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.

Substance use disorders (SUDs) are an important but understudied aspect of treating patients diagnosed with cancer. Substance use can affect cancer treatment outcomes, including morbidity and mortality.^1,2 Additionally, patients with cancer and SUD may have unique psychosocial needs that require close attention and management. There is a paucity of data regarding the best approach to treating such patients. For example, cocaine use may increase the cardiovascular and hematologic risk of some traditional chemotherapy agents.^3,4 Newer targeted agents and immunotherapies remain understudied with respect to SUD risk.

Although the US Department of Veterans Affairs (VA) has established helpful clinical practice guidelines for the treatment of SUD, there are no guidelines for treating patients with SUD and cancer.⁵ Clinicians have limited confidence in treatment approach, and treatment is inconsistent among oncologists nationwide even within the same practice. Furthermore, it can be challenging to safely prescribe opioids for cancer-related pain in individuals with SUD. There is a high risk of SUD and mental health disorders in veterans, making this population particularly vulnerable. We report a case of a male with metastatic pancreatic cancer, severe opioid use disorder (OUD) and moderate cocaine use disorder (CUD) who received pain management and cancer treatment under the direction of a multidisciplinary team approach.

Case Report

A 63-year-old male with a medical history of HIV treated with highly active antiretroviral therapy (HAART), compensated cirrhosis, severe OUD, moderate CUD, and sedative use disorder in sustained remission was admitted to the West Haven campus of the VA Connecticut Healthcare System (VACHS) with abdominal pain, weight loss and fatigue. He used heroin 1 month prior to his admission and reported regular cocaine and marijuana use (Table 1). He was diagnosed with HIV in 1989, and his medical history included herpes zoster and oral candidiasis but no other opportunistic infections. Several months prior to this admission, he had an undetectable viral load and CD4 count of 688.

At the time of this admission, the patient was adherent to methadone treatment. He reported increased abdominal pain. Computed tomography (CT) showed a 2.4-cm mass in the pancreatic uncinate process, multiple liver metastases, retroperitoneal lymphadenopathy, and small lung nodules. A CT-guided liver biopsy showed adenocarcinoma consistent with a primary cancer of the pancreas. Given the complexity of the case, a multidisciplinary team approach was used to treat his cancer and the sequelae safely, including the oncology team, community living center team, palliative care team, and interprofessional opioid reassessment clinic team (ORC).

Cancer Treatment

Chemotherapy with FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) was recommended. The first cycle of treatment originally was planned for the outpatient setting, and a peripherally inserted central catheter (PICC) line was placed. However, after a urine toxicology test was positive for cocaine, the PICC line was removed due to concern for possible use of PICC line for nonprescribed substance use. The patient expressed suicidal ideation at the time and was admitted for psychiatric consult and pain control. Cycle 1 FOLFIRINOX was started during this admission. A PICC line was again put in place and then removed before discharge. A celiac plexus block was performed several days after this admission for pain control.

Given concern about cocaine use increasing the risk of cardiac toxicity with FOLFIRINOX treatment, treating providers sconsulted with the community living center (CLC) about possible admission for future chemotherapy administration and pain management. The CLC at VACHS has 38 beds for rehabilitation, long-term care, and hospice with the mission to restore each veteran to his or her highest level of well-being. After discussion with this patient and CLC staff, he agreed to a CLC admission. The patient agreed to remain in the facility, wear a secure care device, and not leave without staff accompaniment. He was able to obtain a 2-hour pass to pay bills and rent. During the 2 months he was admitted to the CLC he would present to the VACHS Cancer Center for chemotherapy every 2 weeks. He completed 6 cycles of chemotherapy while admitted. During the admission, he was transferred to active medical service for 2 days for fever and malaise, and then returned to the CLC. The patient elected to leave the CLC after 2 months as the inability to see close friends was interfering with his quality of life.

Upon being discharged from the CLC, shared decision making took place with the patient to establish a new treatment plan. In collaboration with the patient, a plan was made to admit him every 2 weeks for continued chemotherapy. A PICC line was placed on each day of admission and removed prior to discharge. It was also agreed that treatment would be delayed if a urine drug test was positive for cocaine on the morning of admission. The patient was also seen by ORC every 2 weeks after being discharged from the CLC.

Imaging after cycle 6 showed decreased size of liver metastases, retroperitoneal lymph nodes, and pancreas mass. Cancer antigen 19-9 (CA19-9) tumor marker was reduced from 3513 U/mL pretreatment to 50 U/mL after cycle 7. Chemotherapy cycle 7 was delayed 6 days due to active cocaine and heroin use. A repeat urine was obtained several days later, which was negative for cocaine, and he was admitted for cycle 7 chemotherapy. Using this treatment approach of admissions for every cycle, the patient was able to receive 11 cycles of FOLFIRINOX with clinical benefit.

Palliative Care/Pain Management

Safely treating the patient’s malignant pain in the context of his OUD was critically important. In order to do this the palliative care team worked closely alongside ORC, is a multidisciplinary team consisting of health care providers (HCPs) from addiction psychiatry, internal medicine, health psychology and pharmacy who are consulted to evaluate veterans’ current opioid regimens and make recommendations to optimize both safety and efficacy. ORC followed this particular veteran as an outpatient and consulted on pain issues during his admission. They recommended the continuation of methadone at 120 mg daily and increased oral oxycodone to 30 mg every 6 hours, and then further increased to 45 mg every 6 hours. He continued to have increased pain despite higher doses of oxycodone, and pain medication was changed to oral hydromorphone 28 mg every 6 hours with the continuation of methadone. ORC and the palliative care team obtained consent from the veteran and a release of Information form signed by the patient to contact his community methadone clinic for further collaboration around pain management throughout the time caring for the veteran.

Even with improvement in disease based on imaging and tumor markers, opioid medications could not be decreased in this case. This is likely in part due to the multidimensional nature of pain. Careful assessment of the biologic, emotional, social, and spiritual contributors to pain is needed in the management of pain, especially at end of life.⁶ Nonpharmacologic pain management strategies used in this case included a transcutaneous electrical nerve stimulation unit, moist heat, celiac plexus block, and emotional support.

Psychosocial Issues/Substance Use

Psychosocial support for the patient was provided by the interdisciplinary palliative care team and the ORC team in both the inpatient and outpatient settings. Despite efforts from case management to get the veteran home services once discharged from the CLC, he declined repeatedly. Thus, the CLC social worker obtained a guardian alert for the veteran on discharge.

Close outpatient follow-up for medical and psychosocial support was very critical. When an outpatient, the veteran was scheduled for biweekly appointments with palliative care or ORC. When admitted to the hospital, the palliative care team medical director and psychologist conducted joint visits with him. Although he denied depressed mood and anxiety throughout his treatment, he often reflected on regrets that he had as he faced the end of his life. Specifically, he shared thoughts about being estranged from his surviving brother given his long struggle with substance use. Although he did not think a relationship was possible with his brother at the end of life, he still cared deeply for him and wanted to make him aware of his pancreatic cancer diagnosis. This was particularly important to him because their late brother had also died of pancreatic cancer. It was the patient’s wish at the end of his life to alert his surviving brother of his diagnosis so he and his children could get adequate screening throughout their lives. Although he had spoken of this desire often, it wasn’t until his disease progressed and he elected to transition to hospice that he felt ready to write the letter. The palliative care team assisted the veteran in writing and mailing a letter to his brother informing him of his diagnosis and transition to hospice as well as communicating that his brother and his family had been in his thoughts at the end of his life. The patient’s brother received this letter and with assistance from the CLC social worker made arrangements to visit the veteran at bedside at the inpatient CLC hospice unit the final days of his life.

Discussion

There are very little data on the safety of cancer-directed therapy in patients with active SUD. The limited studies that have been done showed conflicting results.

A retrospective study among women with co-occurring SUD and locally advanced cervical cancer who were undergoing primary radiation therapy found that SUD was not associated with a difference in toxicity or survival outcomes.⁷ However, other research suggests that SUD may be associated with an increase in all-cause mortality as well as other adverse outcomes for patients and health care systems (eg, emergency department visits, hospitalizations).⁸ A retrospective study of patients with a history of SUD and nonsmall cell lung cancer showed that these patients had higher rates of depression, less family support, increased rates of missed appointments, more emergency department visits and more hospitalizations.⁹ Patients with chronic myeloid leukemia or myelodysplastic syndromes who had long-term cocaine use had a 6-fold increased risk of death, which was not found in patients who had long-term alcohol or marijuana use.²

The limited data highlight the need for careful consideration of ways to mitigate potentially adverse outcomes in this population while still providing clinically indicated cancer treatment. Integrated VA health care systems provide unique resources that can maximize veteran safety during cancer treatment. Utilization of VA resources and close interdisciplinary collaboration across VA HCPs can help to ensure equitable access to state-of-the-art cancer therapies for veterans with comorbid SUD.

VA Services for Patients With Comorbidities

This case highlights several distinct aspects of VA health care that make it possible to safely treat individuals with complex comorbidities. One important aspect of this was collaboration with the CLC to admit the veteran for his initial treatment after a positive cocaine test. CLC admission was nonpunitive and allowed ongoing involvement in the VA community. This provided an essential, safe, and structured environment in which 6 cycles of chemotherapy could be delivered.

Although the patient left the CLC after 2 months due to floor restrictions negatively impacting his quality of life and ability to spend time with close friends, several important events occurred during this stay. First, the patient established close relationships with the CLC staff and the palliative care team; both groups followed him throughout his inpatient and outpatient care. These relationships proved essential throughout his care as they were the foundation of difficult conversations about substance use, treatment adherence, and eventually, transition to hospice.

In addition, the opportunity to administer 6 cycles of chemotherapy at the CLC was enough to lead to clinical benefit and radiographic response to treatment. Clinical benefits while in the CLC included maintenance of a good appetite, 15-lb weight gain and preserved performance status (ECOG [Eastern Cooperative Group]-1), which allowed him to actively participate in multiple social and recreational activities while in the CLC. From early conversations, this patient was clear that he wanted treatment as long as his life could be prolonged with good quality of life. Having evidence of the benefit of treatment, at least initially, increased the patient’s confidence in treatment. There were a few conversations when the challenges of treatment mounted (eg, pain, needs for abstinence from cocaine prior to admission for chemotherapy, frequent doctor appointments), and the patient would remind himself of these data to recommit himself to treatment. The opportunity to admit him to the inpatient VA facility, including bed availability for 3 days during his treatment once he left the CLC was important. This plan to admit the patient following a negative urine toxicology test for cocaine was made collaboratively with the veteran and the oncology and palliative care teams. The plan allowed the patient to achieve his treatment goals while maintaining his safety and reducing theoretical cardiac toxicities with his cancer treatment.

Finally, the availability of a multidisciplinary team approach including palliative care, oncology, psychology, addiction medicine and addiction psychiatry, was critical for addressing the veteran’s malignant pain. Palliative care worked in close collaboration with the ORC to prescribe and renew pain medications. ORC offered ongoing consultation on pain management in the context of OUD. As the veteran’s cancer progressed and functional decline prohibited his daily attendance at the community methadone clinic, palliative care and ORC met with the methadone clinic to arrange a less frequent methadone pickup schedule (the patient previously needed daily pickup). Non-VA settings may not have access to these resources to safely treat the biopsychosocial issues that arise in complex cases.

Substance Use and Cancer Treatments

This case raises several critical questions for oncologic care. Cocaine and fluorouracil are both associated with cardiotoxicity, and many oncologists would not feel it is safe to administer a regimen containing fluorouracil to a patient with active cocaine use. The National Comprehensive Cancer Network (NCCN) panel recommends FOLFIRINOX as a preferred category 1 recommendation for first-line treatment of patients with advanced pancreas cancer with good performance status.¹⁰ This recommendation is based on the PRODIGE trial, which has shown improved overall survival (OS): 11.1 vs 6.8 months for patients who received single-agent gemcitabine.¹¹ If patients are not candidates for FOLFIRINOX and have good performance status, the NCCN recommends gemcitabine plus albumin-bound paclitaxel with category 1 level of evidence based on the IMPACT trial, which showed improvement in OS (8.7 vs 6.6 months compared with single-agent gemcitabine).¹²

Some oncologists may have additional concerns administering fluorouracil treatment alternatives (such as gemcitabine and albumin-bound paclitaxel) to individuals with active SUD because of concerns about altered mental status impacting the ability to report important adverse effects. In the absence of sufficient data, HCPs must determine whether they feel it is safe to administer these agents in individuals with active cocaine use. However, denying these patients the possible benefits of standard-of-care life-prolonging therapies without established data raises concerns regarding the ethics of such practices. There is concern that the stigma surrounding cocaine use might contribute to withholding treatment, while treatment is continued for individuals taking prescribed stimulant medications that also have cardiotoxicity risks. VA health care facilities are uniquely situated to use all available resources to address these issues using interprofessional patient-centered care and determine the most optimal treatment based on a risk/benefit discussion between the patient and the HCP.

SUD Screening

This case begs the question of whether oncologists are adequately screening for a range of SUDs, and when they encounter an issue, how they are addressing it. Many oncologists do not receive adequate training on assessment of current or recent substance use. There are health care and systems-level practices that may increase patient safety for individuals with ongoing substance use who are undergoing cancer treatment. Training on obtaining appropriate substance use histories, motivational interviewing to resolve ambivalence about substance use in the direction of change, and shared decision making about treatment options could increase confidence in understanding and addressing substance use issues. It is also important to educate oncologists on how to address patients who return to or continued substance use during treatment. In this case the collaboration from palliative care, psychology, addiction medicine, and addiction psychiatry through the ORC was essential in assisting with ongoing assessment of substance use, guiding difficult conversations about the impact of substance use on the treatment plan, and identifying risk-mitigation strategies. Close collaboration and full utilization of all VA resources allowed this patient to receive first-line treatment for pancreatic cancer in order to reach his goal of prolonging his life while maintaining acceptable quality of life. Table 2 provides best practices for management of patients with comorbid SUD and cancer.

More research is needed into cancer treatment for patients with SUD, especially in the current era of cancer care using novel cancer treatments leading to significantly improved survival in many cancer types. Ideally, oncologists should be routinely or consistently screening patients for substance use, including alcohol. The patient should participate in this decision-making process after being educated about the risks and benefits. These patients can be followed using a multimodal approach to increase their rates of success and improve their quality of life. Although the literature is limited and no formal guidelines are available, VA oncologists are fortunate to have a range of resources available to them to navigate these difficult cases. Veterans have elevated rates of SUD, making this a critical issue to consider in the VA.¹³ It is the hope that this case can highlight how to take advantage of the many VA resources in order to ensure equitable cancer care for all veterans.

Conclusions

This case demonstrates that cancer-directed treatment is safe and feasible in a patient with advanced pancreatic cancer and coexisting active SUD by using a multidisciplinary approach. The multidisciplinary team included palliative care, oncology, psychology, addiction medicine, and addiction psychiatry. Critical steps for a successful outcome include gathering history about SUD; motivational interviewing to resolve ambivalence about treatment for SUD; shared decision making about cancer treatment; and risk-reduction strategies in pain and SUD management.

Treatment advancements in many cancer types have led to significantly longer survival, and it is critical to develop safe protocols to treat patients with active SUD so they also can derive benefit from these very significant medical advancements.

Acknowledgments

Michal Rose, MD, Director of VACHS Cancer Center, and Chandrika Kumar, MD, Director of VACHS Community Living Center, for their collaboration in care for this veteran.

Substance use disorders (SUDs) are an important but understudied aspect of treating patients diagnosed with cancer. Substance use can affect cancer treatment outcomes, including morbidity and mortality.^1,2 Additionally, patients with cancer and SUD may have unique psychosocial needs that require close attention and management. There is a paucity of data regarding the best approach to treating such patients. For example, cocaine use may increase the cardiovascular and hematologic risk of some traditional chemotherapy agents.^3,4 Newer targeted agents and immunotherapies remain understudied with respect to SUD risk.

Although the US Department of Veterans Affairs (VA) has established helpful clinical practice guidelines for the treatment of SUD, there are no guidelines for treating patients with SUD and cancer.⁵ Clinicians have limited confidence in treatment approach, and treatment is inconsistent among oncologists nationwide even within the same practice. Furthermore, it can be challenging to safely prescribe opioids for cancer-related pain in individuals with SUD. There is a high risk of SUD and mental health disorders in veterans, making this population particularly vulnerable. We report a case of a male with metastatic pancreatic cancer, severe opioid use disorder (OUD) and moderate cocaine use disorder (CUD) who received pain management and cancer treatment under the direction of a multidisciplinary team approach.

Case Report

A 63-year-old male with a medical history of HIV treated with highly active antiretroviral therapy (HAART), compensated cirrhosis, severe OUD, moderate CUD, and sedative use disorder in sustained remission was admitted to the West Haven campus of the VA Connecticut Healthcare System (VACHS) with abdominal pain, weight loss and fatigue. He used heroin 1 month prior to his admission and reported regular cocaine and marijuana use (Table 1). He was diagnosed with HIV in 1989, and his medical history included herpes zoster and oral candidiasis but no other opportunistic infections. Several months prior to this admission, he had an undetectable viral load and CD4 count of 688.

At the time of this admission, the patient was adherent to methadone treatment. He reported increased abdominal pain. Computed tomography (CT) showed a 2.4-cm mass in the pancreatic uncinate process, multiple liver metastases, retroperitoneal lymphadenopathy, and small lung nodules. A CT-guided liver biopsy showed adenocarcinoma consistent with a primary cancer of the pancreas. Given the complexity of the case, a multidisciplinary team approach was used to treat his cancer and the sequelae safely, including the oncology team, community living center team, palliative care team, and interprofessional opioid reassessment clinic team (ORC).

Cancer Treatment

Chemotherapy with FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) was recommended. The first cycle of treatment originally was planned for the outpatient setting, and a peripherally inserted central catheter (PICC) line was placed. However, after a urine toxicology test was positive for cocaine, the PICC line was removed due to concern for possible use of PICC line for nonprescribed substance use. The patient expressed suicidal ideation at the time and was admitted for psychiatric consult and pain control. Cycle 1 FOLFIRINOX was started during this admission. A PICC line was again put in place and then removed before discharge. A celiac plexus block was performed several days after this admission for pain control.

Given concern about cocaine use increasing the risk of cardiac toxicity with FOLFIRINOX treatment, treating providers sconsulted with the community living center (CLC) about possible admission for future chemotherapy administration and pain management. The CLC at VACHS has 38 beds for rehabilitation, long-term care, and hospice with the mission to restore each veteran to his or her highest level of well-being. After discussion with this patient and CLC staff, he agreed to a CLC admission. The patient agreed to remain in the facility, wear a secure care device, and not leave without staff accompaniment. He was able to obtain a 2-hour pass to pay bills and rent. During the 2 months he was admitted to the CLC he would present to the VACHS Cancer Center for chemotherapy every 2 weeks. He completed 6 cycles of chemotherapy while admitted. During the admission, he was transferred to active medical service for 2 days for fever and malaise, and then returned to the CLC. The patient elected to leave the CLC after 2 months as the inability to see close friends was interfering with his quality of life.

Upon being discharged from the CLC, shared decision making took place with the patient to establish a new treatment plan. In collaboration with the patient, a plan was made to admit him every 2 weeks for continued chemotherapy. A PICC line was placed on each day of admission and removed prior to discharge. It was also agreed that treatment would be delayed if a urine drug test was positive for cocaine on the morning of admission. The patient was also seen by ORC every 2 weeks after being discharged from the CLC.

Imaging after cycle 6 showed decreased size of liver metastases, retroperitoneal lymph nodes, and pancreas mass. Cancer antigen 19-9 (CA19-9) tumor marker was reduced from 3513 U/mL pretreatment to 50 U/mL after cycle 7. Chemotherapy cycle 7 was delayed 6 days due to active cocaine and heroin use. A repeat urine was obtained several days later, which was negative for cocaine, and he was admitted for cycle 7 chemotherapy. Using this treatment approach of admissions for every cycle, the patient was able to receive 11 cycles of FOLFIRINOX with clinical benefit.

Palliative Care/Pain Management

Safely treating the patient’s malignant pain in the context of his OUD was critically important. In order to do this the palliative care team worked closely alongside ORC, is a multidisciplinary team consisting of health care providers (HCPs) from addiction psychiatry, internal medicine, health psychology and pharmacy who are consulted to evaluate veterans’ current opioid regimens and make recommendations to optimize both safety and efficacy. ORC followed this particular veteran as an outpatient and consulted on pain issues during his admission. They recommended the continuation of methadone at 120 mg daily and increased oral oxycodone to 30 mg every 6 hours, and then further increased to 45 mg every 6 hours. He continued to have increased pain despite higher doses of oxycodone, and pain medication was changed to oral hydromorphone 28 mg every 6 hours with the continuation of methadone. ORC and the palliative care team obtained consent from the veteran and a release of Information form signed by the patient to contact his community methadone clinic for further collaboration around pain management throughout the time caring for the veteran.

Even with improvement in disease based on imaging and tumor markers, opioid medications could not be decreased in this case. This is likely in part due to the multidimensional nature of pain. Careful assessment of the biologic, emotional, social, and spiritual contributors to pain is needed in the management of pain, especially at end of life.⁶ Nonpharmacologic pain management strategies used in this case included a transcutaneous electrical nerve stimulation unit, moist heat, celiac plexus block, and emotional support.

Psychosocial Issues/Substance Use

Psychosocial support for the patient was provided by the interdisciplinary palliative care team and the ORC team in both the inpatient and outpatient settings. Despite efforts from case management to get the veteran home services once discharged from the CLC, he declined repeatedly. Thus, the CLC social worker obtained a guardian alert for the veteran on discharge.

Close outpatient follow-up for medical and psychosocial support was very critical. When an outpatient, the veteran was scheduled for biweekly appointments with palliative care or ORC. When admitted to the hospital, the palliative care team medical director and psychologist conducted joint visits with him. Although he denied depressed mood and anxiety throughout his treatment, he often reflected on regrets that he had as he faced the end of his life. Specifically, he shared thoughts about being estranged from his surviving brother given his long struggle with substance use. Although he did not think a relationship was possible with his brother at the end of life, he still cared deeply for him and wanted to make him aware of his pancreatic cancer diagnosis. This was particularly important to him because their late brother had also died of pancreatic cancer. It was the patient’s wish at the end of his life to alert his surviving brother of his diagnosis so he and his children could get adequate screening throughout their lives. Although he had spoken of this desire often, it wasn’t until his disease progressed and he elected to transition to hospice that he felt ready to write the letter. The palliative care team assisted the veteran in writing and mailing a letter to his brother informing him of his diagnosis and transition to hospice as well as communicating that his brother and his family had been in his thoughts at the end of his life. The patient’s brother received this letter and with assistance from the CLC social worker made arrangements to visit the veteran at bedside at the inpatient CLC hospice unit the final days of his life.

Discussion

There are very little data on the safety of cancer-directed therapy in patients with active SUD. The limited studies that have been done showed conflicting results.

A retrospective study among women with co-occurring SUD and locally advanced cervical cancer who were undergoing primary radiation therapy found that SUD was not associated with a difference in toxicity or survival outcomes.⁷ However, other research suggests that SUD may be associated with an increase in all-cause mortality as well as other adverse outcomes for patients and health care systems (eg, emergency department visits, hospitalizations).⁸ A retrospective study of patients with a history of SUD and nonsmall cell lung cancer showed that these patients had higher rates of depression, less family support, increased rates of missed appointments, more emergency department visits and more hospitalizations.⁹ Patients with chronic myeloid leukemia or myelodysplastic syndromes who had long-term cocaine use had a 6-fold increased risk of death, which was not found in patients who had long-term alcohol or marijuana use.²

The limited data highlight the need for careful consideration of ways to mitigate potentially adverse outcomes in this population while still providing clinically indicated cancer treatment. Integrated VA health care systems provide unique resources that can maximize veteran safety during cancer treatment. Utilization of VA resources and close interdisciplinary collaboration across VA HCPs can help to ensure equitable access to state-of-the-art cancer therapies for veterans with comorbid SUD.

VA Services for Patients With Comorbidities

This case highlights several distinct aspects of VA health care that make it possible to safely treat individuals with complex comorbidities. One important aspect of this was collaboration with the CLC to admit the veteran for his initial treatment after a positive cocaine test. CLC admission was nonpunitive and allowed ongoing involvement in the VA community. This provided an essential, safe, and structured environment in which 6 cycles of chemotherapy could be delivered.

Although the patient left the CLC after 2 months due to floor restrictions negatively impacting his quality of life and ability to spend time with close friends, several important events occurred during this stay. First, the patient established close relationships with the CLC staff and the palliative care team; both groups followed him throughout his inpatient and outpatient care. These relationships proved essential throughout his care as they were the foundation of difficult conversations about substance use, treatment adherence, and eventually, transition to hospice.

In addition, the opportunity to administer 6 cycles of chemotherapy at the CLC was enough to lead to clinical benefit and radiographic response to treatment. Clinical benefits while in the CLC included maintenance of a good appetite, 15-lb weight gain and preserved performance status (ECOG [Eastern Cooperative Group]-1), which allowed him to actively participate in multiple social and recreational activities while in the CLC. From early conversations, this patient was clear that he wanted treatment as long as his life could be prolonged with good quality of life. Having evidence of the benefit of treatment, at least initially, increased the patient’s confidence in treatment. There were a few conversations when the challenges of treatment mounted (eg, pain, needs for abstinence from cocaine prior to admission for chemotherapy, frequent doctor appointments), and the patient would remind himself of these data to recommit himself to treatment. The opportunity to admit him to the inpatient VA facility, including bed availability for 3 days during his treatment once he left the CLC was important. This plan to admit the patient following a negative urine toxicology test for cocaine was made collaboratively with the veteran and the oncology and palliative care teams. The plan allowed the patient to achieve his treatment goals while maintaining his safety and reducing theoretical cardiac toxicities with his cancer treatment.

Finally, the availability of a multidisciplinary team approach including palliative care, oncology, psychology, addiction medicine and addiction psychiatry, was critical for addressing the veteran’s malignant pain. Palliative care worked in close collaboration with the ORC to prescribe and renew pain medications. ORC offered ongoing consultation on pain management in the context of OUD. As the veteran’s cancer progressed and functional decline prohibited his daily attendance at the community methadone clinic, palliative care and ORC met with the methadone clinic to arrange a less frequent methadone pickup schedule (the patient previously needed daily pickup). Non-VA settings may not have access to these resources to safely treat the biopsychosocial issues that arise in complex cases.

Substance Use and Cancer Treatments

This case raises several critical questions for oncologic care. Cocaine and fluorouracil are both associated with cardiotoxicity, and many oncologists would not feel it is safe to administer a regimen containing fluorouracil to a patient with active cocaine use. The National Comprehensive Cancer Network (NCCN) panel recommends FOLFIRINOX as a preferred category 1 recommendation for first-line treatment of patients with advanced pancreas cancer with good performance status.¹⁰ This recommendation is based on the PRODIGE trial, which has shown improved overall survival (OS): 11.1 vs 6.8 months for patients who received single-agent gemcitabine.¹¹ If patients are not candidates for FOLFIRINOX and have good performance status, the NCCN recommends gemcitabine plus albumin-bound paclitaxel with category 1 level of evidence based on the IMPACT trial, which showed improvement in OS (8.7 vs 6.6 months compared with single-agent gemcitabine).¹²

Some oncologists may have additional concerns administering fluorouracil treatment alternatives (such as gemcitabine and albumin-bound paclitaxel) to individuals with active SUD because of concerns about altered mental status impacting the ability to report important adverse effects. In the absence of sufficient data, HCPs must determine whether they feel it is safe to administer these agents in individuals with active cocaine use. However, denying these patients the possible benefits of standard-of-care life-prolonging therapies without established data raises concerns regarding the ethics of such practices. There is concern that the stigma surrounding cocaine use might contribute to withholding treatment, while treatment is continued for individuals taking prescribed stimulant medications that also have cardiotoxicity risks. VA health care facilities are uniquely situated to use all available resources to address these issues using interprofessional patient-centered care and determine the most optimal treatment based on a risk/benefit discussion between the patient and the HCP.

SUD Screening

This case begs the question of whether oncologists are adequately screening for a range of SUDs, and when they encounter an issue, how they are addressing it. Many oncologists do not receive adequate training on assessment of current or recent substance use. There are health care and systems-level practices that may increase patient safety for individuals with ongoing substance use who are undergoing cancer treatment. Training on obtaining appropriate substance use histories, motivational interviewing to resolve ambivalence about substance use in the direction of change, and shared decision making about treatment options could increase confidence in understanding and addressing substance use issues. It is also important to educate oncologists on how to address patients who return to or continued substance use during treatment. In this case the collaboration from palliative care, psychology, addiction medicine, and addiction psychiatry through the ORC was essential in assisting with ongoing assessment of substance use, guiding difficult conversations about the impact of substance use on the treatment plan, and identifying risk-mitigation strategies. Close collaboration and full utilization of all VA resources allowed this patient to receive first-line treatment for pancreatic cancer in order to reach his goal of prolonging his life while maintaining acceptable quality of life. Table 2 provides best practices for management of patients with comorbid SUD and cancer.

More research is needed into cancer treatment for patients with SUD, especially in the current era of cancer care using novel cancer treatments leading to significantly improved survival in many cancer types. Ideally, oncologists should be routinely or consistently screening patients for substance use, including alcohol. The patient should participate in this decision-making process after being educated about the risks and benefits. These patients can be followed using a multimodal approach to increase their rates of success and improve their quality of life. Although the literature is limited and no formal guidelines are available, VA oncologists are fortunate to have a range of resources available to them to navigate these difficult cases. Veterans have elevated rates of SUD, making this a critical issue to consider in the VA.¹³ It is the hope that this case can highlight how to take advantage of the many VA resources in order to ensure equitable cancer care for all veterans.

Conclusions

This case demonstrates that cancer-directed treatment is safe and feasible in a patient with advanced pancreatic cancer and coexisting active SUD by using a multidisciplinary approach. The multidisciplinary team included palliative care, oncology, psychology, addiction medicine, and addiction psychiatry. Critical steps for a successful outcome include gathering history about SUD; motivational interviewing to resolve ambivalence about treatment for SUD; shared decision making about cancer treatment; and risk-reduction strategies in pain and SUD management.

Treatment advancements in many cancer types have led to significantly longer survival, and it is critical to develop safe protocols to treat patients with active SUD so they also can derive benefit from these very significant medical advancements.

Acknowledgments

Michal Rose, MD, Director of VACHS Cancer Center, and Chandrika Kumar, MD, Director of VACHS Community Living Center, for their collaboration in care for this veteran.

Substance use disorders (SUDs) are an important but understudied aspect of treating patients diagnosed with cancer. Substance use can affect cancer treatment outcomes, including morbidity and mortality.^1,2 Additionally, patients with cancer and SUD may have unique psychosocial needs that require close attention and management. There is a paucity of data regarding the best approach to treating such patients. For example, cocaine use may increase the cardiovascular and hematologic risk of some traditional chemotherapy agents.^3,4 Newer targeted agents and immunotherapies remain understudied with respect to SUD risk.

Although the US Department of Veterans Affairs (VA) has established helpful clinical practice guidelines for the treatment of SUD, there are no guidelines for treating patients with SUD and cancer.⁵ Clinicians have limited confidence in treatment approach, and treatment is inconsistent among oncologists nationwide even within the same practice. Furthermore, it can be challenging to safely prescribe opioids for cancer-related pain in individuals with SUD. There is a high risk of SUD and mental health disorders in veterans, making this population particularly vulnerable. We report a case of a male with metastatic pancreatic cancer, severe opioid use disorder (OUD) and moderate cocaine use disorder (CUD) who received pain management and cancer treatment under the direction of a multidisciplinary team approach.

Case Report

A 63-year-old male with a medical history of HIV treated with highly active antiretroviral therapy (HAART), compensated cirrhosis, severe OUD, moderate CUD, and sedative use disorder in sustained remission was admitted to the West Haven campus of the VA Connecticut Healthcare System (VACHS) with abdominal pain, weight loss and fatigue. He used heroin 1 month prior to his admission and reported regular cocaine and marijuana use (Table 1). He was diagnosed with HIV in 1989, and his medical history included herpes zoster and oral candidiasis but no other opportunistic infections. Several months prior to this admission, he had an undetectable viral load and CD4 count of 688.

At the time of this admission, the patient was adherent to methadone treatment. He reported increased abdominal pain. Computed tomography (CT) showed a 2.4-cm mass in the pancreatic uncinate process, multiple liver metastases, retroperitoneal lymphadenopathy, and small lung nodules. A CT-guided liver biopsy showed adenocarcinoma consistent with a primary cancer of the pancreas. Given the complexity of the case, a multidisciplinary team approach was used to treat his cancer and the sequelae safely, including the oncology team, community living center team, palliative care team, and interprofessional opioid reassessment clinic team (ORC).

Cancer Treatment

Chemotherapy with FOLFIRINOX (leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) was recommended. The first cycle of treatment originally was planned for the outpatient setting, and a peripherally inserted central catheter (PICC) line was placed. However, after a urine toxicology test was positive for cocaine, the PICC line was removed due to concern for possible use of PICC line for nonprescribed substance use. The patient expressed suicidal ideation at the time and was admitted for psychiatric consult and pain control. Cycle 1 FOLFIRINOX was started during this admission. A PICC line was again put in place and then removed before discharge. A celiac plexus block was performed several days after this admission for pain control.

Given concern about cocaine use increasing the risk of cardiac toxicity with FOLFIRINOX treatment, treating providers sconsulted with the community living center (CLC) about possible admission for future chemotherapy administration and pain management. The CLC at VACHS has 38 beds for rehabilitation, long-term care, and hospice with the mission to restore each veteran to his or her highest level of well-being. After discussion with this patient and CLC staff, he agreed to a CLC admission. The patient agreed to remain in the facility, wear a secure care device, and not leave without staff accompaniment. He was able to obtain a 2-hour pass to pay bills and rent. During the 2 months he was admitted to the CLC he would present to the VACHS Cancer Center for chemotherapy every 2 weeks. He completed 6 cycles of chemotherapy while admitted. During the admission, he was transferred to active medical service for 2 days for fever and malaise, and then returned to the CLC. The patient elected to leave the CLC after 2 months as the inability to see close friends was interfering with his quality of life.

Upon being discharged from the CLC, shared decision making took place with the patient to establish a new treatment plan. In collaboration with the patient, a plan was made to admit him every 2 weeks for continued chemotherapy. A PICC line was placed on each day of admission and removed prior to discharge. It was also agreed that treatment would be delayed if a urine drug test was positive for cocaine on the morning of admission. The patient was also seen by ORC every 2 weeks after being discharged from the CLC.

Imaging after cycle 6 showed decreased size of liver metastases, retroperitoneal lymph nodes, and pancreas mass. Cancer antigen 19-9 (CA19-9) tumor marker was reduced from 3513 U/mL pretreatment to 50 U/mL after cycle 7. Chemotherapy cycle 7 was delayed 6 days due to active cocaine and heroin use. A repeat urine was obtained several days later, which was negative for cocaine, and he was admitted for cycle 7 chemotherapy. Using this treatment approach of admissions for every cycle, the patient was able to receive 11 cycles of FOLFIRINOX with clinical benefit.

Palliative Care/Pain Management

Safely treating the patient’s malignant pain in the context of his OUD was critically important. In order to do this the palliative care team worked closely alongside ORC, is a multidisciplinary team consisting of health care providers (HCPs) from addiction psychiatry, internal medicine, health psychology and pharmacy who are consulted to evaluate veterans’ current opioid regimens and make recommendations to optimize both safety and efficacy. ORC followed this particular veteran as an outpatient and consulted on pain issues during his admission. They recommended the continuation of methadone at 120 mg daily and increased oral oxycodone to 30 mg every 6 hours, and then further increased to 45 mg every 6 hours. He continued to have increased pain despite higher doses of oxycodone, and pain medication was changed to oral hydromorphone 28 mg every 6 hours with the continuation of methadone. ORC and the palliative care team obtained consent from the veteran and a release of Information form signed by the patient to contact his community methadone clinic for further collaboration around pain management throughout the time caring for the veteran.

Even with improvement in disease based on imaging and tumor markers, opioid medications could not be decreased in this case. This is likely in part due to the multidimensional nature of pain. Careful assessment of the biologic, emotional, social, and spiritual contributors to pain is needed in the management of pain, especially at end of life.⁶ Nonpharmacologic pain management strategies used in this case included a transcutaneous electrical nerve stimulation unit, moist heat, celiac plexus block, and emotional support.

Psychosocial Issues/Substance Use

Psychosocial support for the patient was provided by the interdisciplinary palliative care team and the ORC team in both the inpatient and outpatient settings. Despite efforts from case management to get the veteran home services once discharged from the CLC, he declined repeatedly. Thus, the CLC social worker obtained a guardian alert for the veteran on discharge.

Close outpatient follow-up for medical and psychosocial support was very critical. When an outpatient, the veteran was scheduled for biweekly appointments with palliative care or ORC. When admitted to the hospital, the palliative care team medical director and psychologist conducted joint visits with him. Although he denied depressed mood and anxiety throughout his treatment, he often reflected on regrets that he had as he faced the end of his life. Specifically, he shared thoughts about being estranged from his surviving brother given his long struggle with substance use. Although he did not think a relationship was possible with his brother at the end of life, he still cared deeply for him and wanted to make him aware of his pancreatic cancer diagnosis. This was particularly important to him because their late brother had also died of pancreatic cancer. It was the patient’s wish at the end of his life to alert his surviving brother of his diagnosis so he and his children could get adequate screening throughout their lives. Although he had spoken of this desire often, it wasn’t until his disease progressed and he elected to transition to hospice that he felt ready to write the letter. The palliative care team assisted the veteran in writing and mailing a letter to his brother informing him of his diagnosis and transition to hospice as well as communicating that his brother and his family had been in his thoughts at the end of his life. The patient’s brother received this letter and with assistance from the CLC social worker made arrangements to visit the veteran at bedside at the inpatient CLC hospice unit the final days of his life.

Discussion

There are very little data on the safety of cancer-directed therapy in patients with active SUD. The limited studies that have been done showed conflicting results.

A retrospective study among women with co-occurring SUD and locally advanced cervical cancer who were undergoing primary radiation therapy found that SUD was not associated with a difference in toxicity or survival outcomes.⁷ However, other research suggests that SUD may be associated with an increase in all-cause mortality as well as other adverse outcomes for patients and health care systems (eg, emergency department visits, hospitalizations).⁸ A retrospective study of patients with a history of SUD and nonsmall cell lung cancer showed that these patients had higher rates of depression, less family support, increased rates of missed appointments, more emergency department visits and more hospitalizations.⁹ Patients with chronic myeloid leukemia or myelodysplastic syndromes who had long-term cocaine use had a 6-fold increased risk of death, which was not found in patients who had long-term alcohol or marijuana use.²

The limited data highlight the need for careful consideration of ways to mitigate potentially adverse outcomes in this population while still providing clinically indicated cancer treatment. Integrated VA health care systems provide unique resources that can maximize veteran safety during cancer treatment. Utilization of VA resources and close interdisciplinary collaboration across VA HCPs can help to ensure equitable access to state-of-the-art cancer therapies for veterans with comorbid SUD.

VA Services for Patients With Comorbidities

This case highlights several distinct aspects of VA health care that make it possible to safely treat individuals with complex comorbidities. One important aspect of this was collaboration with the CLC to admit the veteran for his initial treatment after a positive cocaine test. CLC admission was nonpunitive and allowed ongoing involvement in the VA community. This provided an essential, safe, and structured environment in which 6 cycles of chemotherapy could be delivered.

Although the patient left the CLC after 2 months due to floor restrictions negatively impacting his quality of life and ability to spend time with close friends, several important events occurred during this stay. First, the patient established close relationships with the CLC staff and the palliative care team; both groups followed him throughout his inpatient and outpatient care. These relationships proved essential throughout his care as they were the foundation of difficult conversations about substance use, treatment adherence, and eventually, transition to hospice.

In addition, the opportunity to administer 6 cycles of chemotherapy at the CLC was enough to lead to clinical benefit and radiographic response to treatment. Clinical benefits while in the CLC included maintenance of a good appetite, 15-lb weight gain and preserved performance status (ECOG [Eastern Cooperative Group]-1), which allowed him to actively participate in multiple social and recreational activities while in the CLC. From early conversations, this patient was clear that he wanted treatment as long as his life could be prolonged with good quality of life. Having evidence of the benefit of treatment, at least initially, increased the patient’s confidence in treatment. There were a few conversations when the challenges of treatment mounted (eg, pain, needs for abstinence from cocaine prior to admission for chemotherapy, frequent doctor appointments), and the patient would remind himself of these data to recommit himself to treatment. The opportunity to admit him to the inpatient VA facility, including bed availability for 3 days during his treatment once he left the CLC was important. This plan to admit the patient following a negative urine toxicology test for cocaine was made collaboratively with the veteran and the oncology and palliative care teams. The plan allowed the patient to achieve his treatment goals while maintaining his safety and reducing theoretical cardiac toxicities with his cancer treatment.

Finally, the availability of a multidisciplinary team approach including palliative care, oncology, psychology, addiction medicine and addiction psychiatry, was critical for addressing the veteran’s malignant pain. Palliative care worked in close collaboration with the ORC to prescribe and renew pain medications. ORC offered ongoing consultation on pain management in the context of OUD. As the veteran’s cancer progressed and functional decline prohibited his daily attendance at the community methadone clinic, palliative care and ORC met with the methadone clinic to arrange a less frequent methadone pickup schedule (the patient previously needed daily pickup). Non-VA settings may not have access to these resources to safely treat the biopsychosocial issues that arise in complex cases.

Substance Use and Cancer Treatments

This case raises several critical questions for oncologic care. Cocaine and fluorouracil are both associated with cardiotoxicity, and many oncologists would not feel it is safe to administer a regimen containing fluorouracil to a patient with active cocaine use. The National Comprehensive Cancer Network (NCCN) panel recommends FOLFIRINOX as a preferred category 1 recommendation for first-line treatment of patients with advanced pancreas cancer with good performance status.¹⁰ This recommendation is based on the PRODIGE trial, which has shown improved overall survival (OS): 11.1 vs 6.8 months for patients who received single-agent gemcitabine.¹¹ If patients are not candidates for FOLFIRINOX and have good performance status, the NCCN recommends gemcitabine plus albumin-bound paclitaxel with category 1 level of evidence based on the IMPACT trial, which showed improvement in OS (8.7 vs 6.6 months compared with single-agent gemcitabine).¹²

Some oncologists may have additional concerns administering fluorouracil treatment alternatives (such as gemcitabine and albumin-bound paclitaxel) to individuals with active SUD because of concerns about altered mental status impacting the ability to report important adverse effects. In the absence of sufficient data, HCPs must determine whether they feel it is safe to administer these agents in individuals with active cocaine use. However, denying these patients the possible benefits of standard-of-care life-prolonging therapies without established data raises concerns regarding the ethics of such practices. There is concern that the stigma surrounding cocaine use might contribute to withholding treatment, while treatment is continued for individuals taking prescribed stimulant medications that also have cardiotoxicity risks. VA health care facilities are uniquely situated to use all available resources to address these issues using interprofessional patient-centered care and determine the most optimal treatment based on a risk/benefit discussion between the patient and the HCP.

SUD Screening

This case begs the question of whether oncologists are adequately screening for a range of SUDs, and when they encounter an issue, how they are addressing it. Many oncologists do not receive adequate training on assessment of current or recent substance use. There are health care and systems-level practices that may increase patient safety for individuals with ongoing substance use who are undergoing cancer treatment. Training on obtaining appropriate substance use histories, motivational interviewing to resolve ambivalence about substance use in the direction of change, and shared decision making about treatment options could increase confidence in understanding and addressing substance use issues. It is also important to educate oncologists on how to address patients who return to or continued substance use during treatment. In this case the collaboration from palliative care, psychology, addiction medicine, and addiction psychiatry through the ORC was essential in assisting with ongoing assessment of substance use, guiding difficult conversations about the impact of substance use on the treatment plan, and identifying risk-mitigation strategies. Close collaboration and full utilization of all VA resources allowed this patient to receive first-line treatment for pancreatic cancer in order to reach his goal of prolonging his life while maintaining acceptable quality of life. Table 2 provides best practices for management of patients with comorbid SUD and cancer.

More research is needed into cancer treatment for patients with SUD, especially in the current era of cancer care using novel cancer treatments leading to significantly improved survival in many cancer types. Ideally, oncologists should be routinely or consistently screening patients for substance use, including alcohol. The patient should participate in this decision-making process after being educated about the risks and benefits. These patients can be followed using a multimodal approach to increase their rates of success and improve their quality of life. Although the literature is limited and no formal guidelines are available, VA oncologists are fortunate to have a range of resources available to them to navigate these difficult cases. Veterans have elevated rates of SUD, making this a critical issue to consider in the VA.¹³ It is the hope that this case can highlight how to take advantage of the many VA resources in order to ensure equitable cancer care for all veterans.

Conclusions

This case demonstrates that cancer-directed treatment is safe and feasible in a patient with advanced pancreatic cancer and coexisting active SUD by using a multidisciplinary approach. The multidisciplinary team included palliative care, oncology, psychology, addiction medicine, and addiction psychiatry. Critical steps for a successful outcome include gathering history about SUD; motivational interviewing to resolve ambivalence about treatment for SUD; shared decision making about cancer treatment; and risk-reduction strategies in pain and SUD management.

Treatment advancements in many cancer types have led to significantly longer survival, and it is critical to develop safe protocols to treat patients with active SUD so they also can derive benefit from these very significant medical advancements.

Acknowledgments

Michal Rose, MD, Director of VACHS Cancer Center, and Chandrika Kumar, MD, Director of VACHS Community Living Center, for their collaboration in care for this veteran.

Veterans living with cancer need comprehensive assessment that includes supportive psychosocial care. The National Comprehensive Cancer Network (NCCN) and American College of Surgeons Commission on Cancer require accredited cancer centers to evaluate psychosocial distress and provide appropriate triage and treatment for all patients.^1-3 Implementing psychosocial distress screening can be difficult because of procedural barriers and time constraints, clinic and supportive care resources, and lack of knowledge about how to access supportive services.

Distress screening protocols must be designed to address the specific needs of each population. To improve screening for cancer-related distress, deliver effective supportive services, and gain agreement on distress screening standards of care, the Coleman Foundation supported development of the Coleman Supportive Oncology Collaborative (CSOC), a project of 135 interdisciplinary health care professionals from 25 Chicago-area cancer care institutions.⁴

The Jesse Brown US Department of Veterans Affairs (VA) Medical Center (JBVAMC) was chosen to assess cancer-related concerns among veterans using the CSOC screening tool and to improve access to supportive oncology. JBVAMC provides care to approximately 49,000 veterans in Chicago, Illinois, and northwestern Indiana. The JBVAMC patient population includes a large number of veterans with dual diagnoses (co-occurring substance use and mental health disorders) and veterans experiencing homelessness.

Delivering integrated screening and oncologic care that is culture and age appropriate is particularly important for veterans given their unique risk factors. The veteran population is considered vulnerable in terms of health status, psychological functioning, and social context. Veterans who use the VA health system as a principal source of care have poorer health, greater comorbid medical conditions, and an increased risk of mortality and suicide compared with the general population.^5,6 Poorer health status in veterans also may relate to old age, low income, poor education, psychological health, and minority race.^7-9

Past studies point to unique risk factors for cancer and poor cancer adjustment among veterans, which may complicate cancer treatment and end-of-life/survivorship care. Veteran-specific risk factors include military-related exposures, particularly Agent Orange and morbidity/mortality secondary to comorbid medical and psychiatric conditions (eg, chronic obstructive pulmonary disease, diabetes mellitus, and posttraumatic stress disorder [PTSD]).^10-12 Moreover, the geriatric veteran population continues to grow,with increasing rates of cancer that require unique considerations for effective cancer care.^13,14 Despite this, there are minimal data to inform best practices and supportive care approaches for veterans with cancer. Lack of guidelines specific to veterans and other populations with increased psychosocial challenges may impede successful cancer care, making distress screening procedures particularly important. This is especially the case for the JBVAMC, which serves primarily African American urban-dwelling veterans who experience high rates of cancer disparities, including increased rates of mortality and increased levels of psychosocial distress.^15,16

The goals of this program were to (1) examine levels of psychological, physical, financial, and treatment-related distress in a large sample of urban-dwelling veterans; (2) create a streamlined, sustainable process to screen a large number of veterans receiving cancer care in the outpatient setting and connect them with available supportive services; and (3) educate oncology physicians, nurses, and other staff about cancer-related distress and concerns using in-service trainings and interpersonal interactions to improve patient care. Our program was based on a Primary Care Mental Health Integration (PCMHI) model that embeds health psychologists in general medical clinics to better reach veterans dealing with mental health issues. We tailored for palliative care involvement.

Studies of this model have shown that mental health integration improves access to mental health services and mental health treatment outcomes and has higher patient and provider satisfaction.¹⁷ We were also influenced by the construct of the patient aligned care team (PACT) social worker who, in this veteran-centered approach, often functions as a care coordinator. Social work responsibilities include assessment of patients’ stressors including adjusting to the medical conditions, identifying untreated or undertreated mental health or substance abuse issues, economic instability, legal problems, and inadequate housing and transportation, which can often be exacerbated during cancer treatment.¹⁸

Methods

This institutional review board at JBVAMC reviewed and exempted this quality improvement program using the SQUIRE framework.¹⁹ It was led by a group of palliative care clinicians, psychologists, and administrators who have worked with the oncology service for many years, primarily in the care of hospitalized patients. Common palliative care services include providing care for patients with serious illness diagnosis through the illness trajectory.

Setting

At the start of this program, we assessed the current clinic workflow to determine how to best screen and assist veterans experiencing distress. We met with team members individually to identify the best method of clinic integration, including attending medical oncologists, medical oncology fellows, psychology interns, oncology nursing staff, the oncology nurse coordinator, and clinic clerks.

The JBVAMC provides cancer care through 4 half-day medical hematology-oncology clinics that serve about 50 patients per half-day clinic. The clinics are staffed by hematology-oncology fellows supervised by hematology-oncology attending physicians, who are affiliated with 2 academic medical centers. These clinics are staffed by 3 registered nurses (RNs) and a licensed practical nurse (LPN) and are adjacent to a chemotherapy infusion clinic with unique nursing staff. The JBVAMC also provides a variety of supportive care services, including extensive mental health and substance use treatment, physical and occupational therapy, acupuncture, nutrition, social work, and housing services. Following our assessment, it was evident that there were a low number of referrals from oncology clinics to supportive care services, mostly due to lack of knowledge of resources and unclear referral procedures.

Based on clinical volume, we determined that our screening program could best be implemented through a stepped approach beginning in one clinic and expanding thereafter. We began by having a palliative care physician and health psychology intern embedded in 1 weekly half-day clinic and a health psychology intern embedded in a second weekly half-day clinic. Our program included 2 health psychology interns (for each academic year of the program) who were supervised by a JBVA health psychologist.

About 15 months after successful integration within the first 2 half-day clinics, we expanded the screening program to staff an additional half-day medical oncology clinic with a palliative care APRN. This allowed us to expand the screening tool distribution and collection to 3 of 4 of the weekly half-day oncology clinics as well as to meet individually with veterans experiencing high levels of distress. Veterans were flagged as having high distress levels by either the results of their completed screening tool or by referral from a medical oncology physician. We initially established screening in clinics that were sufficiently staffed to ensure that screens were appropriately distributed and reviewed. Patients seen in nonparticipating clinics were referred to outpatient social work, mental health and/or outpatient palliative care according to oncology fellows’ clinical assessments of the patient. All oncology fellows received education about distress screening and methods for referring to supportive care. Our clinic screening program extended from February 2017 through January 2020.

Screening

Program staff screened patients with new cancer diagnoses, then identified patients for follow-up screens. This tracking allowed staff to identify patients with oncology appointments that day and cross-reference patients needing a follow-up screen.

Following feedback from the clinic nurses, we determined that nurses would provide the distress tool to patients in paper form after they completed their assessment of vitals and waited to be seen by their medical oncologist. The patient would then deliver their completed form to the nurse who would combine it with the patient’s clinic notes for the oncologist to review. Veterans who reported elevated 4-question Patient Health Questionnaire (PHQ-4) scores ≥ 6 were seen immediately by program staff. Veterans were referred to social work or psychiatry services for a same day visit if they endorsed a high level of psychological distress during clinical examination. They were referred for other supportive care services if they were determined to have practical, family, or nutrition unmet distress needs by either the program staff or oncology fellows. Program staff provided guidance to medical oncology fellows for needed referrals including social work, mental health, and palliative care follow ups (eAppendix A available at doi:10.12788/fp.0158).

Veterans referred for supportive care services were contacted by the relevant clinical administrator by phone to schedule an intake; for social work referrals, patients were either seen in a walk-in office located in a colocated building or contacted by a social worker by phone.

Our screening tool was the Coleman Foundation Supportive Oncology Collaborative Screening Tool, compiled from validated instruments. Patients completed this screening tool, which includes the PHQ-4, NCCN problem list concerns, adapted Mini Nutrition Assessment and PROMIS Pain and Fatigue measure (eAppendix B available at doi:10.12788/fp.0158).^20-22

We also worked with the VA Computerized Patient Record System (CPRS) to create an electronic template for the screening tool. Completed screening tools were manually entered by the physician, psychologists, or APRN into the CPRS chart.

We analyzed the different supportive care services available at the JBVAMC and noticed that many supportive services were available, yet these services were often separated. Therefore, we created a consult flowsheet to assist oncologists in placing referrals. These supportive care services include mental health services, a cancer support group, home health care, social services, nutrition, physical medicine and rehabilitation, and other specialty services.

Patient Education

The psychology and nursing staff created a patient information bulletin board where patients could access information about supportive services available at JBVAMC. This board required frequent replenishment of handouts because patients consulted the board regularly. Handouts and folders about common clinical issues also were placed in the clinic treatment rooms. We partnered with 2 local cancer support centers, Gilda’s Club and the Cancer Support Center, to make referrals for family members and/or caregivers who would benefit from additional support.

We provided in-service trainings for oncology fellows, including trainings on PTSD and substance abuse and their relationship to cancer care at the VA. These topics were chosen based on the feedback program staff received about perceived knowledge gaps from the oncology fellows. This program allowed for multiple informal conversations between that program staff and oncology fellows about overall patient care. We held trainings with the cancer coordinator and clinical nursing staff on strategies to identify and follow-up on cancer-related distress, and with oncology fellows to review the importance of distress screening and to instruct fellows on instructions for the consult flowsheet.

Funding

This program was funded by the Chicago-based Coleman Foundation as part of the CSOC. Funding was used to support a portion of time for administrative and clinical work of program staff, as well as data collection and analysis.

Results

We established 3 half-day integrated clinics where patients were screened and referred for services based on supportive oncology needs. In addition to our primary activities to screen and refer veterans, we held multiple educational sessions for colleagues, developed a workflow template, and integrated patient education materials into the clinics.

Screening

Veterans completed 1010 distress screens in 3 of 4 half-day oncology clinics over the 2.5-year project period. Veterans were screened at initial diagnosis and every 3 months, or during changes in their clinical care or disease status. As a result, 579 patients completed screening, with some patients doing several follow-up screens during their care. Integration of palliative care providers and health psychologists was instrumental in facilitating screening in these busy general medical oncology clinics. Most veterans were receptive to completing surveys with few refusing to fill out the survey.²³ Medical oncology fellows often used the completed screener to inform their review of systems (by reviewing the Coleman screener Physical and Other Concerns section) and connect with the supportive care staff present in clinic for patient’s identifying severe needs (ie, mental health distress or complex psychosocial needs). Veterans’ rates of distress needs and successfuloutcomes of integration with mental health and social work services have been reported elsewhere.²³

The mean (SD) age for veterans in this cohort was 72 (9.5) years. Participants were primarily African American veterans (70%), with mostly advanced disease (Table 1). Participants endorsed elevated distress needs compared with other patient populations screened in Chicago through the CSOC for depressed mood, pain, housing, transportation, and physical, nutrition, and treatment concerns.²³ Elevated presence of needs was especially prominent for food, housing and insurance/medical needs; physical concerns; nutrition, and treatment- or care-related concerns. Veterans in this cohort reported extensive financial and housing concerns: 10.4% reported food and housing concerns, 18.6% reported transportation concerns, and 9.0% reported issues paying for medical care or medications (Table 2).²⁰ Anecdotally, many experienced job loss or strain with their cancer diagnosis or were living at the poverty level before their diagnosis.

Discussion

This project created a successful program to screen veterans for psychosocial distress and triage them to appropriate services. During the project, patients in VA-outpatient oncology clinics reported significant cancer-related distress due to baseline psychosocial needs, changes in emotional and physical functioning, logistical and financial challenges of receiving cancer care, and lack of instrumental support.²³

Staff education supported successful buy-in, development and implementation of supportive oncology programs. We used a combination of in-service trainings, online trainings, and handouts to provide evidence for distress screening.²⁴ Highlighting the evidence-base that demonstrates how cancer-related distress screening improves cancer and quality of life outcomes helped to address physician reluctance to accept the additional requirements needed to address veterans’ psychosocial needs and care concerns. To increase buy-in and collaboration among team members and foster heightened understanding between providers and patients, we recommend creating accessible education for all staff levels.

One specific area of education we focused on was primary palliative care, which includes the core competencies of communication and symptom management recommended for generalists and specialists of all disciplines.²⁵ Program staff supported oncology fellows in developing their primary palliative care skills by being available to discuss basic symptom management and communication issues. VA cancer care programs could benefit from ongoing palliative care education of oncology staff to facilitate primary palliative care as well as earlier integration of secondary palliative care when needed.²⁶ Secondary palliative care or care provided directly by the palliative care team assists with complex symptom management or communication issues. For these needs, oncology fellows were encouraged to refer to either the palliative care staff available in one of the half-day clinics or to the outpatient palliative care clinic. As a unique strength, the VA allows veterans to receive concurrent cancer-directed therapy and hospice care, which enables earlier referrals to hospice care and higher quality end-of-life care and emphasizes the need for primary palliative care in oncology.^27,28

Integrating supportive oncology team members, such as licensed clinical social worker and psychology interns, was successful. This was modeled on the VA PACT, which focuses on prevention, health promotion, coordination and chronic disease management.²⁹ Social determinants of health have a major impact on health outcomes especially in veteran-specific and African American populations, making screening for distress critical.^30-32 The VA Office of Health Equity actively addresses health inequities by supporting initiation of screening programs for social determinants of health, including education, employment, exposure to abuse and violence, food insecurity, housing instability, legal needs, social isolation, transportation needs, and utility needs. This is especially needed for African-American individuals who are not only more likely to experience cancer, but also more likely to be negatively impacted by the consequences of cancer diagnosis/treatment, such as complications related to one’s job security, access to care, adverse effects, and other highly distressing needs.^33,34

Our program found that veterans with cancer often had concerns associated with food and housing insecurity, transportation and paying for medication or medical care, and screening allowed health care providers to detect and address these social determinants of health through referrals to VA and community-specific programs. Social workers integrated into VA cancer clinics are uniquely equipped to coordinate distress screening and support continuity of care by virtue of their training, connections to preexisting VA supportive services, and knowledge of community resources. This model could be used in other VA specialty clinics serving veterans with chronic illness and those with high levels of physical frailty.³⁵

Our ability to roll out distress screening was scaffolded by technological integration into existing VA systems (eg, screening results in CPRS and electronic referrals). Screening procedures could have been even more efficient with improved technology (Table 3). For example, technological limitations made it challenging to easily identify patients due for screening, requiring a cumbersome process of tracking, collecting and entering patients’ paper forms. Health care providers seeking to develop a distress screening program should consider investing in technology that allows for identification of patients requiring screening at a predetermined interval, completion of screening via tablet or personal device, integration of screening responses into the electronic health record, and automatic generation of notifications to the treating physician and appropriate support services.

Conclusions

Veterans with cancer benefited from enhanced screening and psychosocial service availability, similar to a PCMHI model. Robust screening programs helped advocate for veterans dealing with the effects of poverty through identification of need and referral to existing VA programs and services quickly and efficiently. Providing comprehensive care within ambulatory cancer clinics can address cancer-related distress and any potential barriers to care in real time. VA hospitals typically offer an array of supportive services to address veterans’ psychosocial needs, yet these services tend to be siloed. Integrated referrals can help to resolve such access barriers. Since many veterans with burdensome cancers are not able to see their VA primary care physician regularly, offering comprehensive care within medical oncology ensures complete and integrated care that includes psychosocial screening.

We believe that this program is an example of a mechanism for oncologists and palliative care clinicians to integrate their care in a way that identifies needs and triages services for vulnerable veterans. As colleagues have written, “it is fundamental to our commitment to veterans that we ensure comparable, high quality care regardless of a veteran’s gender, race, or where they live.^”34 Health care providers may underestimate the extensive change a cancer diagnosis can have on a patient’s quality of life. Cancer diagnosis and treatment have a large impact on all individuals, but this impact may be greater for individuals in poverty due to inability to work from home, inflexible work hours, and limited support structures. By creating screening programs with psychosocial integration in oncology clinics such as we have described, we hope to improve access to more equitable care for vulnerable veterans.

Veterans living with cancer need comprehensive assessment that includes supportive psychosocial care. The National Comprehensive Cancer Network (NCCN) and American College of Surgeons Commission on Cancer require accredited cancer centers to evaluate psychosocial distress and provide appropriate triage and treatment for all patients.^1-3 Implementing psychosocial distress screening can be difficult because of procedural barriers and time constraints, clinic and supportive care resources, and lack of knowledge about how to access supportive services.

Distress screening protocols must be designed to address the specific needs of each population. To improve screening for cancer-related distress, deliver effective supportive services, and gain agreement on distress screening standards of care, the Coleman Foundation supported development of the Coleman Supportive Oncology Collaborative (CSOC), a project of 135 interdisciplinary health care professionals from 25 Chicago-area cancer care institutions.⁴

The Jesse Brown US Department of Veterans Affairs (VA) Medical Center (JBVAMC) was chosen to assess cancer-related concerns among veterans using the CSOC screening tool and to improve access to supportive oncology. JBVAMC provides care to approximately 49,000 veterans in Chicago, Illinois, and northwestern Indiana. The JBVAMC patient population includes a large number of veterans with dual diagnoses (co-occurring substance use and mental health disorders) and veterans experiencing homelessness.

Delivering integrated screening and oncologic care that is culture and age appropriate is particularly important for veterans given their unique risk factors. The veteran population is considered vulnerable in terms of health status, psychological functioning, and social context. Veterans who use the VA health system as a principal source of care have poorer health, greater comorbid medical conditions, and an increased risk of mortality and suicide compared with the general population.^5,6 Poorer health status in veterans also may relate to old age, low income, poor education, psychological health, and minority race.^7-9

Past studies point to unique risk factors for cancer and poor cancer adjustment among veterans, which may complicate cancer treatment and end-of-life/survivorship care. Veteran-specific risk factors include military-related exposures, particularly Agent Orange and morbidity/mortality secondary to comorbid medical and psychiatric conditions (eg, chronic obstructive pulmonary disease, diabetes mellitus, and posttraumatic stress disorder [PTSD]).^10-12 Moreover, the geriatric veteran population continues to grow,with increasing rates of cancer that require unique considerations for effective cancer care.^13,14 Despite this, there are minimal data to inform best practices and supportive care approaches for veterans with cancer. Lack of guidelines specific to veterans and other populations with increased psychosocial challenges may impede successful cancer care, making distress screening procedures particularly important. This is especially the case for the JBVAMC, which serves primarily African American urban-dwelling veterans who experience high rates of cancer disparities, including increased rates of mortality and increased levels of psychosocial distress.^15,16

The goals of this program were to (1) examine levels of psychological, physical, financial, and treatment-related distress in a large sample of urban-dwelling veterans; (2) create a streamlined, sustainable process to screen a large number of veterans receiving cancer care in the outpatient setting and connect them with available supportive services; and (3) educate oncology physicians, nurses, and other staff about cancer-related distress and concerns using in-service trainings and interpersonal interactions to improve patient care. Our program was based on a Primary Care Mental Health Integration (PCMHI) model that embeds health psychologists in general medical clinics to better reach veterans dealing with mental health issues. We tailored for palliative care involvement.

Studies of this model have shown that mental health integration improves access to mental health services and mental health treatment outcomes and has higher patient and provider satisfaction.¹⁷ We were also influenced by the construct of the patient aligned care team (PACT) social worker who, in this veteran-centered approach, often functions as a care coordinator. Social work responsibilities include assessment of patients’ stressors including adjusting to the medical conditions, identifying untreated or undertreated mental health or substance abuse issues, economic instability, legal problems, and inadequate housing and transportation, which can often be exacerbated during cancer treatment.¹⁸

Methods

This institutional review board at JBVAMC reviewed and exempted this quality improvement program using the SQUIRE framework.¹⁹ It was led by a group of palliative care clinicians, psychologists, and administrators who have worked with the oncology service for many years, primarily in the care of hospitalized patients. Common palliative care services include providing care for patients with serious illness diagnosis through the illness trajectory.

Setting

At the start of this program, we assessed the current clinic workflow to determine how to best screen and assist veterans experiencing distress. We met with team members individually to identify the best method of clinic integration, including attending medical oncologists, medical oncology fellows, psychology interns, oncology nursing staff, the oncology nurse coordinator, and clinic clerks.

The JBVAMC provides cancer care through 4 half-day medical hematology-oncology clinics that serve about 50 patients per half-day clinic. The clinics are staffed by hematology-oncology fellows supervised by hematology-oncology attending physicians, who are affiliated with 2 academic medical centers. These clinics are staffed by 3 registered nurses (RNs) and a licensed practical nurse (LPN) and are adjacent to a chemotherapy infusion clinic with unique nursing staff. The JBVAMC also provides a variety of supportive care services, including extensive mental health and substance use treatment, physical and occupational therapy, acupuncture, nutrition, social work, and housing services. Following our assessment, it was evident that there were a low number of referrals from oncology clinics to supportive care services, mostly due to lack of knowledge of resources and unclear referral procedures.

Based on clinical volume, we determined that our screening program could best be implemented through a stepped approach beginning in one clinic and expanding thereafter. We began by having a palliative care physician and health psychology intern embedded in 1 weekly half-day clinic and a health psychology intern embedded in a second weekly half-day clinic. Our program included 2 health psychology interns (for each academic year of the program) who were supervised by a JBVA health psychologist.

About 15 months after successful integration within the first 2 half-day clinics, we expanded the screening program to staff an additional half-day medical oncology clinic with a palliative care APRN. This allowed us to expand the screening tool distribution and collection to 3 of 4 of the weekly half-day oncology clinics as well as to meet individually with veterans experiencing high levels of distress. Veterans were flagged as having high distress levels by either the results of their completed screening tool or by referral from a medical oncology physician. We initially established screening in clinics that were sufficiently staffed to ensure that screens were appropriately distributed and reviewed. Patients seen in nonparticipating clinics were referred to outpatient social work, mental health and/or outpatient palliative care according to oncology fellows’ clinical assessments of the patient. All oncology fellows received education about distress screening and methods for referring to supportive care. Our clinic screening program extended from February 2017 through January 2020.

Screening

Program staff screened patients with new cancer diagnoses, then identified patients for follow-up screens. This tracking allowed staff to identify patients with oncology appointments that day and cross-reference patients needing a follow-up screen.

Following feedback from the clinic nurses, we determined that nurses would provide the distress tool to patients in paper form after they completed their assessment of vitals and waited to be seen by their medical oncologist. The patient would then deliver their completed form to the nurse who would combine it with the patient’s clinic notes for the oncologist to review. Veterans who reported elevated 4-question Patient Health Questionnaire (PHQ-4) scores ≥ 6 were seen immediately by program staff. Veterans were referred to social work or psychiatry services for a same day visit if they endorsed a high level of psychological distress during clinical examination. They were referred for other supportive care services if they were determined to have practical, family, or nutrition unmet distress needs by either the program staff or oncology fellows. Program staff provided guidance to medical oncology fellows for needed referrals including social work, mental health, and palliative care follow ups (eAppendix A available at doi:10.12788/fp.0158).

Veterans referred for supportive care services were contacted by the relevant clinical administrator by phone to schedule an intake; for social work referrals, patients were either seen in a walk-in office located in a colocated building or contacted by a social worker by phone.

Our screening tool was the Coleman Foundation Supportive Oncology Collaborative Screening Tool, compiled from validated instruments. Patients completed this screening tool, which includes the PHQ-4, NCCN problem list concerns, adapted Mini Nutrition Assessment and PROMIS Pain and Fatigue measure (eAppendix B available at doi:10.12788/fp.0158).^20-22

We also worked with the VA Computerized Patient Record System (CPRS) to create an electronic template for the screening tool. Completed screening tools were manually entered by the physician, psychologists, or APRN into the CPRS chart.

We analyzed the different supportive care services available at the JBVAMC and noticed that many supportive services were available, yet these services were often separated. Therefore, we created a consult flowsheet to assist oncologists in placing referrals. These supportive care services include mental health services, a cancer support group, home health care, social services, nutrition, physical medicine and rehabilitation, and other specialty services.

Patient Education

The psychology and nursing staff created a patient information bulletin board where patients could access information about supportive services available at JBVAMC. This board required frequent replenishment of handouts because patients consulted the board regularly. Handouts and folders about common clinical issues also were placed in the clinic treatment rooms. We partnered with 2 local cancer support centers, Gilda’s Club and the Cancer Support Center, to make referrals for family members and/or caregivers who would benefit from additional support.

We provided in-service trainings for oncology fellows, including trainings on PTSD and substance abuse and their relationship to cancer care at the VA. These topics were chosen based on the feedback program staff received about perceived knowledge gaps from the oncology fellows. This program allowed for multiple informal conversations between that program staff and oncology fellows about overall patient care. We held trainings with the cancer coordinator and clinical nursing staff on strategies to identify and follow-up on cancer-related distress, and with oncology fellows to review the importance of distress screening and to instruct fellows on instructions for the consult flowsheet.

Funding

This program was funded by the Chicago-based Coleman Foundation as part of the CSOC. Funding was used to support a portion of time for administrative and clinical work of program staff, as well as data collection and analysis.

Results

We established 3 half-day integrated clinics where patients were screened and referred for services based on supportive oncology needs. In addition to our primary activities to screen and refer veterans, we held multiple educational sessions for colleagues, developed a workflow template, and integrated patient education materials into the clinics.

Screening

Veterans completed 1010 distress screens in 3 of 4 half-day oncology clinics over the 2.5-year project period. Veterans were screened at initial diagnosis and every 3 months, or during changes in their clinical care or disease status. As a result, 579 patients completed screening, with some patients doing several follow-up screens during their care. Integration of palliative care providers and health psychologists was instrumental in facilitating screening in these busy general medical oncology clinics. Most veterans were receptive to completing surveys with few refusing to fill out the survey.²³ Medical oncology fellows often used the completed screener to inform their review of systems (by reviewing the Coleman screener Physical and Other Concerns section) and connect with the supportive care staff present in clinic for patient’s identifying severe needs (ie, mental health distress or complex psychosocial needs). Veterans’ rates of distress needs and successfuloutcomes of integration with mental health and social work services have been reported elsewhere.²³

The mean (SD) age for veterans in this cohort was 72 (9.5) years. Participants were primarily African American veterans (70%), with mostly advanced disease (Table 1). Participants endorsed elevated distress needs compared with other patient populations screened in Chicago through the CSOC for depressed mood, pain, housing, transportation, and physical, nutrition, and treatment concerns.²³ Elevated presence of needs was especially prominent for food, housing and insurance/medical needs; physical concerns; nutrition, and treatment- or care-related concerns. Veterans in this cohort reported extensive financial and housing concerns: 10.4% reported food and housing concerns, 18.6% reported transportation concerns, and 9.0% reported issues paying for medical care or medications (Table 2).²⁰ Anecdotally, many experienced job loss or strain with their cancer diagnosis or were living at the poverty level before their diagnosis.

Discussion

This project created a successful program to screen veterans for psychosocial distress and triage them to appropriate services. During the project, patients in VA-outpatient oncology clinics reported significant cancer-related distress due to baseline psychosocial needs, changes in emotional and physical functioning, logistical and financial challenges of receiving cancer care, and lack of instrumental support.²³

Staff education supported successful buy-in, development and implementation of supportive oncology programs. We used a combination of in-service trainings, online trainings, and handouts to provide evidence for distress screening.²⁴ Highlighting the evidence-base that demonstrates how cancer-related distress screening improves cancer and quality of life outcomes helped to address physician reluctance to accept the additional requirements needed to address veterans’ psychosocial needs and care concerns. To increase buy-in and collaboration among team members and foster heightened understanding between providers and patients, we recommend creating accessible education for all staff levels.

One specific area of education we focused on was primary palliative care, which includes the core competencies of communication and symptom management recommended for generalists and specialists of all disciplines.²⁵ Program staff supported oncology fellows in developing their primary palliative care skills by being available to discuss basic symptom management and communication issues. VA cancer care programs could benefit from ongoing palliative care education of oncology staff to facilitate primary palliative care as well as earlier integration of secondary palliative care when needed.²⁶ Secondary palliative care or care provided directly by the palliative care team assists with complex symptom management or communication issues. For these needs, oncology fellows were encouraged to refer to either the palliative care staff available in one of the half-day clinics or to the outpatient palliative care clinic. As a unique strength, the VA allows veterans to receive concurrent cancer-directed therapy and hospice care, which enables earlier referrals to hospice care and higher quality end-of-life care and emphasizes the need for primary palliative care in oncology.^27,28

Integrating supportive oncology team members, such as licensed clinical social worker and psychology interns, was successful. This was modeled on the VA PACT, which focuses on prevention, health promotion, coordination and chronic disease management.²⁹ Social determinants of health have a major impact on health outcomes especially in veteran-specific and African American populations, making screening for distress critical.^30-32 The VA Office of Health Equity actively addresses health inequities by supporting initiation of screening programs for social determinants of health, including education, employment, exposure to abuse and violence, food insecurity, housing instability, legal needs, social isolation, transportation needs, and utility needs. This is especially needed for African-American individuals who are not only more likely to experience cancer, but also more likely to be negatively impacted by the consequences of cancer diagnosis/treatment, such as complications related to one’s job security, access to care, adverse effects, and other highly distressing needs.^33,34

Our program found that veterans with cancer often had concerns associated with food and housing insecurity, transportation and paying for medication or medical care, and screening allowed health care providers to detect and address these social determinants of health through referrals to VA and community-specific programs. Social workers integrated into VA cancer clinics are uniquely equipped to coordinate distress screening and support continuity of care by virtue of their training, connections to preexisting VA supportive services, and knowledge of community resources. This model could be used in other VA specialty clinics serving veterans with chronic illness and those with high levels of physical frailty.³⁵

Our ability to roll out distress screening was scaffolded by technological integration into existing VA systems (eg, screening results in CPRS and electronic referrals). Screening procedures could have been even more efficient with improved technology (Table 3). For example, technological limitations made it challenging to easily identify patients due for screening, requiring a cumbersome process of tracking, collecting and entering patients’ paper forms. Health care providers seeking to develop a distress screening program should consider investing in technology that allows for identification of patients requiring screening at a predetermined interval, completion of screening via tablet or personal device, integration of screening responses into the electronic health record, and automatic generation of notifications to the treating physician and appropriate support services.

Conclusions

Veterans with cancer benefited from enhanced screening and psychosocial service availability, similar to a PCMHI model. Robust screening programs helped advocate for veterans dealing with the effects of poverty through identification of need and referral to existing VA programs and services quickly and efficiently. Providing comprehensive care within ambulatory cancer clinics can address cancer-related distress and any potential barriers to care in real time. VA hospitals typically offer an array of supportive services to address veterans’ psychosocial needs, yet these services tend to be siloed. Integrated referrals can help to resolve such access barriers. Since many veterans with burdensome cancers are not able to see their VA primary care physician regularly, offering comprehensive care within medical oncology ensures complete and integrated care that includes psychosocial screening.

We believe that this program is an example of a mechanism for oncologists and palliative care clinicians to integrate their care in a way that identifies needs and triages services for vulnerable veterans. As colleagues have written, “it is fundamental to our commitment to veterans that we ensure comparable, high quality care regardless of a veteran’s gender, race, or where they live.^”34 Health care providers may underestimate the extensive change a cancer diagnosis can have on a patient’s quality of life. Cancer diagnosis and treatment have a large impact on all individuals, but this impact may be greater for individuals in poverty due to inability to work from home, inflexible work hours, and limited support structures. By creating screening programs with psychosocial integration in oncology clinics such as we have described, we hope to improve access to more equitable care for vulnerable veterans.

Veterans living with cancer need comprehensive assessment that includes supportive psychosocial care. The National Comprehensive Cancer Network (NCCN) and American College of Surgeons Commission on Cancer require accredited cancer centers to evaluate psychosocial distress and provide appropriate triage and treatment for all patients.^1-3 Implementing psychosocial distress screening can be difficult because of procedural barriers and time constraints, clinic and supportive care resources, and lack of knowledge about how to access supportive services.

Distress screening protocols must be designed to address the specific needs of each population. To improve screening for cancer-related distress, deliver effective supportive services, and gain agreement on distress screening standards of care, the Coleman Foundation supported development of the Coleman Supportive Oncology Collaborative (CSOC), a project of 135 interdisciplinary health care professionals from 25 Chicago-area cancer care institutions.⁴

The Jesse Brown US Department of Veterans Affairs (VA) Medical Center (JBVAMC) was chosen to assess cancer-related concerns among veterans using the CSOC screening tool and to improve access to supportive oncology. JBVAMC provides care to approximately 49,000 veterans in Chicago, Illinois, and northwestern Indiana. The JBVAMC patient population includes a large number of veterans with dual diagnoses (co-occurring substance use and mental health disorders) and veterans experiencing homelessness.

Delivering integrated screening and oncologic care that is culture and age appropriate is particularly important for veterans given their unique risk factors. The veteran population is considered vulnerable in terms of health status, psychological functioning, and social context. Veterans who use the VA health system as a principal source of care have poorer health, greater comorbid medical conditions, and an increased risk of mortality and suicide compared with the general population.^5,6 Poorer health status in veterans also may relate to old age, low income, poor education, psychological health, and minority race.^7-9

Past studies point to unique risk factors for cancer and poor cancer adjustment among veterans, which may complicate cancer treatment and end-of-life/survivorship care. Veteran-specific risk factors include military-related exposures, particularly Agent Orange and morbidity/mortality secondary to comorbid medical and psychiatric conditions (eg, chronic obstructive pulmonary disease, diabetes mellitus, and posttraumatic stress disorder [PTSD]).^10-12 Moreover, the geriatric veteran population continues to grow,with increasing rates of cancer that require unique considerations for effective cancer care.^13,14 Despite this, there are minimal data to inform best practices and supportive care approaches for veterans with cancer. Lack of guidelines specific to veterans and other populations with increased psychosocial challenges may impede successful cancer care, making distress screening procedures particularly important. This is especially the case for the JBVAMC, which serves primarily African American urban-dwelling veterans who experience high rates of cancer disparities, including increased rates of mortality and increased levels of psychosocial distress.^15,16

The goals of this program were to (1) examine levels of psychological, physical, financial, and treatment-related distress in a large sample of urban-dwelling veterans; (2) create a streamlined, sustainable process to screen a large number of veterans receiving cancer care in the outpatient setting and connect them with available supportive services; and (3) educate oncology physicians, nurses, and other staff about cancer-related distress and concerns using in-service trainings and interpersonal interactions to improve patient care. Our program was based on a Primary Care Mental Health Integration (PCMHI) model that embeds health psychologists in general medical clinics to better reach veterans dealing with mental health issues. We tailored for palliative care involvement.

Studies of this model have shown that mental health integration improves access to mental health services and mental health treatment outcomes and has higher patient and provider satisfaction.¹⁷ We were also influenced by the construct of the patient aligned care team (PACT) social worker who, in this veteran-centered approach, often functions as a care coordinator. Social work responsibilities include assessment of patients’ stressors including adjusting to the medical conditions, identifying untreated or undertreated mental health or substance abuse issues, economic instability, legal problems, and inadequate housing and transportation, which can often be exacerbated during cancer treatment.¹⁸

Methods

This institutional review board at JBVAMC reviewed and exempted this quality improvement program using the SQUIRE framework.¹⁹ It was led by a group of palliative care clinicians, psychologists, and administrators who have worked with the oncology service for many years, primarily in the care of hospitalized patients. Common palliative care services include providing care for patients with serious illness diagnosis through the illness trajectory.

Setting

At the start of this program, we assessed the current clinic workflow to determine how to best screen and assist veterans experiencing distress. We met with team members individually to identify the best method of clinic integration, including attending medical oncologists, medical oncology fellows, psychology interns, oncology nursing staff, the oncology nurse coordinator, and clinic clerks.

The JBVAMC provides cancer care through 4 half-day medical hematology-oncology clinics that serve about 50 patients per half-day clinic. The clinics are staffed by hematology-oncology fellows supervised by hematology-oncology attending physicians, who are affiliated with 2 academic medical centers. These clinics are staffed by 3 registered nurses (RNs) and a licensed practical nurse (LPN) and are adjacent to a chemotherapy infusion clinic with unique nursing staff. The JBVAMC also provides a variety of supportive care services, including extensive mental health and substance use treatment, physical and occupational therapy, acupuncture, nutrition, social work, and housing services. Following our assessment, it was evident that there were a low number of referrals from oncology clinics to supportive care services, mostly due to lack of knowledge of resources and unclear referral procedures.

Based on clinical volume, we determined that our screening program could best be implemented through a stepped approach beginning in one clinic and expanding thereafter. We began by having a palliative care physician and health psychology intern embedded in 1 weekly half-day clinic and a health psychology intern embedded in a second weekly half-day clinic. Our program included 2 health psychology interns (for each academic year of the program) who were supervised by a JBVA health psychologist.

About 15 months after successful integration within the first 2 half-day clinics, we expanded the screening program to staff an additional half-day medical oncology clinic with a palliative care APRN. This allowed us to expand the screening tool distribution and collection to 3 of 4 of the weekly half-day oncology clinics as well as to meet individually with veterans experiencing high levels of distress. Veterans were flagged as having high distress levels by either the results of their completed screening tool or by referral from a medical oncology physician. We initially established screening in clinics that were sufficiently staffed to ensure that screens were appropriately distributed and reviewed. Patients seen in nonparticipating clinics were referred to outpatient social work, mental health and/or outpatient palliative care according to oncology fellows’ clinical assessments of the patient. All oncology fellows received education about distress screening and methods for referring to supportive care. Our clinic screening program extended from February 2017 through January 2020.

Screening

Program staff screened patients with new cancer diagnoses, then identified patients for follow-up screens. This tracking allowed staff to identify patients with oncology appointments that day and cross-reference patients needing a follow-up screen.

Following feedback from the clinic nurses, we determined that nurses would provide the distress tool to patients in paper form after they completed their assessment of vitals and waited to be seen by their medical oncologist. The patient would then deliver their completed form to the nurse who would combine it with the patient’s clinic notes for the oncologist to review. Veterans who reported elevated 4-question Patient Health Questionnaire (PHQ-4) scores ≥ 6 were seen immediately by program staff. Veterans were referred to social work or psychiatry services for a same day visit if they endorsed a high level of psychological distress during clinical examination. They were referred for other supportive care services if they were determined to have practical, family, or nutrition unmet distress needs by either the program staff or oncology fellows. Program staff provided guidance to medical oncology fellows for needed referrals including social work, mental health, and palliative care follow ups (eAppendix A available at doi:10.12788/fp.0158).

Veterans referred for supportive care services were contacted by the relevant clinical administrator by phone to schedule an intake; for social work referrals, patients were either seen in a walk-in office located in a colocated building or contacted by a social worker by phone.

Our screening tool was the Coleman Foundation Supportive Oncology Collaborative Screening Tool, compiled from validated instruments. Patients completed this screening tool, which includes the PHQ-4, NCCN problem list concerns, adapted Mini Nutrition Assessment and PROMIS Pain and Fatigue measure (eAppendix B available at doi:10.12788/fp.0158).^20-22

We also worked with the VA Computerized Patient Record System (CPRS) to create an electronic template for the screening tool. Completed screening tools were manually entered by the physician, psychologists, or APRN into the CPRS chart.

We analyzed the different supportive care services available at the JBVAMC and noticed that many supportive services were available, yet these services were often separated. Therefore, we created a consult flowsheet to assist oncologists in placing referrals. These supportive care services include mental health services, a cancer support group, home health care, social services, nutrition, physical medicine and rehabilitation, and other specialty services.

Patient Education

The psychology and nursing staff created a patient information bulletin board where patients could access information about supportive services available at JBVAMC. This board required frequent replenishment of handouts because patients consulted the board regularly. Handouts and folders about common clinical issues also were placed in the clinic treatment rooms. We partnered with 2 local cancer support centers, Gilda’s Club and the Cancer Support Center, to make referrals for family members and/or caregivers who would benefit from additional support.

We provided in-service trainings for oncology fellows, including trainings on PTSD and substance abuse and their relationship to cancer care at the VA. These topics were chosen based on the feedback program staff received about perceived knowledge gaps from the oncology fellows. This program allowed for multiple informal conversations between that program staff and oncology fellows about overall patient care. We held trainings with the cancer coordinator and clinical nursing staff on strategies to identify and follow-up on cancer-related distress, and with oncology fellows to review the importance of distress screening and to instruct fellows on instructions for the consult flowsheet.

Funding

This program was funded by the Chicago-based Coleman Foundation as part of the CSOC. Funding was used to support a portion of time for administrative and clinical work of program staff, as well as data collection and analysis.

Results

We established 3 half-day integrated clinics where patients were screened and referred for services based on supportive oncology needs. In addition to our primary activities to screen and refer veterans, we held multiple educational sessions for colleagues, developed a workflow template, and integrated patient education materials into the clinics.

Screening

Veterans completed 1010 distress screens in 3 of 4 half-day oncology clinics over the 2.5-year project period. Veterans were screened at initial diagnosis and every 3 months, or during changes in their clinical care or disease status. As a result, 579 patients completed screening, with some patients doing several follow-up screens during their care. Integration of palliative care providers and health psychologists was instrumental in facilitating screening in these busy general medical oncology clinics. Most veterans were receptive to completing surveys with few refusing to fill out the survey.²³ Medical oncology fellows often used the completed screener to inform their review of systems (by reviewing the Coleman screener Physical and Other Concerns section) and connect with the supportive care staff present in clinic for patient’s identifying severe needs (ie, mental health distress or complex psychosocial needs). Veterans’ rates of distress needs and successfuloutcomes of integration with mental health and social work services have been reported elsewhere.²³

The mean (SD) age for veterans in this cohort was 72 (9.5) years. Participants were primarily African American veterans (70%), with mostly advanced disease (Table 1). Participants endorsed elevated distress needs compared with other patient populations screened in Chicago through the CSOC for depressed mood, pain, housing, transportation, and physical, nutrition, and treatment concerns.²³ Elevated presence of needs was especially prominent for food, housing and insurance/medical needs; physical concerns; nutrition, and treatment- or care-related concerns. Veterans in this cohort reported extensive financial and housing concerns: 10.4% reported food and housing concerns, 18.6% reported transportation concerns, and 9.0% reported issues paying for medical care or medications (Table 2).²⁰ Anecdotally, many experienced job loss or strain with their cancer diagnosis or were living at the poverty level before their diagnosis.

Discussion

This project created a successful program to screen veterans for psychosocial distress and triage them to appropriate services. During the project, patients in VA-outpatient oncology clinics reported significant cancer-related distress due to baseline psychosocial needs, changes in emotional and physical functioning, logistical and financial challenges of receiving cancer care, and lack of instrumental support.²³

Staff education supported successful buy-in, development and implementation of supportive oncology programs. We used a combination of in-service trainings, online trainings, and handouts to provide evidence for distress screening.²⁴ Highlighting the evidence-base that demonstrates how cancer-related distress screening improves cancer and quality of life outcomes helped to address physician reluctance to accept the additional requirements needed to address veterans’ psychosocial needs and care concerns. To increase buy-in and collaboration among team members and foster heightened understanding between providers and patients, we recommend creating accessible education for all staff levels.

One specific area of education we focused on was primary palliative care, which includes the core competencies of communication and symptom management recommended for generalists and specialists of all disciplines.²⁵ Program staff supported oncology fellows in developing their primary palliative care skills by being available to discuss basic symptom management and communication issues. VA cancer care programs could benefit from ongoing palliative care education of oncology staff to facilitate primary palliative care as well as earlier integration of secondary palliative care when needed.²⁶ Secondary palliative care or care provided directly by the palliative care team assists with complex symptom management or communication issues. For these needs, oncology fellows were encouraged to refer to either the palliative care staff available in one of the half-day clinics or to the outpatient palliative care clinic. As a unique strength, the VA allows veterans to receive concurrent cancer-directed therapy and hospice care, which enables earlier referrals to hospice care and higher quality end-of-life care and emphasizes the need for primary palliative care in oncology.^27,28

Integrating supportive oncology team members, such as licensed clinical social worker and psychology interns, was successful. This was modeled on the VA PACT, which focuses on prevention, health promotion, coordination and chronic disease management.²⁹ Social determinants of health have a major impact on health outcomes especially in veteran-specific and African American populations, making screening for distress critical.^30-32 The VA Office of Health Equity actively addresses health inequities by supporting initiation of screening programs for social determinants of health, including education, employment, exposure to abuse and violence, food insecurity, housing instability, legal needs, social isolation, transportation needs, and utility needs. This is especially needed for African-American individuals who are not only more likely to experience cancer, but also more likely to be negatively impacted by the consequences of cancer diagnosis/treatment, such as complications related to one’s job security, access to care, adverse effects, and other highly distressing needs.^33,34

Our program found that veterans with cancer often had concerns associated with food and housing insecurity, transportation and paying for medication or medical care, and screening allowed health care providers to detect and address these social determinants of health through referrals to VA and community-specific programs. Social workers integrated into VA cancer clinics are uniquely equipped to coordinate distress screening and support continuity of care by virtue of their training, connections to preexisting VA supportive services, and knowledge of community resources. This model could be used in other VA specialty clinics serving veterans with chronic illness and those with high levels of physical frailty.³⁵

Our ability to roll out distress screening was scaffolded by technological integration into existing VA systems (eg, screening results in CPRS and electronic referrals). Screening procedures could have been even more efficient with improved technology (Table 3). For example, technological limitations made it challenging to easily identify patients due for screening, requiring a cumbersome process of tracking, collecting and entering patients’ paper forms. Health care providers seeking to develop a distress screening program should consider investing in technology that allows for identification of patients requiring screening at a predetermined interval, completion of screening via tablet or personal device, integration of screening responses into the electronic health record, and automatic generation of notifications to the treating physician and appropriate support services.

Conclusions

Veterans with cancer benefited from enhanced screening and psychosocial service availability, similar to a PCMHI model. Robust screening programs helped advocate for veterans dealing with the effects of poverty through identification of need and referral to existing VA programs and services quickly and efficiently. Providing comprehensive care within ambulatory cancer clinics can address cancer-related distress and any potential barriers to care in real time. VA hospitals typically offer an array of supportive services to address veterans’ psychosocial needs, yet these services tend to be siloed. Integrated referrals can help to resolve such access barriers. Since many veterans with burdensome cancers are not able to see their VA primary care physician regularly, offering comprehensive care within medical oncology ensures complete and integrated care that includes psychosocial screening.

We believe that this program is an example of a mechanism for oncologists and palliative care clinicians to integrate their care in a way that identifies needs and triages services for vulnerable veterans. As colleagues have written, “it is fundamental to our commitment to veterans that we ensure comparable, high quality care regardless of a veteran’s gender, race, or where they live.^”34 Health care providers may underestimate the extensive change a cancer diagnosis can have on a patient’s quality of life. Cancer diagnosis and treatment have a large impact on all individuals, but this impact may be greater for individuals in poverty due to inability to work from home, inflexible work hours, and limited support structures. By creating screening programs with psychosocial integration in oncology clinics such as we have described, we hope to improve access to more equitable care for vulnerable veterans.

Known as the “6 rainbow herbicides,” based on their identifying color on storage containers, the United States widely deployed the herbicides agents orange, green, pink, purple, white, and blue during the Vietnam War to deny the enemy cover and destroy crops.¹ Unfortunately, all these herbicides were found to have contained some form of carcinogen. Agent Blue’s active ingredient consisted of sodium cacodylate trihydrate (C₂H₆AsNaO₂), a compound that is metabolized into the organic form of the carcinogen arsenic before eventually converting into its relatively less toxic inorganic form.² Agent Orange’s defoliating agent is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). All rainbow herbicides except Agent Blue were unintentionally contaminated with carcinogenic dioxins. Agent Blue contained the carcinogen cacodylic acid, an organoarsenic acid. Today, herbicides no longer contain polychlorinated dibenzo-p-dioxins such as TCDD or arsenic due to strict manufacturing restrictions.^2,3 In the treatment of veteran populations, knowledge of the 6 rainbow herbicides’ carcinogenic potential is important.

Between 1962 and 1971, the United States sprayed more than 45 million liters of Agent Orange on Vietnam and at least 366 kg of TCDD on South Vietnam.^1,4 However, because Agent Orange was not a known carcinogen during the Vietnam War, records of exposure are poor. Additionally, individuals in Vietnam during this period were not the only ones exposed to this carcinogen as Agent Orange also was sprayed in Thailand and Korea.⁵ Even today there are still locations in Vietnam where Agent Orange concentrations exceed internationally acceptable levels. The Da Nang, Bien Hoa, and Phu Cat airports in Vietnam have been found to have dioxin levels exceeding 1000 ppt (parts of dioxin per trillion parts of lipid) toxicity equivalence in the soil. Although the Vietnam government is working toward decontaminating these and many other dioxin hotspots, residents in these locations are exposed to higher than internationally acceptable levels of dioxin.⁶

Despite receiving less media attention, Vietnam War veterans and Vietnamese soldiers and civilians were exposed to significant amounts of arsenic-based Agent Blue. Arsenic is a compound which has no environmental half-life and is carcinogenic humans if inhaled or ingested.² Between 1962 and 1971, the United States distributed 7.8 million liters of Agent Blue containing 1,232,400 kg of arsenic across 300,000 hectares of rice paddies, 100,000 hectares of forest, and perimeters of all military bases during the Vietnam War.^2,5 According to a review by Saha and colleagues, lower levels of arsenic exposure are associated with acute and chronic diseases, including cancers, of all organ systems.⁷

The following case presentation involves a Vietnam War veteran aged 70 years who was exposed to Agent Orange and developed 3 primary cancers, including cutaneous large B-cell non-Hodgkin lymphoma (NHL), high-grade urothelial carcinoma, and anal carcinoma in situ. Epidemiologically, this is an uncommon occurrence as only 8% of cancer survivors in the United States have been diagnosed with > 1 cancer.⁸

With no family history of cancer, the development of multiple malignancies raises concern for a history of toxin exposure. This report of a Vietnam War veteran with multiple conditions found to be associated with Agent Orange exposure provides an opportunity to discuss the role this exposure may have on the development of a comprehensive list of medical conditions as described by the literature. Additionally, the potential contributions of other confounding toxin exposures such as cigarette smoking, excessive alcohol use, and potential Agent Blue exposure on our patients’ health will be discussed.

Case Presentation

A male aged 70 years with Stage IV primary cutaneous large B-cell NHL, incompletely resected high-grade urothelial cancer, carcinoma in situ of the anal canal, and peripheral arterial disease (PAD) presented to the primary care clinic at the Washington DC Veterans Affairs Medical Center (DCVAMC) with concern for left leg ischemia. He also reported 2 large telangiectasias on his back for 6 months accompanied by lymphadenopathy and intermittent night sweats.

He was last seen at the DCVAMC 15 months prior after his twelfth dose of rituximab treatment for NHL. However, the patient failed to return for completion of his treatment due to frustration with the lengthy chemotherapy and follow-up process. Additionally, the patient's history included 3 failed arterial stents with complete nonadherence to the prescribed clopidogrel, resulting in the failure of 3 more subsequent graft placements. On presentation, the patient continued to report nonadherence with the clopidogrel.

The patient’s medical history included coronary artery disease (CAD) status after 2 stents in the left anterior descending artery and 1 stent in the proximal circumflex artery placed 4 years prior. He also had a history of hypertension, type 2 diabetes mellitus (T2DM), amyloid light-chain (AL) amyloidosis, aortic aneurysm, cataracts, obesity, treated hepatitis B and C, and posttraumatic stress disorder. He had no family history of cancer or AL amyloidosis; however, he noted that he was estranged from his family.

His social history was notable for active cigarette smoking up to 3 packs per day for 40 years and consuming large quantities of alcohol—at one point as many as 20 beers per day over a period of 4.5 years. He had a distant history of cocaine use but no current use, which was supported with negative urinary toxicology screens for illicit drugs over the past year.

Our patient also reported a history of Agent Orange exposure. As an artilleryman in the US Army III Corps, he was deployed for about 1 year in the most heavily sprayed regions of Vietnam, including Bien Hua, Long Binh, Xuan Loc, and Camp Zion for about 2 to 4 months at each location.

Hospital Course

The patient was treated on an inpatient basis for expedited workup and treatment for his urothelial carcinoma, NHL, and ischemic limb. His urothelial carcinoma was successfully resected, and the telangiectasias on his back were biopsied and found to be consistent with his known cutaneous large B-cell NHL, for which plans to resume outpatient chemotherapy were made. The patient’s 3 arterial grafts in his left leg were confirmed to have failed, and the patient was counseled that he would soon likely require an amputation of his ischemic leg.

Discussion

We must rely on our patient’s historical recall as there are no widely available laboratory tests or physical examination findings to confirm and/or determine the magnitude of TCDD or arsenic exposure.^9-11

Exposures

The patient was stationed in Bien Hoa, the second highest dioxin-contaminated air base in Vietnam (Figure).⁶ Dioxin also is known to be a particularly persistent environmental pollutant, such that in January 2018, Bien Hoa was found to still have dioxin levels higher than what is considered internationally acceptable. In fact, these levels were deemed significant enough to lead the United States and Vietnamese government to sign a memorandum of intent to begin cleanup of this airport.⁶ TCDD is known to have a half-life of about 7.6 years, and its long half-life is mainly attributed to its slow elimination process from its stores within the liver and fat, consisting of passive excretion through the gut wall and slow metabolism by the liver.^12,13 Thus, as an artilleryman mainly operating 105 howitzers within the foliage of Vietnam, our patient was exposed not only to high levels of this persistent environmental pollutant on a daily basis, but this toxin likely remained within his system for many years after his return from Vietnam.

Our patient also had a convincing history for potential Agent Blue exposure through both inhalation and ingestion of contaminated food and water. Additionally, his description of deforestations occurring within a matter of days increased the level of suspicion for Agent Blue exposure. This is because Agent Blue was the herbicide of choice for missions requiring rapid deforestation, achieving defoliation as quickly as 1 to 2 days.¹⁴ Additionally, our patient was stationed within cities in southern Vietnam near Agent Blue hot spots, such as Da Nang and Saigon, and Agent Blue was sprayed along the perimeter of all military bases.²

Levels of Evidence

Using the Veterans and Agent Orange Update in 2018 as our guide, we reviewed the quality of evidence suggesting an association between many of our patient’s comorbidities to Agent Orange exposure.⁵ This publication categorizes the level of evidence for association between health conditions and Agent Orange exposure in 4 main categories (Table 1).

In the Veterans and Agent Orange Update, NHL notably has a sufficient level of evidence of association with Agent Orange exposure.⁵ Although our patient’s extensive history of polysubstance use confounds the effect Agent Orange may have had on his health, cutaneous large B-cell NHL is an interesting exception as literature does not support even a correlative link between smoking and excessive alcohol use with primary cutaneous large B-cell NHL. Several case-control studies have found little to no association with cigarette smoking and the large B-cell subtype of NHL.^15,16 Moreover, several studies have found that moderate- to-heavy alcohol use, especially beer, may have a protective effect against the development of NHL.¹⁷ Of note, our patient’s alcoholic beverage of choice was beer. Regarding our patient’s distant history of cocaine use, it has been reported that cocaine use, in the absence of an HIV infection, has not been found to increase the risk of developing NHL.¹⁸ Similarly, arsenic exposure has not been associated with NHL in the literature.^19,20

The 2018 update also upgraded bladder carcinoma from having inadequate or insufficient to a limited or suggestive level of evidence for association.⁵ However, our patient’s most significant risk factor for bladder cancer was smoking, with a meta-analysis of 430,000 patients reporting a risk ratio (RR) of 3.14 for current cigarette smokers.²¹ The patient’s arsenic exposure from Agent Blue also increased his risk of developing bladder cancer. Several studies suggest a strong association between environmental arsenic exposure and bladder cancer.^22-26 A 30-year meta-analysis of 40 studies by Saint-Jacques and colleagues reported that the incidence of bladder cancer was found to increase in a dose-dependent manner, with higher concentrations of arsenic contaminated wate, with incidence rising from 2.7 to 5.8 times as the amount of arsenic contamination water increased from 10 to 150 mg/L.

Our patient’s history is concerning for higher than average Agent Blue exposure compared with that of most Vietnam War veterans. Given the dose-dependent effect of arsenic on bladder cancer risk, both our patient’s history of smoking and Agent Blue exposure are risk factors in the development of his bladder cancer.²² These likely played a more significant role in his development of bladder cancer than did his Agent Orange exposure.

Finally, smoking is the most significant risk factor in our patient’s development of anal carcinoma in situ. The 2018 Agent Orange update does report limited/suggested evidence of no association between Agent Orange and anal carcinoma.⁵ It also is unknown whether Agent Blue exposure is a contributing cause to his development of anal carcinoma in situ.²⁷ However, current smokers are at significant risk of developing anal cancer independent of age.^28-30 Given our patient’s extensive smoking history, this is the most likely contributing factor.

Conclusions

This case describes a Vietnam War veteran with significant exposure to rainbow herbicides and considerable polysubstance who developed 3 primary cancers and several chronic medical conditions. His exposure to Agents Orange and Blue likely contributed to his medical problems, but these associations are confounded by his substance use, particularly cigarette smoking. Of all his comorbidities, our patient’s NHL is the condition most likely to be associated with his history of Agent Orange exposure. His Agent Blue exposure also increased his risk for developing bladder cancer, cardiovascular disease, and PAD.

This case also highlights the importance of evaluating Vietnam War veterans for rainbow herbicide exposure and the complexity associated with attributing diseases to these exposures. All veterans who served in the inland waterways of Vietnam between 1962 and 1975; in the Korean Demilitarized Zone between April 1, 1968 and August 31, 1971; or in Thailand between February 28, 1961 and May 7, 1975 were at risk of rainbow herbicide exposure. These veterans may not only be eligible for disability compensation but also should be screened for associated comorbidities as outlined by current research.⁴² We hope that this report will serve as an aid in achieving this mission.

Known as the “6 rainbow herbicides,” based on their identifying color on storage containers, the United States widely deployed the herbicides agents orange, green, pink, purple, white, and blue during the Vietnam War to deny the enemy cover and destroy crops.¹ Unfortunately, all these herbicides were found to have contained some form of carcinogen. Agent Blue’s active ingredient consisted of sodium cacodylate trihydrate (C₂H₆AsNaO₂), a compound that is metabolized into the organic form of the carcinogen arsenic before eventually converting into its relatively less toxic inorganic form.² Agent Orange’s defoliating agent is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). All rainbow herbicides except Agent Blue were unintentionally contaminated with carcinogenic dioxins. Agent Blue contained the carcinogen cacodylic acid, an organoarsenic acid. Today, herbicides no longer contain polychlorinated dibenzo-p-dioxins such as TCDD or arsenic due to strict manufacturing restrictions.^2,3 In the treatment of veteran populations, knowledge of the 6 rainbow herbicides’ carcinogenic potential is important.

Between 1962 and 1971, the United States sprayed more than 45 million liters of Agent Orange on Vietnam and at least 366 kg of TCDD on South Vietnam.^1,4 However, because Agent Orange was not a known carcinogen during the Vietnam War, records of exposure are poor. Additionally, individuals in Vietnam during this period were not the only ones exposed to this carcinogen as Agent Orange also was sprayed in Thailand and Korea.⁵ Even today there are still locations in Vietnam where Agent Orange concentrations exceed internationally acceptable levels. The Da Nang, Bien Hoa, and Phu Cat airports in Vietnam have been found to have dioxin levels exceeding 1000 ppt (parts of dioxin per trillion parts of lipid) toxicity equivalence in the soil. Although the Vietnam government is working toward decontaminating these and many other dioxin hotspots, residents in these locations are exposed to higher than internationally acceptable levels of dioxin.⁶

Despite receiving less media attention, Vietnam War veterans and Vietnamese soldiers and civilians were exposed to significant amounts of arsenic-based Agent Blue. Arsenic is a compound which has no environmental half-life and is carcinogenic humans if inhaled or ingested.² Between 1962 and 1971, the United States distributed 7.8 million liters of Agent Blue containing 1,232,400 kg of arsenic across 300,000 hectares of rice paddies, 100,000 hectares of forest, and perimeters of all military bases during the Vietnam War.^2,5 According to a review by Saha and colleagues, lower levels of arsenic exposure are associated with acute and chronic diseases, including cancers, of all organ systems.⁷

The following case presentation involves a Vietnam War veteran aged 70 years who was exposed to Agent Orange and developed 3 primary cancers, including cutaneous large B-cell non-Hodgkin lymphoma (NHL), high-grade urothelial carcinoma, and anal carcinoma in situ. Epidemiologically, this is an uncommon occurrence as only 8% of cancer survivors in the United States have been diagnosed with > 1 cancer.⁸

With no family history of cancer, the development of multiple malignancies raises concern for a history of toxin exposure. This report of a Vietnam War veteran with multiple conditions found to be associated with Agent Orange exposure provides an opportunity to discuss the role this exposure may have on the development of a comprehensive list of medical conditions as described by the literature. Additionally, the potential contributions of other confounding toxin exposures such as cigarette smoking, excessive alcohol use, and potential Agent Blue exposure on our patients’ health will be discussed.

Case Presentation

A male aged 70 years with Stage IV primary cutaneous large B-cell NHL, incompletely resected high-grade urothelial cancer, carcinoma in situ of the anal canal, and peripheral arterial disease (PAD) presented to the primary care clinic at the Washington DC Veterans Affairs Medical Center (DCVAMC) with concern for left leg ischemia. He also reported 2 large telangiectasias on his back for 6 months accompanied by lymphadenopathy and intermittent night sweats.

He was last seen at the DCVAMC 15 months prior after his twelfth dose of rituximab treatment for NHL. However, the patient failed to return for completion of his treatment due to frustration with the lengthy chemotherapy and follow-up process. Additionally, the patient's history included 3 failed arterial stents with complete nonadherence to the prescribed clopidogrel, resulting in the failure of 3 more subsequent graft placements. On presentation, the patient continued to report nonadherence with the clopidogrel.

The patient’s medical history included coronary artery disease (CAD) status after 2 stents in the left anterior descending artery and 1 stent in the proximal circumflex artery placed 4 years prior. He also had a history of hypertension, type 2 diabetes mellitus (T2DM), amyloid light-chain (AL) amyloidosis, aortic aneurysm, cataracts, obesity, treated hepatitis B and C, and posttraumatic stress disorder. He had no family history of cancer or AL amyloidosis; however, he noted that he was estranged from his family.

His social history was notable for active cigarette smoking up to 3 packs per day for 40 years and consuming large quantities of alcohol—at one point as many as 20 beers per day over a period of 4.5 years. He had a distant history of cocaine use but no current use, which was supported with negative urinary toxicology screens for illicit drugs over the past year.

Our patient also reported a history of Agent Orange exposure. As an artilleryman in the US Army III Corps, he was deployed for about 1 year in the most heavily sprayed regions of Vietnam, including Bien Hua, Long Binh, Xuan Loc, and Camp Zion for about 2 to 4 months at each location.

Hospital Course

The patient was treated on an inpatient basis for expedited workup and treatment for his urothelial carcinoma, NHL, and ischemic limb. His urothelial carcinoma was successfully resected, and the telangiectasias on his back were biopsied and found to be consistent with his known cutaneous large B-cell NHL, for which plans to resume outpatient chemotherapy were made. The patient’s 3 arterial grafts in his left leg were confirmed to have failed, and the patient was counseled that he would soon likely require an amputation of his ischemic leg.

Discussion

We must rely on our patient’s historical recall as there are no widely available laboratory tests or physical examination findings to confirm and/or determine the magnitude of TCDD or arsenic exposure.^9-11

Exposures

The patient was stationed in Bien Hoa, the second highest dioxin-contaminated air base in Vietnam (Figure).⁶ Dioxin also is known to be a particularly persistent environmental pollutant, such that in January 2018, Bien Hoa was found to still have dioxin levels higher than what is considered internationally acceptable. In fact, these levels were deemed significant enough to lead the United States and Vietnamese government to sign a memorandum of intent to begin cleanup of this airport.⁶ TCDD is known to have a half-life of about 7.6 years, and its long half-life is mainly attributed to its slow elimination process from its stores within the liver and fat, consisting of passive excretion through the gut wall and slow metabolism by the liver.^12,13 Thus, as an artilleryman mainly operating 105 howitzers within the foliage of Vietnam, our patient was exposed not only to high levels of this persistent environmental pollutant on a daily basis, but this toxin likely remained within his system for many years after his return from Vietnam.

Our patient also had a convincing history for potential Agent Blue exposure through both inhalation and ingestion of contaminated food and water. Additionally, his description of deforestations occurring within a matter of days increased the level of suspicion for Agent Blue exposure. This is because Agent Blue was the herbicide of choice for missions requiring rapid deforestation, achieving defoliation as quickly as 1 to 2 days.¹⁴ Additionally, our patient was stationed within cities in southern Vietnam near Agent Blue hot spots, such as Da Nang and Saigon, and Agent Blue was sprayed along the perimeter of all military bases.²

Levels of Evidence

Using the Veterans and Agent Orange Update in 2018 as our guide, we reviewed the quality of evidence suggesting an association between many of our patient’s comorbidities to Agent Orange exposure.⁵ This publication categorizes the level of evidence for association between health conditions and Agent Orange exposure in 4 main categories (Table 1).

In the Veterans and Agent Orange Update, NHL notably has a sufficient level of evidence of association with Agent Orange exposure.⁵ Although our patient’s extensive history of polysubstance use confounds the effect Agent Orange may have had on his health, cutaneous large B-cell NHL is an interesting exception as literature does not support even a correlative link between smoking and excessive alcohol use with primary cutaneous large B-cell NHL. Several case-control studies have found little to no association with cigarette smoking and the large B-cell subtype of NHL.^15,16 Moreover, several studies have found that moderate- to-heavy alcohol use, especially beer, may have a protective effect against the development of NHL.¹⁷ Of note, our patient’s alcoholic beverage of choice was beer. Regarding our patient’s distant history of cocaine use, it has been reported that cocaine use, in the absence of an HIV infection, has not been found to increase the risk of developing NHL.¹⁸ Similarly, arsenic exposure has not been associated with NHL in the literature.^19,20

The 2018 update also upgraded bladder carcinoma from having inadequate or insufficient to a limited or suggestive level of evidence for association.⁵ However, our patient’s most significant risk factor for bladder cancer was smoking, with a meta-analysis of 430,000 patients reporting a risk ratio (RR) of 3.14 for current cigarette smokers.²¹ The patient’s arsenic exposure from Agent Blue also increased his risk of developing bladder cancer. Several studies suggest a strong association between environmental arsenic exposure and bladder cancer.^22-26 A 30-year meta-analysis of 40 studies by Saint-Jacques and colleagues reported that the incidence of bladder cancer was found to increase in a dose-dependent manner, with higher concentrations of arsenic contaminated wate, with incidence rising from 2.7 to 5.8 times as the amount of arsenic contamination water increased from 10 to 150 mg/L.

Our patient’s history is concerning for higher than average Agent Blue exposure compared with that of most Vietnam War veterans. Given the dose-dependent effect of arsenic on bladder cancer risk, both our patient’s history of smoking and Agent Blue exposure are risk factors in the development of his bladder cancer.²² These likely played a more significant role in his development of bladder cancer than did his Agent Orange exposure.

Finally, smoking is the most significant risk factor in our patient’s development of anal carcinoma in situ. The 2018 Agent Orange update does report limited/suggested evidence of no association between Agent Orange and anal carcinoma.⁵ It also is unknown whether Agent Blue exposure is a contributing cause to his development of anal carcinoma in situ.²⁷ However, current smokers are at significant risk of developing anal cancer independent of age.^28-30 Given our patient’s extensive smoking history, this is the most likely contributing factor.

Conclusions

This case describes a Vietnam War veteran with significant exposure to rainbow herbicides and considerable polysubstance who developed 3 primary cancers and several chronic medical conditions. His exposure to Agents Orange and Blue likely contributed to his medical problems, but these associations are confounded by his substance use, particularly cigarette smoking. Of all his comorbidities, our patient’s NHL is the condition most likely to be associated with his history of Agent Orange exposure. His Agent Blue exposure also increased his risk for developing bladder cancer, cardiovascular disease, and PAD.

This case also highlights the importance of evaluating Vietnam War veterans for rainbow herbicide exposure and the complexity associated with attributing diseases to these exposures. All veterans who served in the inland waterways of Vietnam between 1962 and 1975; in the Korean Demilitarized Zone between April 1, 1968 and August 31, 1971; or in Thailand between February 28, 1961 and May 7, 1975 were at risk of rainbow herbicide exposure. These veterans may not only be eligible for disability compensation but also should be screened for associated comorbidities as outlined by current research.⁴² We hope that this report will serve as an aid in achieving this mission.

Known as the “6 rainbow herbicides,” based on their identifying color on storage containers, the United States widely deployed the herbicides agents orange, green, pink, purple, white, and blue during the Vietnam War to deny the enemy cover and destroy crops.¹ Unfortunately, all these herbicides were found to have contained some form of carcinogen. Agent Blue’s active ingredient consisted of sodium cacodylate trihydrate (C₂H₆AsNaO₂), a compound that is metabolized into the organic form of the carcinogen arsenic before eventually converting into its relatively less toxic inorganic form.² Agent Orange’s defoliating agent is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). All rainbow herbicides except Agent Blue were unintentionally contaminated with carcinogenic dioxins. Agent Blue contained the carcinogen cacodylic acid, an organoarsenic acid. Today, herbicides no longer contain polychlorinated dibenzo-p-dioxins such as TCDD or arsenic due to strict manufacturing restrictions.^2,3 In the treatment of veteran populations, knowledge of the 6 rainbow herbicides’ carcinogenic potential is important.

Between 1962 and 1971, the United States sprayed more than 45 million liters of Agent Orange on Vietnam and at least 366 kg of TCDD on South Vietnam.^1,4 However, because Agent Orange was not a known carcinogen during the Vietnam War, records of exposure are poor. Additionally, individuals in Vietnam during this period were not the only ones exposed to this carcinogen as Agent Orange also was sprayed in Thailand and Korea.⁵ Even today there are still locations in Vietnam where Agent Orange concentrations exceed internationally acceptable levels. The Da Nang, Bien Hoa, and Phu Cat airports in Vietnam have been found to have dioxin levels exceeding 1000 ppt (parts of dioxin per trillion parts of lipid) toxicity equivalence in the soil. Although the Vietnam government is working toward decontaminating these and many other dioxin hotspots, residents in these locations are exposed to higher than internationally acceptable levels of dioxin.⁶

Despite receiving less media attention, Vietnam War veterans and Vietnamese soldiers and civilians were exposed to significant amounts of arsenic-based Agent Blue. Arsenic is a compound which has no environmental half-life and is carcinogenic humans if inhaled or ingested.² Between 1962 and 1971, the United States distributed 7.8 million liters of Agent Blue containing 1,232,400 kg of arsenic across 300,000 hectares of rice paddies, 100,000 hectares of forest, and perimeters of all military bases during the Vietnam War.^2,5 According to a review by Saha and colleagues, lower levels of arsenic exposure are associated with acute and chronic diseases, including cancers, of all organ systems.⁷

The following case presentation involves a Vietnam War veteran aged 70 years who was exposed to Agent Orange and developed 3 primary cancers, including cutaneous large B-cell non-Hodgkin lymphoma (NHL), high-grade urothelial carcinoma, and anal carcinoma in situ. Epidemiologically, this is an uncommon occurrence as only 8% of cancer survivors in the United States have been diagnosed with > 1 cancer.⁸

With no family history of cancer, the development of multiple malignancies raises concern for a history of toxin exposure. This report of a Vietnam War veteran with multiple conditions found to be associated with Agent Orange exposure provides an opportunity to discuss the role this exposure may have on the development of a comprehensive list of medical conditions as described by the literature. Additionally, the potential contributions of other confounding toxin exposures such as cigarette smoking, excessive alcohol use, and potential Agent Blue exposure on our patients’ health will be discussed.

Case Presentation

A male aged 70 years with Stage IV primary cutaneous large B-cell NHL, incompletely resected high-grade urothelial cancer, carcinoma in situ of the anal canal, and peripheral arterial disease (PAD) presented to the primary care clinic at the Washington DC Veterans Affairs Medical Center (DCVAMC) with concern for left leg ischemia. He also reported 2 large telangiectasias on his back for 6 months accompanied by lymphadenopathy and intermittent night sweats.

He was last seen at the DCVAMC 15 months prior after his twelfth dose of rituximab treatment for NHL. However, the patient failed to return for completion of his treatment due to frustration with the lengthy chemotherapy and follow-up process. Additionally, the patient's history included 3 failed arterial stents with complete nonadherence to the prescribed clopidogrel, resulting in the failure of 3 more subsequent graft placements. On presentation, the patient continued to report nonadherence with the clopidogrel.

The patient’s medical history included coronary artery disease (CAD) status after 2 stents in the left anterior descending artery and 1 stent in the proximal circumflex artery placed 4 years prior. He also had a history of hypertension, type 2 diabetes mellitus (T2DM), amyloid light-chain (AL) amyloidosis, aortic aneurysm, cataracts, obesity, treated hepatitis B and C, and posttraumatic stress disorder. He had no family history of cancer or AL amyloidosis; however, he noted that he was estranged from his family.

His social history was notable for active cigarette smoking up to 3 packs per day for 40 years and consuming large quantities of alcohol—at one point as many as 20 beers per day over a period of 4.5 years. He had a distant history of cocaine use but no current use, which was supported with negative urinary toxicology screens for illicit drugs over the past year.

Our patient also reported a history of Agent Orange exposure. As an artilleryman in the US Army III Corps, he was deployed for about 1 year in the most heavily sprayed regions of Vietnam, including Bien Hua, Long Binh, Xuan Loc, and Camp Zion for about 2 to 4 months at each location.

Hospital Course

The patient was treated on an inpatient basis for expedited workup and treatment for his urothelial carcinoma, NHL, and ischemic limb. His urothelial carcinoma was successfully resected, and the telangiectasias on his back were biopsied and found to be consistent with his known cutaneous large B-cell NHL, for which plans to resume outpatient chemotherapy were made. The patient’s 3 arterial grafts in his left leg were confirmed to have failed, and the patient was counseled that he would soon likely require an amputation of his ischemic leg.

Discussion

We must rely on our patient’s historical recall as there are no widely available laboratory tests or physical examination findings to confirm and/or determine the magnitude of TCDD or arsenic exposure.^9-11

Exposures

The patient was stationed in Bien Hoa, the second highest dioxin-contaminated air base in Vietnam (Figure).⁶ Dioxin also is known to be a particularly persistent environmental pollutant, such that in January 2018, Bien Hoa was found to still have dioxin levels higher than what is considered internationally acceptable. In fact, these levels were deemed significant enough to lead the United States and Vietnamese government to sign a memorandum of intent to begin cleanup of this airport.⁶ TCDD is known to have a half-life of about 7.6 years, and its long half-life is mainly attributed to its slow elimination process from its stores within the liver and fat, consisting of passive excretion through the gut wall and slow metabolism by the liver.^12,13 Thus, as an artilleryman mainly operating 105 howitzers within the foliage of Vietnam, our patient was exposed not only to high levels of this persistent environmental pollutant on a daily basis, but this toxin likely remained within his system for many years after his return from Vietnam.

Our patient also had a convincing history for potential Agent Blue exposure through both inhalation and ingestion of contaminated food and water. Additionally, his description of deforestations occurring within a matter of days increased the level of suspicion for Agent Blue exposure. This is because Agent Blue was the herbicide of choice for missions requiring rapid deforestation, achieving defoliation as quickly as 1 to 2 days.¹⁴ Additionally, our patient was stationed within cities in southern Vietnam near Agent Blue hot spots, such as Da Nang and Saigon, and Agent Blue was sprayed along the perimeter of all military bases.²

Levels of Evidence

Using the Veterans and Agent Orange Update in 2018 as our guide, we reviewed the quality of evidence suggesting an association between many of our patient’s comorbidities to Agent Orange exposure.⁵ This publication categorizes the level of evidence for association between health conditions and Agent Orange exposure in 4 main categories (Table 1).

In the Veterans and Agent Orange Update, NHL notably has a sufficient level of evidence of association with Agent Orange exposure.⁵ Although our patient’s extensive history of polysubstance use confounds the effect Agent Orange may have had on his health, cutaneous large B-cell NHL is an interesting exception as literature does not support even a correlative link between smoking and excessive alcohol use with primary cutaneous large B-cell NHL. Several case-control studies have found little to no association with cigarette smoking and the large B-cell subtype of NHL.^15,16 Moreover, several studies have found that moderate- to-heavy alcohol use, especially beer, may have a protective effect against the development of NHL.¹⁷ Of note, our patient’s alcoholic beverage of choice was beer. Regarding our patient’s distant history of cocaine use, it has been reported that cocaine use, in the absence of an HIV infection, has not been found to increase the risk of developing NHL.¹⁸ Similarly, arsenic exposure has not been associated with NHL in the literature.^19,20

The 2018 update also upgraded bladder carcinoma from having inadequate or insufficient to a limited or suggestive level of evidence for association.⁵ However, our patient’s most significant risk factor for bladder cancer was smoking, with a meta-analysis of 430,000 patients reporting a risk ratio (RR) of 3.14 for current cigarette smokers.²¹ The patient’s arsenic exposure from Agent Blue also increased his risk of developing bladder cancer. Several studies suggest a strong association between environmental arsenic exposure and bladder cancer.^22-26 A 30-year meta-analysis of 40 studies by Saint-Jacques and colleagues reported that the incidence of bladder cancer was found to increase in a dose-dependent manner, with higher concentrations of arsenic contaminated wate, with incidence rising from 2.7 to 5.8 times as the amount of arsenic contamination water increased from 10 to 150 mg/L.

Our patient’s history is concerning for higher than average Agent Blue exposure compared with that of most Vietnam War veterans. Given the dose-dependent effect of arsenic on bladder cancer risk, both our patient’s history of smoking and Agent Blue exposure are risk factors in the development of his bladder cancer.²² These likely played a more significant role in his development of bladder cancer than did his Agent Orange exposure.

Finally, smoking is the most significant risk factor in our patient’s development of anal carcinoma in situ. The 2018 Agent Orange update does report limited/suggested evidence of no association between Agent Orange and anal carcinoma.⁵ It also is unknown whether Agent Blue exposure is a contributing cause to his development of anal carcinoma in situ.²⁷ However, current smokers are at significant risk of developing anal cancer independent of age.^28-30 Given our patient’s extensive smoking history, this is the most likely contributing factor.

Conclusions

This case describes a Vietnam War veteran with significant exposure to rainbow herbicides and considerable polysubstance who developed 3 primary cancers and several chronic medical conditions. His exposure to Agents Orange and Blue likely contributed to his medical problems, but these associations are confounded by his substance use, particularly cigarette smoking. Of all his comorbidities, our patient’s NHL is the condition most likely to be associated with his history of Agent Orange exposure. His Agent Blue exposure also increased his risk for developing bladder cancer, cardiovascular disease, and PAD.

This case also highlights the importance of evaluating Vietnam War veterans for rainbow herbicide exposure and the complexity associated with attributing diseases to these exposures. All veterans who served in the inland waterways of Vietnam between 1962 and 1975; in the Korean Demilitarized Zone between April 1, 1968 and August 31, 1971; or in Thailand between February 28, 1961 and May 7, 1975 were at risk of rainbow herbicide exposure. These veterans may not only be eligible for disability compensation but also should be screened for associated comorbidities as outlined by current research.⁴² We hope that this report will serve as an aid in achieving this mission.