, I kneeled on top of a patient in the middle of CPR and saw myself. She was 41 years old, no comorbidities, a full life ahead of her. The first time we fought Covid, everyone was old and sickly. They weren’t ‘me.’ This sweet woman was ‘me.’ We ran a full code on her for 1 hour and 26 minutes in front of her fiancé. He cried out to God to save her. He cried out to us to save her. We did everything in our power to save her. We weren’t able to. Three nurses, a pharmacy tech, an x-ray tech, and our HMG doctor hugged, prayed, and cried together after. She was living her life, got Covid, and died.”

Why she wants people to pay attention: “Our COVID-19 patients are young, they’re healthy, they’re able to answer our questions and immediately crash. We don’t have time to catch our breath between one code to the next. This COVID-19 is a much more violent disease, and I can no longer keep quiet. Someone has to say it. Someone has to say, ‘You can believe what you want to believe,’ but I’m seeing it with my own eyes, I’m holding their hands while they die, I’m bagging their body for the morgue. See this crisis through my eyes – please!”

What’s happening with her coworkers: “We’ve had some pretty bad days. We’re all crying and we’re afraid for each other now. We feel like it could be any of us at any point. I’m feeling that I don’t want to let it get to me, but it is. At home, we pray every night. The other night, one of my twins said: ‘I pray that you don’t get coronavirus and die.’ I can’t help but think: 5-year-olds should pray for unicorns and rainbows, not that their mom could die at work.”

Please stop playing politics: “America has become so divided and the vaccine somehow became the evil thing instead of the fact that the vaccine is the savior. I waited in line to get my vaccine because the scientists came up with something to end all this, but not everyone sees it that way. I feel like people don’t want to see and it shouldn’t matter if you’re a Republican or Democrat – after all, Biden is vaccinated [and] Trump is vaccinated.”
 

COVID-19 perspective from an ED doctor in New York City

Amanda Smith, MD, an ED doctor at Staten Island University Hospital in New York, says she’s sensing a “slow wave coming” when it comes to the Delta variant. The mom of three kids (she has 10-year-old twins and a 12-year-old) thinks often of the first signs of COVID-19 in 2020 and hopes that there won’t be a repeat surge like the initial one in New York City.

It’s hard not to feel frustrated: “I’m annoyed about the Delta variant. Of course, I’ve experienced the ‘I’m not getting the vaccine’ argument, and I’ve been at this long enough that I’m able to compartmentalize my own feelings, but I’m worn down, and I’m aware that I have compassion fatigue. When people complain about their COVID-19 symptoms and say things like ‘If I knew I would feel this horrible, I would have gotten the vaccine,’ I can’t help but feel that this was avoidable. It’s hard to talk to those people. I want to say ‘600,000 dead people weren’t enough to get vaccinated?’ ”

The people avoiding the vaccine: “There are the absolute deniers who will never get vaccinated and aren’t going to change their minds. Then there are the people who feel invincible, and then there are the folks who think that COVID-19 isn’t that bad, it’s just like the flu, it’s only old people dying and they’re not getting information from an appropriate source. It’s not the flu, it does kill you. Delta kills younger people, and it’s very easy to spread. Every one person who was infected with the original strain could infect two to three others. The Delta variant can infect 8-9, and measles, at 13, is the most contagious, so we need to keep reminding people about this.”

It’s not just about you: “Vaccination campaigns were never about the individual. We live together in a civilized society, and the vaccine is something you do for each other. People don’t understand the importance of breaking the chain of transmission and doing this to help each other and eradicate the spread. I just don’t understand what happened to us that we forgot this.”

A version of this article first appeared on WebMD.com.

With the Delta variant surging across the country, already spread-thin health care workers are facing even sicker –and younger – Americans affected by COVID-19 than at the start of the pandemic.

While the exact toll the pandemic will take on essential workers will remain unknown, one thing is clear: The COVID-19 outbreak they’re experiencing right now on the front lines is a far cry from the original strain. They’re scared, exasperated, and crying out for us to pay attention and get vaccinated.

Five health care workers told this news organization about their experiences working the front lines amid the recent surge and what they think needs to happen – fast.
 

COVID-19 perspective from a paramedic in Connecticut

Michael Battistelli has been an emergency medical services worker for over 20 years and a licensed paramedic in Stratford, Conn., for a decade. He’s also the father of a 5-year-old daughter who isn’t eligible for a vaccination yet. For him, every day has been the same since the start of the pandemic: Surgical mask, N95 mask, face shield, change clothes before going home, and shower as soon as he walks in the door. He’s worried about Delta right now and wants you to be, too.

What keeps him up at night: “It seems like the last time, COVID-19 hit the Pacific Northwest and Northeast first. I hope it’s not the reverse and that it isn’t working its way back up to us here in Connecticut. I’ll add that if we start seeing young people dying, that might be it for me. That might be my final stand as an EMS.”

Why he’s frustrated: “For people to say COVID-19 isn’t real is mind-blowing. I’ve been at this for over a year, and all I think about is how to keep my daughter safe and protect my parents, especially my mom, who is a cancer survivor. When this first started, I brought people into the hospital who thought they would be fine after a day or week in the hospital. They ended up being on ventilators for months – and these were healthy people.”

What he wants to see: “I try not to judge people, but please understand how hard health care workers are working. We’re fatigued and burned out, and we are begging you: Please get vaccinated.”
 

COVID-19 perspective from an ICU director in Tennessee

Todd Rice, MD, FCCP, is an associate professor of medicine in the division of allergy, pulmonary and critical care at Vanderbilt Medical Center in Nashville, Tenn. While this father of two – ages 15 and 17 – trained for a pandemic, specifically Ebola and H1N1, the sheer volume of young COVID-19 patients in the ICU right now is taking a huge toll on him and his staff.

Why he’s frustrated: “First, there are a group of people that are adamantly against getting vaccinated. It doesn’t matter what we do or say. Second, a lot of people are confused and tell me that they don’t have somebody they trust to answer their questions about the vaccine. Third, some of this is driven by our colleagues: In the last 2 weeks, eight pregnant women with COVID-19 were admitted to our ICU. At least six said that their [obstetrician] told them not to get the vaccine while pregnant. That myth is still out there.”

What’s going on in the ICU: “I want people to know that our unvaccinated infected COVID-19 patients are the sickest patients we take care of. Their condition can change on a dime. We think they’re getting better, and suddenly we turn around and they’re near death or they die in seconds. What’s hard for our staff is that many of these patients have been with us for several weeks, and we get to know them. So when this happens, it hurts us even more because we’ve gotten to know them.”

What we need to do: “While it may take time, we have to talk to vaccine-hesitant people one by one and ask them what questions they have and then provide them with the answers they need. I think the next 6 months is going to be all about getting people who are still movable on this and get them to be comfortable that the vaccine is safe, that we didn’t cut corners. Yes, it was developed faster than anything we’ve ever done before, but that’s because it had to be.”
 

COVID-19 perspective from a cardiopulmonary doctor in Florida

Yvonne Billings, MD, director of cardiopulmonary medicine at Cleveland Clinic Martin Health in Stuart, Fla., says the “explosion” of COVID-19 cases right after July 4 has left her and her staff emotionally and physically overwhelmed.

What worries her: “We have great PPE, but we’re all worries because Delta is so contagious, and our colleagues have gotten it. We’ll eat lunch next to each other – socially distanced, of course – and we won’t know if we’ve gotten it by just sitting down to eat.”

What she wants us to do – now: “Everyone needs to listen to the real medical science and understand how much this is impacting everyone’s care. For example, if you need to come to the hospital for something other than COVID-19, you will receive slower care because everyone is so tied up caring for COVID-19 patients.”

Health care workers need to get on board, too: “I look at some of my respiratory therapists who chose not to be vaccinated until this last surge. Many told me that when the younger patients started coming in, they could relate to that. One said: ‘I see this gentleman is 27. I’m 27. I could be in the exact same position.’ I don’t want to see anyone get sick, but I’m hoping that when people see that this affects anyone at any age, they can push politics and what they thought was true about the vaccine aside, and make different choices and move forward.”
 

COVID-19 perspective from a registered nurse in Louisiana

Gina McNemar, 37, an ICU nurse at Baton Rouge General Medical Center in Baton Rouge, La., is wiped out. Her ICU unit is currently full of COVID-19 patients. This mom of 5-year-old twins is so upset about the onslaught of patients in her unit that she sent an email to the CEO of the hospital, which he then shared on Facebook with hundreds of followers. From the email: “This Covid is different. Let me repeat myself: THIS COVID IS NOT THE SAME. ... For the first time since April 2020, I kneeled on top of a patient in the middle of CPR and saw myself. She was 41 years old, no comorbidities, a full life ahead of her. The first time we fought Covid, everyone was old and sickly. They weren’t ‘me.’ This sweet woman was ‘me.’ We ran a full code on her for 1 hour and 26 minutes in front of her fiancé. He cried out to God to save her. He cried out to us to save her. We did everything in our power to save her. We weren’t able to. Three nurses, a pharmacy tech, an x-ray tech, and our HMG doctor hugged, prayed, and cried together after. She was living her life, got Covid, and died.”

Why she wants people to pay attention: “Our COVID-19 patients are young, they’re healthy, they’re able to answer our questions and immediately crash. We don’t have time to catch our breath between one code to the next. This COVID-19 is a much more violent disease, and I can no longer keep quiet. Someone has to say it. Someone has to say, ‘You can believe what you want to believe,’ but I’m seeing it with my own eyes, I’m holding their hands while they die, I’m bagging their body for the morgue. See this crisis through my eyes – please!”

What’s happening with her coworkers: “We’ve had some pretty bad days. We’re all crying and we’re afraid for each other now. We feel like it could be any of us at any point. I’m feeling that I don’t want to let it get to me, but it is. At home, we pray every night. The other night, one of my twins said: ‘I pray that you don’t get coronavirus and die.’ I can’t help but think: 5-year-olds should pray for unicorns and rainbows, not that their mom could die at work.”

Please stop playing politics: “America has become so divided and the vaccine somehow became the evil thing instead of the fact that the vaccine is the savior. I waited in line to get my vaccine because the scientists came up with something to end all this, but not everyone sees it that way. I feel like people don’t want to see and it shouldn’t matter if you’re a Republican or Democrat – after all, Biden is vaccinated [and] Trump is vaccinated.”
 

COVID-19 perspective from an ED doctor in New York City

Amanda Smith, MD, an ED doctor at Staten Island University Hospital in New York, says she’s sensing a “slow wave coming” when it comes to the Delta variant. The mom of three kids (she has 10-year-old twins and a 12-year-old) thinks often of the first signs of COVID-19 in 2020 and hopes that there won’t be a repeat surge like the initial one in New York City.

It’s hard not to feel frustrated: “I’m annoyed about the Delta variant. Of course, I’ve experienced the ‘I’m not getting the vaccine’ argument, and I’ve been at this long enough that I’m able to compartmentalize my own feelings, but I’m worn down, and I’m aware that I have compassion fatigue. When people complain about their COVID-19 symptoms and say things like ‘If I knew I would feel this horrible, I would have gotten the vaccine,’ I can’t help but feel that this was avoidable. It’s hard to talk to those people. I want to say ‘600,000 dead people weren’t enough to get vaccinated?’ ”

The people avoiding the vaccine: “There are the absolute deniers who will never get vaccinated and aren’t going to change their minds. Then there are the people who feel invincible, and then there are the folks who think that COVID-19 isn’t that bad, it’s just like the flu, it’s only old people dying and they’re not getting information from an appropriate source. It’s not the flu, it does kill you. Delta kills younger people, and it’s very easy to spread. Every one person who was infected with the original strain could infect two to three others. The Delta variant can infect 8-9, and measles, at 13, is the most contagious, so we need to keep reminding people about this.”

It’s not just about you: “Vaccination campaigns were never about the individual. We live together in a civilized society, and the vaccine is something you do for each other. People don’t understand the importance of breaking the chain of transmission and doing this to help each other and eradicate the spread. I just don’t understand what happened to us that we forgot this.”

A version of this article first appeared on WebMD.com.

Patients with pulmonary hypertension (PH) as a complication of chronic obstructive pulmonary disease (COPD) have worse functional impairment and higher mortality, compared with patients who have idiopathic pulmonary arterial hypertension (IPAH).

Despite these factors, some patients with more severe PH in COPD may respond to treatment and show clinical improvement after treatment, according to recent research published in the journal CHEST^®.

Carmine Dario Vizza, MD, of the pulmonary hypertension unit, department of cardiovascular and respiratory diseases at Sapienza University of Rome, and colleagues evaluated patients in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) database, enrolled up to August 2020, identifying 68 patients with moderate PH and COPD and 307 patients with severe PH and COPD. The researchers compared the PH and COPD groups with 307 patients who had idiopathic pulmonary arterial hypertension.

Overall, mostly older men made up the group of patients with moderate (50%; mean, 68.5 years) and severe PH in COPD (61%; mean 68.4 years), compared with those who had IPAH (37%; mean 61.7 years. Oral monotherapy for patients with PH and COPD was the main treatment, consisting of phosphodiesterase-5 inhibitors, while most patients with IPAH received endothelin receptor antagonists.

On functional tests, patients in the PH and COPD group tended to perform poorer on the 6-minute walking distance (6MWD) and World Health Organization functional class (WHO FC) than patients with IPAH. Specifically, among 42.7% of patients in both group for whom follow-up data were available, there was a similar frequency of improvement for 6MWD of 30 meters or more from baseline for both PH and COPD and IPAH groups (46.9% vs. 52.6%; P = .294), but there were significant differences between 6MWD between patients with moderate and severe PH and COPD (51.6% vs. 31.6%; P = .04). There was a nonsignificant improvement in WHO FC improvement of one or more classes for 65.6% of patients with PH and COPD and 58.3% of patients with IPAH with follow-up data available, with 28.5% of patients with PH in COPD improving compared with 35.8% of patients with IPAH (P = .078) and nonsignificant differences between moderate and severe PH and COPD (19.0% vs. 30.4%; P = .188).

Comparing outcomes

Follow-up data were available for 84% of patients with IPAH and 94% of patients with PH and COPD. Dr. Dario Vizza and colleagues found 45.7% of patients in the PH and COPD group and 24.9% of patients in the IPAH group died during follow-up, while 1.1% in the PH and COPD group and 1.5% of patients in the IPAH group underwent lung transplantations. For patients with moderate PH and COPD, 31.3% died and none underwent lung transplantation, while 49.0% of patients in the severe PH and COPD group died and 1.4% underwent lung transplantations.

Patients in the moderate PH and COPD group were more likely to discontinue treatment (10.9%), compared with patients with IPAH (6.6%) and patients with severe PH and COPD (5.2%). The most common reasons for discontinuations were tolerability and efficacy failure; the IPAH group had 63% of patients discontinue because of tolerability and 7% for efficacy failure, 47% of patients in the severe PH and COPD group discontinued because of tolerability and efficacy, and 29% discontinued treatment for tolerability and 57% for efficacy failure in the moderate and COPD group.

The researchers said male sex, low 6MWD, and high pulmonary vascular resistance at baseline were predictive of poorer outcomes for PH and COPD, but patients with more severe PH and COPD had better outcomes if they improved by 30 meters or more in 6MWD, or improved in WHO FC after receiving medical therapy. For patients with IPAH response to therapy was better among patients who were younger, had higher WHO FC, had high diffusing capacity of the lung for carbon monoxide, had high mean pulmonary artery pressure, and had low PCO₂.

“Our data suggest that PH-targeted drug therapy in patients with COPD and severe PH may improve exercise tolerance and WHO FC in a subgroup of patients and that patients with COPD and PH who respond to therapy may have a better prognosis than patients who do not show clinical improvement. These findings need to be explored further in prospective, randomized controlled clinical studies,” the authors concluded.
 

More research needed

In a related editorial, James R. Klinger, MD, a pulmonologist with Brown University, Providence, R.I., and the director of the Rhode Island Hospital Pulmonary Hypertension Center in East Providence, said there is a “keen interest” in treating PH in COPD despite a lack of consistency on whether treatment is effective in this patient population. About 80% of PH centers in the United States treat PH in COPD when they treat conditions like lung disease with PAH medication, he pointed out. However, he questioned whether current medications designed for PAH could improve pulmonary hemodynamics for PH in COPD.

“Reasons that the pathobiologic condition of PH-COPD may differ from PAH include the likely exposure of the pulmonary circulation to greater degrees of hypoxia and hypercapnia and the greater loss of alveolar capillaries associated with emphysema,” he said.

The study by Dr. Dario Vizza and colleagues is an attempt to evaluate treatment response for patients with PH and COPD “in a way that allows comparison with patients who have been treated with similar drugs for PAH,” Dr. Klinger said. He noted the study’s retrospective nature, lack of control group, and lack of information on lung disease severity could limit the findings.

“These limitations preclude recommendations for the routine treatment of patients with PH-COPD, but the findings suggest that, despite greater morbidity at baseline, patients with PH-COPD may be nearly as likely to benefit from PAH medications as patients with IPAH,” he said.

“What is needed now is well-designed randomized controlled studies to determine whether improved outcomes can be achieved in this population and which patients are most likely to benefit,” he concluded. “Simply put: How bad does PH need to be in patients with COPD before treatment is helpful, and how severe does COPD need to be before PH treatment is futile?”

The authors reported personal and institutional relationships in the form of grants, consultancies, advisory board memberships, speakers bureau appointments, honoraria, patents, grant and research funding, lectures, travel compensation, and steering committee positions for a variety of pharmaceutical companies, agencies, societies, journals, medical publishing companies, and other organizations. Dr. Klinger reported his institution receives grant support from Acceleron and United Therapeutics in the area of PH, and he has been an unpaid consultant for Bayer.

Patients with pulmonary hypertension (PH) as a complication of chronic obstructive pulmonary disease (COPD) have worse functional impairment and higher mortality, compared with patients who have idiopathic pulmonary arterial hypertension (IPAH).

Despite these factors, some patients with more severe PH in COPD may respond to treatment and show clinical improvement after treatment, according to recent research published in the journal CHEST^®.

Carmine Dario Vizza, MD, of the pulmonary hypertension unit, department of cardiovascular and respiratory diseases at Sapienza University of Rome, and colleagues evaluated patients in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) database, enrolled up to August 2020, identifying 68 patients with moderate PH and COPD and 307 patients with severe PH and COPD. The researchers compared the PH and COPD groups with 307 patients who had idiopathic pulmonary arterial hypertension.

Overall, mostly older men made up the group of patients with moderate (50%; mean, 68.5 years) and severe PH in COPD (61%; mean 68.4 years), compared with those who had IPAH (37%; mean 61.7 years. Oral monotherapy for patients with PH and COPD was the main treatment, consisting of phosphodiesterase-5 inhibitors, while most patients with IPAH received endothelin receptor antagonists.

On functional tests, patients in the PH and COPD group tended to perform poorer on the 6-minute walking distance (6MWD) and World Health Organization functional class (WHO FC) than patients with IPAH. Specifically, among 42.7% of patients in both group for whom follow-up data were available, there was a similar frequency of improvement for 6MWD of 30 meters or more from baseline for both PH and COPD and IPAH groups (46.9% vs. 52.6%; P = .294), but there were significant differences between 6MWD between patients with moderate and severe PH and COPD (51.6% vs. 31.6%; P = .04). There was a nonsignificant improvement in WHO FC improvement of one or more classes for 65.6% of patients with PH and COPD and 58.3% of patients with IPAH with follow-up data available, with 28.5% of patients with PH in COPD improving compared with 35.8% of patients with IPAH (P = .078) and nonsignificant differences between moderate and severe PH and COPD (19.0% vs. 30.4%; P = .188).

Comparing outcomes

Follow-up data were available for 84% of patients with IPAH and 94% of patients with PH and COPD. Dr. Dario Vizza and colleagues found 45.7% of patients in the PH and COPD group and 24.9% of patients in the IPAH group died during follow-up, while 1.1% in the PH and COPD group and 1.5% of patients in the IPAH group underwent lung transplantations. For patients with moderate PH and COPD, 31.3% died and none underwent lung transplantation, while 49.0% of patients in the severe PH and COPD group died and 1.4% underwent lung transplantations.

Patients in the moderate PH and COPD group were more likely to discontinue treatment (10.9%), compared with patients with IPAH (6.6%) and patients with severe PH and COPD (5.2%). The most common reasons for discontinuations were tolerability and efficacy failure; the IPAH group had 63% of patients discontinue because of tolerability and 7% for efficacy failure, 47% of patients in the severe PH and COPD group discontinued because of tolerability and efficacy, and 29% discontinued treatment for tolerability and 57% for efficacy failure in the moderate and COPD group.

The researchers said male sex, low 6MWD, and high pulmonary vascular resistance at baseline were predictive of poorer outcomes for PH and COPD, but patients with more severe PH and COPD had better outcomes if they improved by 30 meters or more in 6MWD, or improved in WHO FC after receiving medical therapy. For patients with IPAH response to therapy was better among patients who were younger, had higher WHO FC, had high diffusing capacity of the lung for carbon monoxide, had high mean pulmonary artery pressure, and had low PCO₂.

“Our data suggest that PH-targeted drug therapy in patients with COPD and severe PH may improve exercise tolerance and WHO FC in a subgroup of patients and that patients with COPD and PH who respond to therapy may have a better prognosis than patients who do not show clinical improvement. These findings need to be explored further in prospective, randomized controlled clinical studies,” the authors concluded.
 

More research needed

In a related editorial, James R. Klinger, MD, a pulmonologist with Brown University, Providence, R.I., and the director of the Rhode Island Hospital Pulmonary Hypertension Center in East Providence, said there is a “keen interest” in treating PH in COPD despite a lack of consistency on whether treatment is effective in this patient population. About 80% of PH centers in the United States treat PH in COPD when they treat conditions like lung disease with PAH medication, he pointed out. However, he questioned whether current medications designed for PAH could improve pulmonary hemodynamics for PH in COPD.

“Reasons that the pathobiologic condition of PH-COPD may differ from PAH include the likely exposure of the pulmonary circulation to greater degrees of hypoxia and hypercapnia and the greater loss of alveolar capillaries associated with emphysema,” he said.

The study by Dr. Dario Vizza and colleagues is an attempt to evaluate treatment response for patients with PH and COPD “in a way that allows comparison with patients who have been treated with similar drugs for PAH,” Dr. Klinger said. He noted the study’s retrospective nature, lack of control group, and lack of information on lung disease severity could limit the findings.

“These limitations preclude recommendations for the routine treatment of patients with PH-COPD, but the findings suggest that, despite greater morbidity at baseline, patients with PH-COPD may be nearly as likely to benefit from PAH medications as patients with IPAH,” he said.

“What is needed now is well-designed randomized controlled studies to determine whether improved outcomes can be achieved in this population and which patients are most likely to benefit,” he concluded. “Simply put: How bad does PH need to be in patients with COPD before treatment is helpful, and how severe does COPD need to be before PH treatment is futile?”

The authors reported personal and institutional relationships in the form of grants, consultancies, advisory board memberships, speakers bureau appointments, honoraria, patents, grant and research funding, lectures, travel compensation, and steering committee positions for a variety of pharmaceutical companies, agencies, societies, journals, medical publishing companies, and other organizations. Dr. Klinger reported his institution receives grant support from Acceleron and United Therapeutics in the area of PH, and he has been an unpaid consultant for Bayer.

Patients with pulmonary hypertension (PH) as a complication of chronic obstructive pulmonary disease (COPD) have worse functional impairment and higher mortality, compared with patients who have idiopathic pulmonary arterial hypertension (IPAH).

Despite these factors, some patients with more severe PH in COPD may respond to treatment and show clinical improvement after treatment, according to recent research published in the journal CHEST^®.

Carmine Dario Vizza, MD, of the pulmonary hypertension unit, department of cardiovascular and respiratory diseases at Sapienza University of Rome, and colleagues evaluated patients in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) database, enrolled up to August 2020, identifying 68 patients with moderate PH and COPD and 307 patients with severe PH and COPD. The researchers compared the PH and COPD groups with 307 patients who had idiopathic pulmonary arterial hypertension.

Overall, mostly older men made up the group of patients with moderate (50%; mean, 68.5 years) and severe PH in COPD (61%; mean 68.4 years), compared with those who had IPAH (37%; mean 61.7 years. Oral monotherapy for patients with PH and COPD was the main treatment, consisting of phosphodiesterase-5 inhibitors, while most patients with IPAH received endothelin receptor antagonists.

On functional tests, patients in the PH and COPD group tended to perform poorer on the 6-minute walking distance (6MWD) and World Health Organization functional class (WHO FC) than patients with IPAH. Specifically, among 42.7% of patients in both group for whom follow-up data were available, there was a similar frequency of improvement for 6MWD of 30 meters or more from baseline for both PH and COPD and IPAH groups (46.9% vs. 52.6%; P = .294), but there were significant differences between 6MWD between patients with moderate and severe PH and COPD (51.6% vs. 31.6%; P = .04). There was a nonsignificant improvement in WHO FC improvement of one or more classes for 65.6% of patients with PH and COPD and 58.3% of patients with IPAH with follow-up data available, with 28.5% of patients with PH in COPD improving compared with 35.8% of patients with IPAH (P = .078) and nonsignificant differences between moderate and severe PH and COPD (19.0% vs. 30.4%; P = .188).

Comparing outcomes

Follow-up data were available for 84% of patients with IPAH and 94% of patients with PH and COPD. Dr. Dario Vizza and colleagues found 45.7% of patients in the PH and COPD group and 24.9% of patients in the IPAH group died during follow-up, while 1.1% in the PH and COPD group and 1.5% of patients in the IPAH group underwent lung transplantations. For patients with moderate PH and COPD, 31.3% died and none underwent lung transplantation, while 49.0% of patients in the severe PH and COPD group died and 1.4% underwent lung transplantations.

Patients in the moderate PH and COPD group were more likely to discontinue treatment (10.9%), compared with patients with IPAH (6.6%) and patients with severe PH and COPD (5.2%). The most common reasons for discontinuations were tolerability and efficacy failure; the IPAH group had 63% of patients discontinue because of tolerability and 7% for efficacy failure, 47% of patients in the severe PH and COPD group discontinued because of tolerability and efficacy, and 29% discontinued treatment for tolerability and 57% for efficacy failure in the moderate and COPD group.

The researchers said male sex, low 6MWD, and high pulmonary vascular resistance at baseline were predictive of poorer outcomes for PH and COPD, but patients with more severe PH and COPD had better outcomes if they improved by 30 meters or more in 6MWD, or improved in WHO FC after receiving medical therapy. For patients with IPAH response to therapy was better among patients who were younger, had higher WHO FC, had high diffusing capacity of the lung for carbon monoxide, had high mean pulmonary artery pressure, and had low PCO₂.

“Our data suggest that PH-targeted drug therapy in patients with COPD and severe PH may improve exercise tolerance and WHO FC in a subgroup of patients and that patients with COPD and PH who respond to therapy may have a better prognosis than patients who do not show clinical improvement. These findings need to be explored further in prospective, randomized controlled clinical studies,” the authors concluded.
 

More research needed

In a related editorial, James R. Klinger, MD, a pulmonologist with Brown University, Providence, R.I., and the director of the Rhode Island Hospital Pulmonary Hypertension Center in East Providence, said there is a “keen interest” in treating PH in COPD despite a lack of consistency on whether treatment is effective in this patient population. About 80% of PH centers in the United States treat PH in COPD when they treat conditions like lung disease with PAH medication, he pointed out. However, he questioned whether current medications designed for PAH could improve pulmonary hemodynamics for PH in COPD.

“Reasons that the pathobiologic condition of PH-COPD may differ from PAH include the likely exposure of the pulmonary circulation to greater degrees of hypoxia and hypercapnia and the greater loss of alveolar capillaries associated with emphysema,” he said.

The study by Dr. Dario Vizza and colleagues is an attempt to evaluate treatment response for patients with PH and COPD “in a way that allows comparison with patients who have been treated with similar drugs for PAH,” Dr. Klinger said. He noted the study’s retrospective nature, lack of control group, and lack of information on lung disease severity could limit the findings.

“These limitations preclude recommendations for the routine treatment of patients with PH-COPD, but the findings suggest that, despite greater morbidity at baseline, patients with PH-COPD may be nearly as likely to benefit from PAH medications as patients with IPAH,” he said.

“What is needed now is well-designed randomized controlled studies to determine whether improved outcomes can be achieved in this population and which patients are most likely to benefit,” he concluded. “Simply put: How bad does PH need to be in patients with COPD before treatment is helpful, and how severe does COPD need to be before PH treatment is futile?”

The authors reported personal and institutional relationships in the form of grants, consultancies, advisory board memberships, speakers bureau appointments, honoraria, patents, grant and research funding, lectures, travel compensation, and steering committee positions for a variety of pharmaceutical companies, agencies, societies, journals, medical publishing companies, and other organizations. Dr. Klinger reported his institution receives grant support from Acceleron and United Therapeutics in the area of PH, and he has been an unpaid consultant for Bayer.

The U.S. Food and Drug Administration has approved Pfizer’s TicoVac vaccine for the treatment of tick-borne encephalitis (TBE). The vaccine is approved outside of the United States, and more than 170 million doses have been administered since 1976. The World Health Organization recommends vaccination for everyone in areas where the annual incidence of clinical disease is highly endemic, defined as more than five cases per 100,000 population, which is primarily the Baltic countries of Europe but includes some regions of Central and East Asia.

GlaxoSmithKline’s Encepur is also approved outside the United States, as is a vaccine from China and two from Russia. The efficacy of all the vaccines is greater than 95%. Pfizer’s protection is 98.7% to 100.0% after the three-dose course. With the new approval, American travelers will be able to get immunized before their departure instead of waiting until they are overseas to start the series.

TicoVac can cause injection-site pain, headache, myalgia, and fever, as is typical with many vaccines.
 

Tick-borne encephalitis

TBE is caused by a flavivirus and is transmitted by the bite of an infected Ixodes scapularis, or deer tick. Like the Powassan virus, another flavivirus, infection can be transmitted in minutes through the tick’s saliva, so early removal of the tick might not prevent illness. This is different than Lyme disease, where vigilance and early removal of the tick can prevent transmission.

Reservoirs for the virus include mice, voles, and shrews. Large mammals (deer, sheep, cattle, goats) also serve to support tick multiplication. In addition to tick bites, ingestion of unpasteurized milk from infected mammals can transmit TBE.

TBE symptoms can range from none to severe encephalitis (brain inflammation). One-quarter of infected people develop encephalitis. Most recover fully, but one-third of those infected can develop lifelong damage and paralysis or cognitive deficits. Death is rare, except in those infected with the Russian strain.

The first phase of a TBE infection is typical of viral infections, with nonspecific fever, headache, nausea, and myalgia. The next phase involves an asymptomatic interval of about a week (range, 1 to 33 days), followed by symptoms of a central nervous system infection.

There is no treatment for TBE and no antivirals with proven benefit. However, a recent case report describes the successful treatment of TBE with favipiravir.

For now, if you are unvaccinated, prevention is the only viable option. If you plan to travel to an endemic region and anticipate participating in outdoor activities (such as hunting or hiking), wear permethrin-treated clothes, use an insecticide, and don’t eat or drink unpasteurized dairy products.

Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved Pfizer’s TicoVac vaccine for the treatment of tick-borne encephalitis (TBE). The vaccine is approved outside of the United States, and more than 170 million doses have been administered since 1976. The World Health Organization recommends vaccination for everyone in areas where the annual incidence of clinical disease is highly endemic, defined as more than five cases per 100,000 population, which is primarily the Baltic countries of Europe but includes some regions of Central and East Asia.

GlaxoSmithKline’s Encepur is also approved outside the United States, as is a vaccine from China and two from Russia. The efficacy of all the vaccines is greater than 95%. Pfizer’s protection is 98.7% to 100.0% after the three-dose course. With the new approval, American travelers will be able to get immunized before their departure instead of waiting until they are overseas to start the series.

TicoVac can cause injection-site pain, headache, myalgia, and fever, as is typical with many vaccines.
 

Tick-borne encephalitis

TBE is caused by a flavivirus and is transmitted by the bite of an infected Ixodes scapularis, or deer tick. Like the Powassan virus, another flavivirus, infection can be transmitted in minutes through the tick’s saliva, so early removal of the tick might not prevent illness. This is different than Lyme disease, where vigilance and early removal of the tick can prevent transmission.

Reservoirs for the virus include mice, voles, and shrews. Large mammals (deer, sheep, cattle, goats) also serve to support tick multiplication. In addition to tick bites, ingestion of unpasteurized milk from infected mammals can transmit TBE.

TBE symptoms can range from none to severe encephalitis (brain inflammation). One-quarter of infected people develop encephalitis. Most recover fully, but one-third of those infected can develop lifelong damage and paralysis or cognitive deficits. Death is rare, except in those infected with the Russian strain.

The first phase of a TBE infection is typical of viral infections, with nonspecific fever, headache, nausea, and myalgia. The next phase involves an asymptomatic interval of about a week (range, 1 to 33 days), followed by symptoms of a central nervous system infection.

There is no treatment for TBE and no antivirals with proven benefit. However, a recent case report describes the successful treatment of TBE with favipiravir.

For now, if you are unvaccinated, prevention is the only viable option. If you plan to travel to an endemic region and anticipate participating in outdoor activities (such as hunting or hiking), wear permethrin-treated clothes, use an insecticide, and don’t eat or drink unpasteurized dairy products.

Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.

A version of this article first appeared on Medscape.com.

The U.S. Food and Drug Administration has approved Pfizer’s TicoVac vaccine for the treatment of tick-borne encephalitis (TBE). The vaccine is approved outside of the United States, and more than 170 million doses have been administered since 1976. The World Health Organization recommends vaccination for everyone in areas where the annual incidence of clinical disease is highly endemic, defined as more than five cases per 100,000 population, which is primarily the Baltic countries of Europe but includes some regions of Central and East Asia.

GlaxoSmithKline’s Encepur is also approved outside the United States, as is a vaccine from China and two from Russia. The efficacy of all the vaccines is greater than 95%. Pfizer’s protection is 98.7% to 100.0% after the three-dose course. With the new approval, American travelers will be able to get immunized before their departure instead of waiting until they are overseas to start the series.

TicoVac can cause injection-site pain, headache, myalgia, and fever, as is typical with many vaccines.
 

Tick-borne encephalitis

TBE is caused by a flavivirus and is transmitted by the bite of an infected Ixodes scapularis, or deer tick. Like the Powassan virus, another flavivirus, infection can be transmitted in minutes through the tick’s saliva, so early removal of the tick might not prevent illness. This is different than Lyme disease, where vigilance and early removal of the tick can prevent transmission.

Reservoirs for the virus include mice, voles, and shrews. Large mammals (deer, sheep, cattle, goats) also serve to support tick multiplication. In addition to tick bites, ingestion of unpasteurized milk from infected mammals can transmit TBE.

TBE symptoms can range from none to severe encephalitis (brain inflammation). One-quarter of infected people develop encephalitis. Most recover fully, but one-third of those infected can develop lifelong damage and paralysis or cognitive deficits. Death is rare, except in those infected with the Russian strain.

The first phase of a TBE infection is typical of viral infections, with nonspecific fever, headache, nausea, and myalgia. The next phase involves an asymptomatic interval of about a week (range, 1 to 33 days), followed by symptoms of a central nervous system infection.

There is no treatment for TBE and no antivirals with proven benefit. However, a recent case report describes the successful treatment of TBE with favipiravir.

For now, if you are unvaccinated, prevention is the only viable option. If you plan to travel to an endemic region and anticipate participating in outdoor activities (such as hunting or hiking), wear permethrin-treated clothes, use an insecticide, and don’t eat or drink unpasteurized dairy products.

Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family’s Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.

A version of this article first appeared on Medscape.com.

Nearly 50,000 veterans are diagnosed with cancer within the Veterans Health Administration annually with prostate cancer (PC) being the most frequently diagnosed, accounting for 29% of all cancers diagnosed.¹ The treatment of PC depends on the stage and risk group at presentation and patient preference. Men with early stage, localized PC can be managed with prostatectomy, radiation therapy, or active surveillance.²

Within the Veterans Health Administration, more patients are treated with radiation therapy than with radical prostatectomy.³ This is in contrast to the civil health system, where more patients are treated with radical prostatectomy than with radiation therapy.^4,5 Radiation therapy for PC can be given externally with external beam radiation therapy or internally with brachytherapy (BT). BT is categorized by the rate at which the radiation dose is delivered and generally grouped as low-dose rate (LDR) or high-dose rate (HDR). LDRBT consists of permanently implanting radioactive seeds, which slowly deliver a radiation dose over an extended period. HDRBT consists of implanting catheters that allow delivery of a radioactive source to be placed temporarily in the prostate and removed after treatment. The utilization of HDRBT has become more common as treatment has evolved to consist of fewer, larger fractions in a shorter time, making it a convenient treatment option for men with PC.⁶ The veteran population has singular medical challenges. These patients differ from the general population and are often underrepresented in medical research and published studies.⁷ There are no studies exploring the treatment-associated toxicities from HDRBT treatment for PC specifically in the veteran population. The objective of this study is to report our findings regarding the veteran-reported and physician-graded toxicities associated with HDRBT as monotherapy in veterans treated through the US Department of Veterans Affairs (VA) for PC.

Methods

We performed a retrospective cohort study of a prospectively maintained, institutional review board-approved database of patients treated with HDRBT for PC. Veterans were seen in consultation at Edward Hines, Jr. VA Hospital (EHJVAH) in Hines, Illinois. This is the only VA hospital in Illinois that offers radiation therapy, so it acted as a tertiary center, receiving referrals from other, neighboring VA hospitals. If the veteran was deemed a good BT candidate and elected to proceed with HDRBT, HDR treatment was performed at a partnering academic institution equipped to provide HDRBT (Loyola University Medical Center).

We selected patients with National Cancer Center Network (NCCN) low- or intermediate-risk PC undergoing definitive HDRBT as monotherapy using 13.5 Gy x 2 fractions delivered over 2 implants that were 1 to 2 weeks apart. Patients who received androgen deprivation therapy (ADT) were excluded from this study. No patients received supplemental external beam radiation. Men with unfavorable intermediate risk PC were offered ADT and BT in accordance with NCCN guidelines. However, patients with unfavorable intermediate-risk PC who declined ADT or who were deemed poor ADT candidates due to comorbidities were treated with HDR as monotherapy and included in this study.⁸

HDR Treatment

Our HDRBT implant procedure and treatment planning details have been previously described.⁹ In brief, patients were implanted with between 17 and 22 catheters based on gland size under transrectal ultrasound guidance. After implantation, computed tomography and, when possible, magnetic resonance imaging of the prostate were obtained and registered for target delineation. The prostate was segmented, and an asymmetric planning target volume of 0 to 5 mm was created and extended to encompass the proximal seminal vesicles. The second fraction was given 1 to 2 weeks after initial treatment, based on patient, physician, and operating room availability.

Health-Related Quality of Life Assessment

Veteran-reported genitourinary (GU), gastrointestinal (GI), and sexual health-related quality of life (hrQOL) were assessed using the validated International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite Short Form (EPIC-26) instruments.^10,11 Baseline veteran-reported hrQOL scores in the GU, GI, and sexual domains were obtained prior to each veteran’s first HDR treatment. Veteran-reported hrQOL scores were assessed at each of the patient’s follow-up appointments. Physician-graded toxicity was assessed Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria.¹² Physician-graded toxicity was assessed at each follow-up visit and reported as the highest grade reported during any follow-up examination.

Follow-up appointments typically occurred at 1 month, 3 months, 6 months, 12 months, and subsequently every 6 months after the second HDR treatment. Follow-up appointments were conducted in the radiation oncology department at EHJVAH.

Minimal Clinically Important Differences

To evaluate the veteran-reported hrQOL, we characterized statistically significant differences in IPSS or EPIC-26 scores over time as compared with baseline values as clinically important or not clinically important through the use of reported minimal clinically important difference (MCID) assessments.^13-15 For the IPSS, we used reported data that showed a change of ≥ 3.0 points represented a clinically meaningful change in urinary function.¹⁴ For the EPIC-26 scores, we used reported data that showed a change of ≥ 6 points for urinary incontinence score, ≥ 5 points for urinary obstruction score, ≥ 4 points for bowel score, and ≥ 10 points for sexual score to represent an MCID.¹⁵

Statistical Analysis

Changes in veteran-reported hrQOL over time were compared using mixed linear effects models, with the time since the last BT implant serving as the fixed variable. Effects were deemed statistically significant if P < .05. If a statistically significant difference from baseline was found at any time point, additional evaluation was done to see if the numerical difference in the assessment led to an MCID as described above. IBM SPSS Statistics for Windows, version 25.0 was used for data analysis.

Results

Seventy-four veterans were included in the study. The median follow-up was 18 months (range 1-43). The demographic and oncologic specifics of the treated veterans are outlined in Table 1.

There was a significant increase in IPSS (P < .001) with reciprocal decline in EPIC-26 urinary incontinence (P = .008) and EPIC-26 urinary obstruction scores (P = .001) from baseline over time (Table 2 and Figure 1). At the 18-month follow-up assessment, there was no longer a significant difference in the EPIC-26 urinary obstruction score from baseline (88.7 vs 84.0, P = .31). The increases in IPSS at the 1-, 3-, and 6-month assessments met the criteria for MCID. The decrease in EPIC-26 urinary incontinence scores at the 1-, 3-, 6-, 12-, and 18-month assessments were found to be an MCID, as were the decrease in EPIC-26 urinary obstruction scores at the 1-, 3-, 6-, and 12-month assessments.

Discussion

We performed a retrospective study of veterans with low- or intermediate-risk PC undergoing definitive HDR prostate BT as monotherapy. We found that veterans experienced immediate declines in GU, GI, and sexual hrQOL after treatment. However, each trended toward a return to baseline over time, with the EPIC-26 urinary obstruction and the EPIC-26 bowel scores showing no difference from the baseline value within 18 months and 12 months, respectively. The physician-reported toxicities were low, with only 1 incidence of grade 3 GU toxicity, no grade 3 GI or sexual toxicities, and no grade 4 or 5 toxicity. This suggests that HDRBT is a well-tolerated and safe, definitive treatment for veterans with localized PC.

In a series similar to ours, Gaudet and colleagues reported on their single institutional results of treating 30 low- or intermediate-risk PC patients with HDRBT as monotherapy.¹⁶ Patients included in their study were civilians from the general population, treated in a similar fashion to the veterans treated in our study. Each patient received 27 Gy in 2 fractions given over 2 implants. The authors collected patient-reported hrQOL results using the IPSS and EPIC questionnaires and found that 57% of patients treated experienced moderate-to-severe urinary symptoms at the 1-month assessment after implantation, with a rapid recovery toward baseline over time. In contrast, GI symptoms did not change from baseline, while sexual symptoms worsened after implantation and failed to return to baseline.

Limitations

To the authors’ knowledge, there are no other studies exploring HDR prostate BT toxicity in a veteran-specific population, and our study is novel in addressing this question. One limitation of the study is the relatively short median follow-up time of 18 months. With this limitation, our data were not yet sufficiently mature to perform biochemical control or overall survival analyses. The next step in our study is to calculate these clinical endpoints from our data after longer follow-up.

An additional limitation to our study is the single institutional nature of the design. While veterans from neighboring VA hospitals were included in the study by way of referral and treatment at our center, the only VA hospital in the state to provide radiation therapy, our patient population remains limited. Further multi-institutional and prospective data are needed to validate our findings.

Conclusions

HDR prostate BT as monotherapy is feasible with a favorable veteran-reported hrQOL and physician-graded toxicity profile. Veterans should be educated about this treatment modality when considering the optimal treatment for their localized prostate cancer.

Nearly 50,000 veterans are diagnosed with cancer within the Veterans Health Administration annually with prostate cancer (PC) being the most frequently diagnosed, accounting for 29% of all cancers diagnosed.¹ The treatment of PC depends on the stage and risk group at presentation and patient preference. Men with early stage, localized PC can be managed with prostatectomy, radiation therapy, or active surveillance.²

Within the Veterans Health Administration, more patients are treated with radiation therapy than with radical prostatectomy.³ This is in contrast to the civil health system, where more patients are treated with radical prostatectomy than with radiation therapy.^4,5 Radiation therapy for PC can be given externally with external beam radiation therapy or internally with brachytherapy (BT). BT is categorized by the rate at which the radiation dose is delivered and generally grouped as low-dose rate (LDR) or high-dose rate (HDR). LDRBT consists of permanently implanting radioactive seeds, which slowly deliver a radiation dose over an extended period. HDRBT consists of implanting catheters that allow delivery of a radioactive source to be placed temporarily in the prostate and removed after treatment. The utilization of HDRBT has become more common as treatment has evolved to consist of fewer, larger fractions in a shorter time, making it a convenient treatment option for men with PC.⁶ The veteran population has singular medical challenges. These patients differ from the general population and are often underrepresented in medical research and published studies.⁷ There are no studies exploring the treatment-associated toxicities from HDRBT treatment for PC specifically in the veteran population. The objective of this study is to report our findings regarding the veteran-reported and physician-graded toxicities associated with HDRBT as monotherapy in veterans treated through the US Department of Veterans Affairs (VA) for PC.

Methods

We performed a retrospective cohort study of a prospectively maintained, institutional review board-approved database of patients treated with HDRBT for PC. Veterans were seen in consultation at Edward Hines, Jr. VA Hospital (EHJVAH) in Hines, Illinois. This is the only VA hospital in Illinois that offers radiation therapy, so it acted as a tertiary center, receiving referrals from other, neighboring VA hospitals. If the veteran was deemed a good BT candidate and elected to proceed with HDRBT, HDR treatment was performed at a partnering academic institution equipped to provide HDRBT (Loyola University Medical Center).

We selected patients with National Cancer Center Network (NCCN) low- or intermediate-risk PC undergoing definitive HDRBT as monotherapy using 13.5 Gy x 2 fractions delivered over 2 implants that were 1 to 2 weeks apart. Patients who received androgen deprivation therapy (ADT) were excluded from this study. No patients received supplemental external beam radiation. Men with unfavorable intermediate risk PC were offered ADT and BT in accordance with NCCN guidelines. However, patients with unfavorable intermediate-risk PC who declined ADT or who were deemed poor ADT candidates due to comorbidities were treated with HDR as monotherapy and included in this study.⁸

HDR Treatment

Our HDRBT implant procedure and treatment planning details have been previously described.⁹ In brief, patients were implanted with between 17 and 22 catheters based on gland size under transrectal ultrasound guidance. After implantation, computed tomography and, when possible, magnetic resonance imaging of the prostate were obtained and registered for target delineation. The prostate was segmented, and an asymmetric planning target volume of 0 to 5 mm was created and extended to encompass the proximal seminal vesicles. The second fraction was given 1 to 2 weeks after initial treatment, based on patient, physician, and operating room availability.

Health-Related Quality of Life Assessment

Veteran-reported genitourinary (GU), gastrointestinal (GI), and sexual health-related quality of life (hrQOL) were assessed using the validated International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite Short Form (EPIC-26) instruments.^10,11 Baseline veteran-reported hrQOL scores in the GU, GI, and sexual domains were obtained prior to each veteran’s first HDR treatment. Veteran-reported hrQOL scores were assessed at each of the patient’s follow-up appointments. Physician-graded toxicity was assessed Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria.¹² Physician-graded toxicity was assessed at each follow-up visit and reported as the highest grade reported during any follow-up examination.

Follow-up appointments typically occurred at 1 month, 3 months, 6 months, 12 months, and subsequently every 6 months after the second HDR treatment. Follow-up appointments were conducted in the radiation oncology department at EHJVAH.

Minimal Clinically Important Differences

To evaluate the veteran-reported hrQOL, we characterized statistically significant differences in IPSS or EPIC-26 scores over time as compared with baseline values as clinically important or not clinically important through the use of reported minimal clinically important difference (MCID) assessments.^13-15 For the IPSS, we used reported data that showed a change of ≥ 3.0 points represented a clinically meaningful change in urinary function.¹⁴ For the EPIC-26 scores, we used reported data that showed a change of ≥ 6 points for urinary incontinence score, ≥ 5 points for urinary obstruction score, ≥ 4 points for bowel score, and ≥ 10 points for sexual score to represent an MCID.¹⁵

Statistical Analysis

Changes in veteran-reported hrQOL over time were compared using mixed linear effects models, with the time since the last BT implant serving as the fixed variable. Effects were deemed statistically significant if P < .05. If a statistically significant difference from baseline was found at any time point, additional evaluation was done to see if the numerical difference in the assessment led to an MCID as described above. IBM SPSS Statistics for Windows, version 25.0 was used for data analysis.

Results

Seventy-four veterans were included in the study. The median follow-up was 18 months (range 1-43). The demographic and oncologic specifics of the treated veterans are outlined in Table 1.

There was a significant increase in IPSS (P < .001) with reciprocal decline in EPIC-26 urinary incontinence (P = .008) and EPIC-26 urinary obstruction scores (P = .001) from baseline over time (Table 2 and Figure 1). At the 18-month follow-up assessment, there was no longer a significant difference in the EPIC-26 urinary obstruction score from baseline (88.7 vs 84.0, P = .31). The increases in IPSS at the 1-, 3-, and 6-month assessments met the criteria for MCID. The decrease in EPIC-26 urinary incontinence scores at the 1-, 3-, 6-, 12-, and 18-month assessments were found to be an MCID, as were the decrease in EPIC-26 urinary obstruction scores at the 1-, 3-, 6-, and 12-month assessments.

Discussion

We performed a retrospective study of veterans with low- or intermediate-risk PC undergoing definitive HDR prostate BT as monotherapy. We found that veterans experienced immediate declines in GU, GI, and sexual hrQOL after treatment. However, each trended toward a return to baseline over time, with the EPIC-26 urinary obstruction and the EPIC-26 bowel scores showing no difference from the baseline value within 18 months and 12 months, respectively. The physician-reported toxicities were low, with only 1 incidence of grade 3 GU toxicity, no grade 3 GI or sexual toxicities, and no grade 4 or 5 toxicity. This suggests that HDRBT is a well-tolerated and safe, definitive treatment for veterans with localized PC.

In a series similar to ours, Gaudet and colleagues reported on their single institutional results of treating 30 low- or intermediate-risk PC patients with HDRBT as monotherapy.¹⁶ Patients included in their study were civilians from the general population, treated in a similar fashion to the veterans treated in our study. Each patient received 27 Gy in 2 fractions given over 2 implants. The authors collected patient-reported hrQOL results using the IPSS and EPIC questionnaires and found that 57% of patients treated experienced moderate-to-severe urinary symptoms at the 1-month assessment after implantation, with a rapid recovery toward baseline over time. In contrast, GI symptoms did not change from baseline, while sexual symptoms worsened after implantation and failed to return to baseline.

Limitations

To the authors’ knowledge, there are no other studies exploring HDR prostate BT toxicity in a veteran-specific population, and our study is novel in addressing this question. One limitation of the study is the relatively short median follow-up time of 18 months. With this limitation, our data were not yet sufficiently mature to perform biochemical control or overall survival analyses. The next step in our study is to calculate these clinical endpoints from our data after longer follow-up.

An additional limitation to our study is the single institutional nature of the design. While veterans from neighboring VA hospitals were included in the study by way of referral and treatment at our center, the only VA hospital in the state to provide radiation therapy, our patient population remains limited. Further multi-institutional and prospective data are needed to validate our findings.

Conclusions

HDR prostate BT as monotherapy is feasible with a favorable veteran-reported hrQOL and physician-graded toxicity profile. Veterans should be educated about this treatment modality when considering the optimal treatment for their localized prostate cancer.

Nearly 50,000 veterans are diagnosed with cancer within the Veterans Health Administration annually with prostate cancer (PC) being the most frequently diagnosed, accounting for 29% of all cancers diagnosed.¹ The treatment of PC depends on the stage and risk group at presentation and patient preference. Men with early stage, localized PC can be managed with prostatectomy, radiation therapy, or active surveillance.²

Within the Veterans Health Administration, more patients are treated with radiation therapy than with radical prostatectomy.³ This is in contrast to the civil health system, where more patients are treated with radical prostatectomy than with radiation therapy.^4,5 Radiation therapy for PC can be given externally with external beam radiation therapy or internally with brachytherapy (BT). BT is categorized by the rate at which the radiation dose is delivered and generally grouped as low-dose rate (LDR) or high-dose rate (HDR). LDRBT consists of permanently implanting radioactive seeds, which slowly deliver a radiation dose over an extended period. HDRBT consists of implanting catheters that allow delivery of a radioactive source to be placed temporarily in the prostate and removed after treatment. The utilization of HDRBT has become more common as treatment has evolved to consist of fewer, larger fractions in a shorter time, making it a convenient treatment option for men with PC.⁶ The veteran population has singular medical challenges. These patients differ from the general population and are often underrepresented in medical research and published studies.⁷ There are no studies exploring the treatment-associated toxicities from HDRBT treatment for PC specifically in the veteran population. The objective of this study is to report our findings regarding the veteran-reported and physician-graded toxicities associated with HDRBT as monotherapy in veterans treated through the US Department of Veterans Affairs (VA) for PC.

Methods

We performed a retrospective cohort study of a prospectively maintained, institutional review board-approved database of patients treated with HDRBT for PC. Veterans were seen in consultation at Edward Hines, Jr. VA Hospital (EHJVAH) in Hines, Illinois. This is the only VA hospital in Illinois that offers radiation therapy, so it acted as a tertiary center, receiving referrals from other, neighboring VA hospitals. If the veteran was deemed a good BT candidate and elected to proceed with HDRBT, HDR treatment was performed at a partnering academic institution equipped to provide HDRBT (Loyola University Medical Center).

We selected patients with National Cancer Center Network (NCCN) low- or intermediate-risk PC undergoing definitive HDRBT as monotherapy using 13.5 Gy x 2 fractions delivered over 2 implants that were 1 to 2 weeks apart. Patients who received androgen deprivation therapy (ADT) were excluded from this study. No patients received supplemental external beam radiation. Men with unfavorable intermediate risk PC were offered ADT and BT in accordance with NCCN guidelines. However, patients with unfavorable intermediate-risk PC who declined ADT or who were deemed poor ADT candidates due to comorbidities were treated with HDR as monotherapy and included in this study.⁸

HDR Treatment

Our HDRBT implant procedure and treatment planning details have been previously described.⁹ In brief, patients were implanted with between 17 and 22 catheters based on gland size under transrectal ultrasound guidance. After implantation, computed tomography and, when possible, magnetic resonance imaging of the prostate were obtained and registered for target delineation. The prostate was segmented, and an asymmetric planning target volume of 0 to 5 mm was created and extended to encompass the proximal seminal vesicles. The second fraction was given 1 to 2 weeks after initial treatment, based on patient, physician, and operating room availability.

Health-Related Quality of Life Assessment

Veteran-reported genitourinary (GU), gastrointestinal (GI), and sexual health-related quality of life (hrQOL) were assessed using the validated International Prostate Symptom Score (IPSS) and the Expanded Prostate Cancer Index Composite Short Form (EPIC-26) instruments.^10,11 Baseline veteran-reported hrQOL scores in the GU, GI, and sexual domains were obtained prior to each veteran’s first HDR treatment. Veteran-reported hrQOL scores were assessed at each of the patient’s follow-up appointments. Physician-graded toxicity was assessed Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria.¹² Physician-graded toxicity was assessed at each follow-up visit and reported as the highest grade reported during any follow-up examination.

Follow-up appointments typically occurred at 1 month, 3 months, 6 months, 12 months, and subsequently every 6 months after the second HDR treatment. Follow-up appointments were conducted in the radiation oncology department at EHJVAH.

Minimal Clinically Important Differences

To evaluate the veteran-reported hrQOL, we characterized statistically significant differences in IPSS or EPIC-26 scores over time as compared with baseline values as clinically important or not clinically important through the use of reported minimal clinically important difference (MCID) assessments.^13-15 For the IPSS, we used reported data that showed a change of ≥ 3.0 points represented a clinically meaningful change in urinary function.¹⁴ For the EPIC-26 scores, we used reported data that showed a change of ≥ 6 points for urinary incontinence score, ≥ 5 points for urinary obstruction score, ≥ 4 points for bowel score, and ≥ 10 points for sexual score to represent an MCID.¹⁵

Statistical Analysis

Changes in veteran-reported hrQOL over time were compared using mixed linear effects models, with the time since the last BT implant serving as the fixed variable. Effects were deemed statistically significant if P < .05. If a statistically significant difference from baseline was found at any time point, additional evaluation was done to see if the numerical difference in the assessment led to an MCID as described above. IBM SPSS Statistics for Windows, version 25.0 was used for data analysis.

Results

Seventy-four veterans were included in the study. The median follow-up was 18 months (range 1-43). The demographic and oncologic specifics of the treated veterans are outlined in Table 1.

There was a significant increase in IPSS (P < .001) with reciprocal decline in EPIC-26 urinary incontinence (P = .008) and EPIC-26 urinary obstruction scores (P = .001) from baseline over time (Table 2 and Figure 1). At the 18-month follow-up assessment, there was no longer a significant difference in the EPIC-26 urinary obstruction score from baseline (88.7 vs 84.0, P = .31). The increases in IPSS at the 1-, 3-, and 6-month assessments met the criteria for MCID. The decrease in EPIC-26 urinary incontinence scores at the 1-, 3-, 6-, 12-, and 18-month assessments were found to be an MCID, as were the decrease in EPIC-26 urinary obstruction scores at the 1-, 3-, 6-, and 12-month assessments.

Discussion

We performed a retrospective study of veterans with low- or intermediate-risk PC undergoing definitive HDR prostate BT as monotherapy. We found that veterans experienced immediate declines in GU, GI, and sexual hrQOL after treatment. However, each trended toward a return to baseline over time, with the EPIC-26 urinary obstruction and the EPIC-26 bowel scores showing no difference from the baseline value within 18 months and 12 months, respectively. The physician-reported toxicities were low, with only 1 incidence of grade 3 GU toxicity, no grade 3 GI or sexual toxicities, and no grade 4 or 5 toxicity. This suggests that HDRBT is a well-tolerated and safe, definitive treatment for veterans with localized PC.

In a series similar to ours, Gaudet and colleagues reported on their single institutional results of treating 30 low- or intermediate-risk PC patients with HDRBT as monotherapy.¹⁶ Patients included in their study were civilians from the general population, treated in a similar fashion to the veterans treated in our study. Each patient received 27 Gy in 2 fractions given over 2 implants. The authors collected patient-reported hrQOL results using the IPSS and EPIC questionnaires and found that 57% of patients treated experienced moderate-to-severe urinary symptoms at the 1-month assessment after implantation, with a rapid recovery toward baseline over time. In contrast, GI symptoms did not change from baseline, while sexual symptoms worsened after implantation and failed to return to baseline.

Limitations

To the authors’ knowledge, there are no other studies exploring HDR prostate BT toxicity in a veteran-specific population, and our study is novel in addressing this question. One limitation of the study is the relatively short median follow-up time of 18 months. With this limitation, our data were not yet sufficiently mature to perform biochemical control or overall survival analyses. The next step in our study is to calculate these clinical endpoints from our data after longer follow-up.

An additional limitation to our study is the single institutional nature of the design. While veterans from neighboring VA hospitals were included in the study by way of referral and treatment at our center, the only VA hospital in the state to provide radiation therapy, our patient population remains limited. Further multi-institutional and prospective data are needed to validate our findings.

Conclusions

HDR prostate BT as monotherapy is feasible with a favorable veteran-reported hrQOL and physician-graded toxicity profile. Veterans should be educated about this treatment modality when considering the optimal treatment for their localized prostate cancer.

Prostate cancer (PC) is the most commonly and newly diagnosed nonskin cancer and the second leading cause of cancer death in men in the United States. About 191,930 cases and about 33,330 deaths from PC were expected for the year 2020.¹ About 1 in 41 men will die of PC. Most men diagnosed with PC are aged > 65 years and do not die of their disease. The 5-year survival rate of localized and regional disease is nearly 100%, and disease with distant metastases is 31%. As a result, more than 3.1 million men in the United States who have been diagnosed with PC are still alive today.¹ Among veterans, there is a substantial population living with PC. Skolarus and Hawley reported in 2014 that an estimated 200,000 veterans with PC were survivors and 12,000 were newly diagnosed.²

In PC, skeletal strength can be affected by several factors, such as aging, malnutrition, androgen-deprivation therapy (ADT), and bone metastasis.^3,4 In fact, most men can live the rest of their life with PC by using strategies to monitor and treat it, once it shows either radiographic or chemical signs of progression.⁵ ADT is the standard of care to treat hormone-sensitive PC, which is associated with significant skeletal-related adverse effects (AEs).^6,7

Men undergoing ADT are 4 times more likely to develop substantial bone deficiency, Shahinian and colleagues found that in men surviving 5 years after PC diagnosis, 19.4% of those who received ADT had a fracture compared with 12% in men who did not (P < .001). The authors established a significant relation between the number of doses of gonadotropin-releasing hormone given in the first 12 months and the risk of fracture.⁸ Of those who progressed to metastatic disease, the first metastatic nonnodal site is most commonly to the bone.⁹ Advanced PC is characterized by increased bone turnover, which further raises concerns for bone health and patient performance.¹⁰

Skeletal-related events (SREs) include pathologic fracture, spinal cord compression, palliative radiation, or surgery to bone, and change in antineoplastic therapy secondary to bone pain. The concept of bone health refers to the prevention, diagnosis, and treatment of idiopathic, pathogenic, and treatment-related bone loss and delay or prevention of SREs.^6,11 Guidelines and expert groups have recommended screening for osteoporosis at the start of ADT with bone mineral density testing, ensuring adequate calcium and vitamin D intake, modifying lifestyle behaviors (smoking cessation, alcohol moderation, and regular exercise), and prescribing bisphosphonates or receptor-activated nuclear factor κ-B ligand inhibitor, denosumab, for men with osteoporosis or who are at general high-fracture risk.^12,13 The overuse of these medications results in undue cost to patients as well as AEs, such as osteonecrosis of the jaw (ONJ), hypocalcemia, and bone/joint pains.^14-17 There are evidence-based guidelines for appropriate use of bisphosphonates and denosumab for delay and prevention of SREs in the setting of advanced PC.¹⁸ These doses also typically differ in frequency to those of osteoporosis.¹⁹ We summarize the evidence and guidance for health care providers who care for patients with PC at various stages and complications from both disease-related and treatment-related comorbidities.

Bone-Strengthening Agents

Overall, there is evidence to support the use of bone-strengthening agents in patients with osteopenia/osteoporosis in the prevention of SREs with significant risk factors for progressive bone demineralization, such as lifestyle factors and, in particular, treatments such as ADT. Bone-remodeling agents for treatment of bony metastasis have been shown to provide therapeutic advantage only in limited instances in the castration-resistant PC (CRPC) setting. Hence, in patients with hormone-sensitive PC due to medication-related AEs, treatment with bone-strengthening agents is indicated only if the patient has a significant preexisting risk for fracture from osteopenia/osteoporosis (Table). The Figure depicts an algorithm for the management of bone health in men with PC who are being treated with ADT.

Denosumab and bisphosphonates have an established role in preventing SREs in metastatic CRPC.²⁰ The choice of denosumab or a bisphosphonate typically varies based on the indication, possible AEs, and cost of therapy. There are multiple studies involving initiation of these agents at various stages of disease to improve both time to progression as well as management of SREs. There is a lack of evidence that bisphosphonates prevent metastatic-bone lesions in castration-sensitive PC; therefore, prophylactic use of this agent is not recommended in patients unless they have significant bone demineralization.^21,22

Bone Health in Patients

Nonmetastatic Hormone-Sensitive PC

ADT forms the backbone of treatment for patients with local and advanced metastatic castration-sensitive PC along with surgical and focal radiotherapy options. Cancer treatment-induced bone loss is known to occur with prolonged use of ADT. The ZEUS trial found no prevention of bone metastasis in patients with high-risk localized PC with the use of ZA in the absence of bone metastasis. A Kaplan-Meier estimated proportion of bone metastases after a median follow-up of 4.8 years was found to be not statistically significant: 14.7% in the ZA group vs 13.2% in the control/placebo group.²⁹ The STAMPEDE trial showed no significant overall survival (OS) benefit with the addition of ZA to ADT vs ADT alone (HR, 0.94; 95% CI, 0.79-1.11; P = .45), 5-year survival with ADT alone was 55% compared to ADT plus ZA with 57% 5-year survival.³⁰ The RADAR trial showed that at 5 years in high Gleason score patients, use of ZA in the absence of bone metastasis was beneficial, but not in low- or intermediate-risk patients. However, at 10-year analysis there was no significant difference in any of the high-stratified groups with or without ZA.³¹

The PR04 trial showed no effect on OS with clodronate compared with placebo in nonmetastatic castration-sensitive PC, with a HR of 1.12 (95% CI, 0.89-1.42; P = .94). The estimated 5-year survival was 80% with placebo and 78% with clodronate; 10-year survival rates were 51% with placebo and 48% with clodronate.³² Data from the HALT trial showed an increased bone mineral density and reduced risk of new vertebral fractures vs placebo (1.5% vs 3.9%, respectively) in the absence of metastatic bone lesions and a reduction in new vertebral fractures in patients with nonmetastatic PC.³³ Most of these studies showed no benefit with the addition of ZA to nonmetastatic PC; although, the HALT trial provides evidence to support use of denosumab in patients with nonmetastatic PC for preventing vertebral fragility fractures in men receiving ADT.

Metastatic Hormone-Sensitive PC

ZA is often used to treat men with metastatic castration-sensitive PC despite limited efficacy and safety data. The CALGB 90202 (Alliance) trial authors found that the early use of ZA was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the ZA group (95% CI, 24.2-40.3) and 29.8 months in the placebo group (stratified HR, 0.97; 95% CI, 0-1.17; 1-sided stratified log-rank P = .39).³⁴ OS was similar between the groups (HR, 0.88; 95% CI, 0.70-1.12; P = .29) as were reported AEs.³⁴ Results from these studies suggest limited benefit in treating patients with metastatic hormone-sensitive PC with bisphosphonates without other medical indications for use. Additional studies suggest similar results for treatment with denosumab to that of bisphosphonate therapies.³⁵

Nonmetastatic CRPC

Reasonable interest among treating clinicians exists to be able to delay or prevent the development of metastatic bone disease in patients who are showing biochemical signs of castration resistance but have not yet developed distant metastatic disease. Time to progression on ADT to castration resistance usually occurs 2 to 3 years following initiation of treatment. This typically occurs in patients with rising prostate-specific antigen (PSA). As per the Prostate Cancer Working Group 3, in the absence of radiologic progression, CRPC is defined by a 25% increase from the nadir (considering a starting value of ≥ 1 ng/mL), with a minimum rise of 2 ng/mL in the setting of castrate serum testosterone < 50 ng/dL despite good adherence to an ADT regimen, with proven serologic castration either by undetectable or a near undetectable nadir of serum testosterone concentration. Therapeutic implications include prevention of SREs as well as time to metastatic bone lesions. The Zometa 704 trial examined the use of ZA to reduce time to first metastatic bone lesion in the setting of patients with nonmetastatic CRPC.³⁶ The trial was discontinued prematurely due to low patient accrual, but initial analysis provided information on the natural history of a rising PSA in this patient population. At 2 years, one-third of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastasis and OS were not reached. Baseline PSA and PSA velocity independently predicted a shorter time to first bone metastasis, metastasis-free survival, and OS.³⁶

Denosumab was also studied in the setting of nonmetastatic CRPC in the Denosumab 147 trial. The study enrolled 1432 patients and found a significantly increased bone metastasis-free survival by a median of 4.2 months over placebo (HR, 0.85; 95% CI, 0.73-0.98; P = .03). Denosumab significantly delayed time to first bone metastasis (HR, 0.84; 95% CI, 0.71-0.98; P = .03). OS was similar between groups (HR, 1.01; 95% CI, 0.85-1.20; P = .91). Rates of AEs and serious AEs were similar between groups, except for ONJ and hypocalcemia. The rates of ONJ for denosumab were 1%, 3%, 4% in years 1,2, 3, respectively; overall, < 5% (n = 33). Hypocalcemia occurred in < 2% (n = 12) in denosumab-treated patients. The authors concluded that in men with CRPC, denosumab significantly prolonged bone metastasis–free survival and delayed time-to-bone metastasis.³⁷ These 2 studies suggest a role of receptor-activated nuclear factor κ-B ligand inhibitor denosumab in patients with nonmetastatic CRPC in the appropriate setting. There were delays in bony metastatic disease, but no difference in OS. Rare denosumab treatment–related specific AEs were noted. Hence, denosumab is not recommended for use in this setting.

Metastatic CRPC

Castration resistance typically occurs 2 to 3 years following initiation of ADT and the most common extranodal site of disease is within the bone in metastatic PC. Disease progression within bones after ADT can be challenging given both the nature of progressive cancer with osteoblastic metastatic lesions and the prolonged effects of ADT on unaffected bone. The Zometa 039 study compared ZA with placebo and found a significant difference in SREs (38% and 49%, respectively; P .03). No survival benefit was observed with the addition of ZA. Use of other bisphosphonates pamidronate and clodronate did not have a similar degree of benefit.^38,39

A phase 3 study of 1904 patients found that denosumab was superior to ZA in delaying the time to first on-study SRE (HR, 0.82; 95% CI, 0.71-0.95) and reducing rates of multiple SREs (HR, 0.82; 95% CI, 0.71-0.94).⁴⁰ This was later confirmed with an additional study that demonstrated treatment with denosumab significantly reduced the risk of developing a first symptomatic SRE, defined as a pathologic fracture, spinal cord compression, necessity for radiation, or surgery (HR, 0.78; 95% CI, 0.66-0.93; P = .005) and first and subsequent symptomatic SREs (rate ratio, 0.78; 95% CI, 0.65-0.92; P = .004) compared with ZA.²⁸ These findings suggest a continued role of denosumab in the treatment of advanced metastatic CRPC from both control of bone disease as well as quality of life and palliation of cancer-related symptoms.

Radium-223 dichloride (radium-223) is an α-emitting radionuclide for treatment of metastatic CRPC with bone metastasis, but otherwise no additional metastatic sites. Radium-223 is a calcium-mimetic that preferentially accumulates into areas of high-bone turnover, such as where bone metastases tend to occur. Radium-223 induces apoptosis of tumor cells through double-stranded DNA breaks. Studies have shown radium-223 to prolong OS and time-to-first symptomatic SRE.⁴¹ The ERA-223 trial showed that when radium-223 was combined with abiraterone acetate, there was an increase in fragility fracture risk compared with placebo combined with abiraterone. Data from the study revealed that the median symptomatic SRE-free survival was 22.3 months (95% CI, 20.4-24.8) in the radium-223 group and 26.0 months (21.8-28.3) in the placebo group. Concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 was associated with increased fracture risk. Osteoporotic fractures were the most common type of fracture in the radium-223 group and of all fracture types, differed the most between the study groups.⁴²

Conclusions

Convincing evidence supports the ongoing use of bisphosphonates and denosumab in patients with osteoporosis, significant osteopenia with risk factors, and in patients with CRPC with bone metastasis. Bone metastases can cause considerable morbidity and mortality among men with advanced PC. Pain, fracture, and neurologic injury can occur with metastatic bone lesions as well as with ADT-related bone loss. Prevention of SREs in patients with PC is a reasonable goal in PC survivors while being mindful of managing the risks of these therapies.

Prostate cancer (PC) is the most commonly and newly diagnosed nonskin cancer and the second leading cause of cancer death in men in the United States. About 191,930 cases and about 33,330 deaths from PC were expected for the year 2020.¹ About 1 in 41 men will die of PC. Most men diagnosed with PC are aged > 65 years and do not die of their disease. The 5-year survival rate of localized and regional disease is nearly 100%, and disease with distant metastases is 31%. As a result, more than 3.1 million men in the United States who have been diagnosed with PC are still alive today.¹ Among veterans, there is a substantial population living with PC. Skolarus and Hawley reported in 2014 that an estimated 200,000 veterans with PC were survivors and 12,000 were newly diagnosed.²

In PC, skeletal strength can be affected by several factors, such as aging, malnutrition, androgen-deprivation therapy (ADT), and bone metastasis.^3,4 In fact, most men can live the rest of their life with PC by using strategies to monitor and treat it, once it shows either radiographic or chemical signs of progression.⁵ ADT is the standard of care to treat hormone-sensitive PC, which is associated with significant skeletal-related adverse effects (AEs).^6,7

Men undergoing ADT are 4 times more likely to develop substantial bone deficiency, Shahinian and colleagues found that in men surviving 5 years after PC diagnosis, 19.4% of those who received ADT had a fracture compared with 12% in men who did not (P < .001). The authors established a significant relation between the number of doses of gonadotropin-releasing hormone given in the first 12 months and the risk of fracture.⁸ Of those who progressed to metastatic disease, the first metastatic nonnodal site is most commonly to the bone.⁹ Advanced PC is characterized by increased bone turnover, which further raises concerns for bone health and patient performance.¹⁰

Skeletal-related events (SREs) include pathologic fracture, spinal cord compression, palliative radiation, or surgery to bone, and change in antineoplastic therapy secondary to bone pain. The concept of bone health refers to the prevention, diagnosis, and treatment of idiopathic, pathogenic, and treatment-related bone loss and delay or prevention of SREs.^6,11 Guidelines and expert groups have recommended screening for osteoporosis at the start of ADT with bone mineral density testing, ensuring adequate calcium and vitamin D intake, modifying lifestyle behaviors (smoking cessation, alcohol moderation, and regular exercise), and prescribing bisphosphonates or receptor-activated nuclear factor κ-B ligand inhibitor, denosumab, for men with osteoporosis or who are at general high-fracture risk.^12,13 The overuse of these medications results in undue cost to patients as well as AEs, such as osteonecrosis of the jaw (ONJ), hypocalcemia, and bone/joint pains.^14-17 There are evidence-based guidelines for appropriate use of bisphosphonates and denosumab for delay and prevention of SREs in the setting of advanced PC.¹⁸ These doses also typically differ in frequency to those of osteoporosis.¹⁹ We summarize the evidence and guidance for health care providers who care for patients with PC at various stages and complications from both disease-related and treatment-related comorbidities.

Bone-Strengthening Agents

Overall, there is evidence to support the use of bone-strengthening agents in patients with osteopenia/osteoporosis in the prevention of SREs with significant risk factors for progressive bone demineralization, such as lifestyle factors and, in particular, treatments such as ADT. Bone-remodeling agents for treatment of bony metastasis have been shown to provide therapeutic advantage only in limited instances in the castration-resistant PC (CRPC) setting. Hence, in patients with hormone-sensitive PC due to medication-related AEs, treatment with bone-strengthening agents is indicated only if the patient has a significant preexisting risk for fracture from osteopenia/osteoporosis (Table). The Figure depicts an algorithm for the management of bone health in men with PC who are being treated with ADT.

Denosumab and bisphosphonates have an established role in preventing SREs in metastatic CRPC.²⁰ The choice of denosumab or a bisphosphonate typically varies based on the indication, possible AEs, and cost of therapy. There are multiple studies involving initiation of these agents at various stages of disease to improve both time to progression as well as management of SREs. There is a lack of evidence that bisphosphonates prevent metastatic-bone lesions in castration-sensitive PC; therefore, prophylactic use of this agent is not recommended in patients unless they have significant bone demineralization.^21,22

Bone Health in Patients

Nonmetastatic Hormone-Sensitive PC

ADT forms the backbone of treatment for patients with local and advanced metastatic castration-sensitive PC along with surgical and focal radiotherapy options. Cancer treatment-induced bone loss is known to occur with prolonged use of ADT. The ZEUS trial found no prevention of bone metastasis in patients with high-risk localized PC with the use of ZA in the absence of bone metastasis. A Kaplan-Meier estimated proportion of bone metastases after a median follow-up of 4.8 years was found to be not statistically significant: 14.7% in the ZA group vs 13.2% in the control/placebo group.²⁹ The STAMPEDE trial showed no significant overall survival (OS) benefit with the addition of ZA to ADT vs ADT alone (HR, 0.94; 95% CI, 0.79-1.11; P = .45), 5-year survival with ADT alone was 55% compared to ADT plus ZA with 57% 5-year survival.³⁰ The RADAR trial showed that at 5 years in high Gleason score patients, use of ZA in the absence of bone metastasis was beneficial, but not in low- or intermediate-risk patients. However, at 10-year analysis there was no significant difference in any of the high-stratified groups with or without ZA.³¹

The PR04 trial showed no effect on OS with clodronate compared with placebo in nonmetastatic castration-sensitive PC, with a HR of 1.12 (95% CI, 0.89-1.42; P = .94). The estimated 5-year survival was 80% with placebo and 78% with clodronate; 10-year survival rates were 51% with placebo and 48% with clodronate.³² Data from the HALT trial showed an increased bone mineral density and reduced risk of new vertebral fractures vs placebo (1.5% vs 3.9%, respectively) in the absence of metastatic bone lesions and a reduction in new vertebral fractures in patients with nonmetastatic PC.³³ Most of these studies showed no benefit with the addition of ZA to nonmetastatic PC; although, the HALT trial provides evidence to support use of denosumab in patients with nonmetastatic PC for preventing vertebral fragility fractures in men receiving ADT.

Metastatic Hormone-Sensitive PC

ZA is often used to treat men with metastatic castration-sensitive PC despite limited efficacy and safety data. The CALGB 90202 (Alliance) trial authors found that the early use of ZA was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the ZA group (95% CI, 24.2-40.3) and 29.8 months in the placebo group (stratified HR, 0.97; 95% CI, 0-1.17; 1-sided stratified log-rank P = .39).³⁴ OS was similar between the groups (HR, 0.88; 95% CI, 0.70-1.12; P = .29) as were reported AEs.³⁴ Results from these studies suggest limited benefit in treating patients with metastatic hormone-sensitive PC with bisphosphonates without other medical indications for use. Additional studies suggest similar results for treatment with denosumab to that of bisphosphonate therapies.³⁵

Nonmetastatic CRPC

Reasonable interest among treating clinicians exists to be able to delay or prevent the development of metastatic bone disease in patients who are showing biochemical signs of castration resistance but have not yet developed distant metastatic disease. Time to progression on ADT to castration resistance usually occurs 2 to 3 years following initiation of treatment. This typically occurs in patients with rising prostate-specific antigen (PSA). As per the Prostate Cancer Working Group 3, in the absence of radiologic progression, CRPC is defined by a 25% increase from the nadir (considering a starting value of ≥ 1 ng/mL), with a minimum rise of 2 ng/mL in the setting of castrate serum testosterone < 50 ng/dL despite good adherence to an ADT regimen, with proven serologic castration either by undetectable or a near undetectable nadir of serum testosterone concentration. Therapeutic implications include prevention of SREs as well as time to metastatic bone lesions. The Zometa 704 trial examined the use of ZA to reduce time to first metastatic bone lesion in the setting of patients with nonmetastatic CRPC.³⁶ The trial was discontinued prematurely due to low patient accrual, but initial analysis provided information on the natural history of a rising PSA in this patient population. At 2 years, one-third of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastasis and OS were not reached. Baseline PSA and PSA velocity independently predicted a shorter time to first bone metastasis, metastasis-free survival, and OS.³⁶

Denosumab was also studied in the setting of nonmetastatic CRPC in the Denosumab 147 trial. The study enrolled 1432 patients and found a significantly increased bone metastasis-free survival by a median of 4.2 months over placebo (HR, 0.85; 95% CI, 0.73-0.98; P = .03). Denosumab significantly delayed time to first bone metastasis (HR, 0.84; 95% CI, 0.71-0.98; P = .03). OS was similar between groups (HR, 1.01; 95% CI, 0.85-1.20; P = .91). Rates of AEs and serious AEs were similar between groups, except for ONJ and hypocalcemia. The rates of ONJ for denosumab were 1%, 3%, 4% in years 1,2, 3, respectively; overall, < 5% (n = 33). Hypocalcemia occurred in < 2% (n = 12) in denosumab-treated patients. The authors concluded that in men with CRPC, denosumab significantly prolonged bone metastasis–free survival and delayed time-to-bone metastasis.³⁷ These 2 studies suggest a role of receptor-activated nuclear factor κ-B ligand inhibitor denosumab in patients with nonmetastatic CRPC in the appropriate setting. There were delays in bony metastatic disease, but no difference in OS. Rare denosumab treatment–related specific AEs were noted. Hence, denosumab is not recommended for use in this setting.

Metastatic CRPC

Castration resistance typically occurs 2 to 3 years following initiation of ADT and the most common extranodal site of disease is within the bone in metastatic PC. Disease progression within bones after ADT can be challenging given both the nature of progressive cancer with osteoblastic metastatic lesions and the prolonged effects of ADT on unaffected bone. The Zometa 039 study compared ZA with placebo and found a significant difference in SREs (38% and 49%, respectively; P .03). No survival benefit was observed with the addition of ZA. Use of other bisphosphonates pamidronate and clodronate did not have a similar degree of benefit.^38,39

A phase 3 study of 1904 patients found that denosumab was superior to ZA in delaying the time to first on-study SRE (HR, 0.82; 95% CI, 0.71-0.95) and reducing rates of multiple SREs (HR, 0.82; 95% CI, 0.71-0.94).⁴⁰ This was later confirmed with an additional study that demonstrated treatment with denosumab significantly reduced the risk of developing a first symptomatic SRE, defined as a pathologic fracture, spinal cord compression, necessity for radiation, or surgery (HR, 0.78; 95% CI, 0.66-0.93; P = .005) and first and subsequent symptomatic SREs (rate ratio, 0.78; 95% CI, 0.65-0.92; P = .004) compared with ZA.²⁸ These findings suggest a continued role of denosumab in the treatment of advanced metastatic CRPC from both control of bone disease as well as quality of life and palliation of cancer-related symptoms.

Radium-223 dichloride (radium-223) is an α-emitting radionuclide for treatment of metastatic CRPC with bone metastasis, but otherwise no additional metastatic sites. Radium-223 is a calcium-mimetic that preferentially accumulates into areas of high-bone turnover, such as where bone metastases tend to occur. Radium-223 induces apoptosis of tumor cells through double-stranded DNA breaks. Studies have shown radium-223 to prolong OS and time-to-first symptomatic SRE.⁴¹ The ERA-223 trial showed that when radium-223 was combined with abiraterone acetate, there was an increase in fragility fracture risk compared with placebo combined with abiraterone. Data from the study revealed that the median symptomatic SRE-free survival was 22.3 months (95% CI, 20.4-24.8) in the radium-223 group and 26.0 months (21.8-28.3) in the placebo group. Concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 was associated with increased fracture risk. Osteoporotic fractures were the most common type of fracture in the radium-223 group and of all fracture types, differed the most between the study groups.⁴²

Conclusions

Convincing evidence supports the ongoing use of bisphosphonates and denosumab in patients with osteoporosis, significant osteopenia with risk factors, and in patients with CRPC with bone metastasis. Bone metastases can cause considerable morbidity and mortality among men with advanced PC. Pain, fracture, and neurologic injury can occur with metastatic bone lesions as well as with ADT-related bone loss. Prevention of SREs in patients with PC is a reasonable goal in PC survivors while being mindful of managing the risks of these therapies.

Prostate cancer (PC) is the most commonly and newly diagnosed nonskin cancer and the second leading cause of cancer death in men in the United States. About 191,930 cases and about 33,330 deaths from PC were expected for the year 2020.¹ About 1 in 41 men will die of PC. Most men diagnosed with PC are aged > 65 years and do not die of their disease. The 5-year survival rate of localized and regional disease is nearly 100%, and disease with distant metastases is 31%. As a result, more than 3.1 million men in the United States who have been diagnosed with PC are still alive today.¹ Among veterans, there is a substantial population living with PC. Skolarus and Hawley reported in 2014 that an estimated 200,000 veterans with PC were survivors and 12,000 were newly diagnosed.²

In PC, skeletal strength can be affected by several factors, such as aging, malnutrition, androgen-deprivation therapy (ADT), and bone metastasis.^3,4 In fact, most men can live the rest of their life with PC by using strategies to monitor and treat it, once it shows either radiographic or chemical signs of progression.⁵ ADT is the standard of care to treat hormone-sensitive PC, which is associated with significant skeletal-related adverse effects (AEs).^6,7

Men undergoing ADT are 4 times more likely to develop substantial bone deficiency, Shahinian and colleagues found that in men surviving 5 years after PC diagnosis, 19.4% of those who received ADT had a fracture compared with 12% in men who did not (P < .001). The authors established a significant relation between the number of doses of gonadotropin-releasing hormone given in the first 12 months and the risk of fracture.⁸ Of those who progressed to metastatic disease, the first metastatic nonnodal site is most commonly to the bone.⁹ Advanced PC is characterized by increased bone turnover, which further raises concerns for bone health and patient performance.¹⁰

Skeletal-related events (SREs) include pathologic fracture, spinal cord compression, palliative radiation, or surgery to bone, and change in antineoplastic therapy secondary to bone pain. The concept of bone health refers to the prevention, diagnosis, and treatment of idiopathic, pathogenic, and treatment-related bone loss and delay or prevention of SREs.^6,11 Guidelines and expert groups have recommended screening for osteoporosis at the start of ADT with bone mineral density testing, ensuring adequate calcium and vitamin D intake, modifying lifestyle behaviors (smoking cessation, alcohol moderation, and regular exercise), and prescribing bisphosphonates or receptor-activated nuclear factor κ-B ligand inhibitor, denosumab, for men with osteoporosis or who are at general high-fracture risk.^12,13 The overuse of these medications results in undue cost to patients as well as AEs, such as osteonecrosis of the jaw (ONJ), hypocalcemia, and bone/joint pains.^14-17 There are evidence-based guidelines for appropriate use of bisphosphonates and denosumab for delay and prevention of SREs in the setting of advanced PC.¹⁸ These doses also typically differ in frequency to those of osteoporosis.¹⁹ We summarize the evidence and guidance for health care providers who care for patients with PC at various stages and complications from both disease-related and treatment-related comorbidities.

Bone-Strengthening Agents

Overall, there is evidence to support the use of bone-strengthening agents in patients with osteopenia/osteoporosis in the prevention of SREs with significant risk factors for progressive bone demineralization, such as lifestyle factors and, in particular, treatments such as ADT. Bone-remodeling agents for treatment of bony metastasis have been shown to provide therapeutic advantage only in limited instances in the castration-resistant PC (CRPC) setting. Hence, in patients with hormone-sensitive PC due to medication-related AEs, treatment with bone-strengthening agents is indicated only if the patient has a significant preexisting risk for fracture from osteopenia/osteoporosis (Table). The Figure depicts an algorithm for the management of bone health in men with PC who are being treated with ADT.

Denosumab and bisphosphonates have an established role in preventing SREs in metastatic CRPC.²⁰ The choice of denosumab or a bisphosphonate typically varies based on the indication, possible AEs, and cost of therapy. There are multiple studies involving initiation of these agents at various stages of disease to improve both time to progression as well as management of SREs. There is a lack of evidence that bisphosphonates prevent metastatic-bone lesions in castration-sensitive PC; therefore, prophylactic use of this agent is not recommended in patients unless they have significant bone demineralization.^21,22

Bone Health in Patients

Nonmetastatic Hormone-Sensitive PC

ADT forms the backbone of treatment for patients with local and advanced metastatic castration-sensitive PC along with surgical and focal radiotherapy options. Cancer treatment-induced bone loss is known to occur with prolonged use of ADT. The ZEUS trial found no prevention of bone metastasis in patients with high-risk localized PC with the use of ZA in the absence of bone metastasis. A Kaplan-Meier estimated proportion of bone metastases after a median follow-up of 4.8 years was found to be not statistically significant: 14.7% in the ZA group vs 13.2% in the control/placebo group.²⁹ The STAMPEDE trial showed no significant overall survival (OS) benefit with the addition of ZA to ADT vs ADT alone (HR, 0.94; 95% CI, 0.79-1.11; P = .45), 5-year survival with ADT alone was 55% compared to ADT plus ZA with 57% 5-year survival.³⁰ The RADAR trial showed that at 5 years in high Gleason score patients, use of ZA in the absence of bone metastasis was beneficial, but not in low- or intermediate-risk patients. However, at 10-year analysis there was no significant difference in any of the high-stratified groups with or without ZA.³¹

The PR04 trial showed no effect on OS with clodronate compared with placebo in nonmetastatic castration-sensitive PC, with a HR of 1.12 (95% CI, 0.89-1.42; P = .94). The estimated 5-year survival was 80% with placebo and 78% with clodronate; 10-year survival rates were 51% with placebo and 48% with clodronate.³² Data from the HALT trial showed an increased bone mineral density and reduced risk of new vertebral fractures vs placebo (1.5% vs 3.9%, respectively) in the absence of metastatic bone lesions and a reduction in new vertebral fractures in patients with nonmetastatic PC.³³ Most of these studies showed no benefit with the addition of ZA to nonmetastatic PC; although, the HALT trial provides evidence to support use of denosumab in patients with nonmetastatic PC for preventing vertebral fragility fractures in men receiving ADT.

Metastatic Hormone-Sensitive PC

ZA is often used to treat men with metastatic castration-sensitive PC despite limited efficacy and safety data. The CALGB 90202 (Alliance) trial authors found that the early use of ZA was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the ZA group (95% CI, 24.2-40.3) and 29.8 months in the placebo group (stratified HR, 0.97; 95% CI, 0-1.17; 1-sided stratified log-rank P = .39).³⁴ OS was similar between the groups (HR, 0.88; 95% CI, 0.70-1.12; P = .29) as were reported AEs.³⁴ Results from these studies suggest limited benefit in treating patients with metastatic hormone-sensitive PC with bisphosphonates without other medical indications for use. Additional studies suggest similar results for treatment with denosumab to that of bisphosphonate therapies.³⁵

Nonmetastatic CRPC

Reasonable interest among treating clinicians exists to be able to delay or prevent the development of metastatic bone disease in patients who are showing biochemical signs of castration resistance but have not yet developed distant metastatic disease. Time to progression on ADT to castration resistance usually occurs 2 to 3 years following initiation of treatment. This typically occurs in patients with rising prostate-specific antigen (PSA). As per the Prostate Cancer Working Group 3, in the absence of radiologic progression, CRPC is defined by a 25% increase from the nadir (considering a starting value of ≥ 1 ng/mL), with a minimum rise of 2 ng/mL in the setting of castrate serum testosterone < 50 ng/dL despite good adherence to an ADT regimen, with proven serologic castration either by undetectable or a near undetectable nadir of serum testosterone concentration. Therapeutic implications include prevention of SREs as well as time to metastatic bone lesions. The Zometa 704 trial examined the use of ZA to reduce time to first metastatic bone lesion in the setting of patients with nonmetastatic CRPC.³⁶ The trial was discontinued prematurely due to low patient accrual, but initial analysis provided information on the natural history of a rising PSA in this patient population. At 2 years, one-third of patients had developed bone metastases. Median bone metastasis-free survival was 30 months. Median time to first bone metastasis and OS were not reached. Baseline PSA and PSA velocity independently predicted a shorter time to first bone metastasis, metastasis-free survival, and OS.³⁶

Denosumab was also studied in the setting of nonmetastatic CRPC in the Denosumab 147 trial. The study enrolled 1432 patients and found a significantly increased bone metastasis-free survival by a median of 4.2 months over placebo (HR, 0.85; 95% CI, 0.73-0.98; P = .03). Denosumab significantly delayed time to first bone metastasis (HR, 0.84; 95% CI, 0.71-0.98; P = .03). OS was similar between groups (HR, 1.01; 95% CI, 0.85-1.20; P = .91). Rates of AEs and serious AEs were similar between groups, except for ONJ and hypocalcemia. The rates of ONJ for denosumab were 1%, 3%, 4% in years 1,2, 3, respectively; overall, < 5% (n = 33). Hypocalcemia occurred in < 2% (n = 12) in denosumab-treated patients. The authors concluded that in men with CRPC, denosumab significantly prolonged bone metastasis–free survival and delayed time-to-bone metastasis.³⁷ These 2 studies suggest a role of receptor-activated nuclear factor κ-B ligand inhibitor denosumab in patients with nonmetastatic CRPC in the appropriate setting. There were delays in bony metastatic disease, but no difference in OS. Rare denosumab treatment–related specific AEs were noted. Hence, denosumab is not recommended for use in this setting.

Metastatic CRPC

Castration resistance typically occurs 2 to 3 years following initiation of ADT and the most common extranodal site of disease is within the bone in metastatic PC. Disease progression within bones after ADT can be challenging given both the nature of progressive cancer with osteoblastic metastatic lesions and the prolonged effects of ADT on unaffected bone. The Zometa 039 study compared ZA with placebo and found a significant difference in SREs (38% and 49%, respectively; P .03). No survival benefit was observed with the addition of ZA. Use of other bisphosphonates pamidronate and clodronate did not have a similar degree of benefit.^38,39

A phase 3 study of 1904 patients found that denosumab was superior to ZA in delaying the time to first on-study SRE (HR, 0.82; 95% CI, 0.71-0.95) and reducing rates of multiple SREs (HR, 0.82; 95% CI, 0.71-0.94).⁴⁰ This was later confirmed with an additional study that demonstrated treatment with denosumab significantly reduced the risk of developing a first symptomatic SRE, defined as a pathologic fracture, spinal cord compression, necessity for radiation, or surgery (HR, 0.78; 95% CI, 0.66-0.93; P = .005) and first and subsequent symptomatic SREs (rate ratio, 0.78; 95% CI, 0.65-0.92; P = .004) compared with ZA.²⁸ These findings suggest a continued role of denosumab in the treatment of advanced metastatic CRPC from both control of bone disease as well as quality of life and palliation of cancer-related symptoms.

Radium-223 dichloride (radium-223) is an α-emitting radionuclide for treatment of metastatic CRPC with bone metastasis, but otherwise no additional metastatic sites. Radium-223 is a calcium-mimetic that preferentially accumulates into areas of high-bone turnover, such as where bone metastases tend to occur. Radium-223 induces apoptosis of tumor cells through double-stranded DNA breaks. Studies have shown radium-223 to prolong OS and time-to-first symptomatic SRE.⁴¹ The ERA-223 trial showed that when radium-223 was combined with abiraterone acetate, there was an increase in fragility fracture risk compared with placebo combined with abiraterone. Data from the study revealed that the median symptomatic SRE-free survival was 22.3 months (95% CI, 20.4-24.8) in the radium-223 group and 26.0 months (21.8-28.3) in the placebo group. Concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 was associated with increased fracture risk. Osteoporotic fractures were the most common type of fracture in the radium-223 group and of all fracture types, differed the most between the study groups.⁴²

Conclusions

Convincing evidence supports the ongoing use of bisphosphonates and denosumab in patients with osteoporosis, significant osteopenia with risk factors, and in patients with CRPC with bone metastasis. Bone metastases can cause considerable morbidity and mortality among men with advanced PC. Pain, fracture, and neurologic injury can occur with metastatic bone lesions as well as with ADT-related bone loss. Prevention of SREs in patients with PC is a reasonable goal in PC survivors while being mindful of managing the risks of these therapies.