Mixed Topics

Editor’s note: In this article, we present an archetypal ethics challenge in hospital medicine. The authors, members of the SHM’s Ethics Special Interest Group and clinical ethics consultants at their respective hospitals, will comment on the questions and practical approaches for hospitalists.

Ms. S, an 82-year-old woman with severe dementia, was initially hospitalized in the ICU with acute on chronic respiratory failure. Prior to admission, Ms. S lived with her daughter, who is her primary caregiver. Ms. S is able to say her daughter’s name, and answer “yes” and “no” to simple questions. She is bed bound, incontinent of urine and feces, and dependent on her daughter for all ADLs.

This admission, Ms. S has been re-intubated 4 times for recurrent respiratory failure. The nursing staff are distressed that she is suffering physically. Her daughter requests to continue all intensive, life-prolonging treatment including mechanical ventilation and artificial nutrition.

During sign out, your colleague remarks that his grandmother was in a similar situation and that his family chose to pursue comfort care. He questions whether Ms. S has any quality of life and asks if you think further intensive care is futile.

On your first day caring for Ms. S, you contact her primary care provider. Her PCP reports that Ms. S and her daughter completed an advance directive (AD) 10 years ago which documents a preference for all life prolonging treatment.
 

Question #1: What are the ethical challenges?

Dr. Chase: In caring for Ms. S, we face a common ethical challenge: how to respect the patient’s prior preferences (autonomy) when the currently requested treatments have diminishing benefits (beneficence) and escalating harms (non-maleficence). Life-prolonging care can have diminishing returns at the end of life. Ms. S’s loss of decision-making capacity adds a layer of complexity. Her AD was completed when she was able to consider decisions about her care, and she might make different decisions in her current state of health. Shared decision-making with a surrogate can be complicated by a surrogate’s anxiety with making life-altering decisions or their desire to avoid guilt or loneliness. Health care professionals face the limits of scientific knowledge in delivering accurate prognostic estimates, probabilities of recovery, and likelihood of benefit from interventions. In addition to the guideposts of ethical principles, some hospitals have policies which advise clinicians to avoid non-beneficial care.

Such situations are emotionally intense and can trigger distress among patients, families, caregivers and health care professionals. Conscious and unconscious bias about a patient’s perceived quality of life undermines equity and can play a role in our recommendations for patients of advanced age, with cognitive impairment, and those who live with a disability.
 

Question #2: How might you meet the patient’s medical needs in line with her goals?

Dr. Khawaja: In order to provide care consistent with the patient’s goals, the first step is to clarify these goals with Ms. S’s surrogate decision-maker, her daughter. In a previously autonomous but presently incapacitated patient, the previously expressed preferences in the form of a written AD should be respected. However, the AD is only a set of preferences completed at a particular time, not medical orders. The clinician and surrogate must consider how to apply the AD to the current clinical circumstances. The clinician should verify that the clinical circumstances specified in the AD have been met and evaluate if the patient’s preferences have changed since she originally completed the AD.

Surrogates are asked to use a Substituted Judgement Standard (i.e., what would the patient choose in this situation if known). This may differ from what the surrogate wants. If not known, surrogates are asked to use the Best Interest Standard (i.e., what would bring the most net benefit to the patient by weighing benefits and risks of treatment options). I often ask the surrogate, “Tell us about your loved one.” Or, “Knowing your loved one, what do you think would be the most important for her right now?”¹

I would also caution against bias in judging quality of life in patients with dementia, and using the term “futility,” as these concepts are inherently subjective. In general, when a colleague raises the issue of futility, I begin by asking, “…futile to achieve what goal?” That can help clarify some of the disagreement as some goals can be accomplished while others cannot.

Finally, I work to include other members of our team in these discussions. The distress of nurses, social workers, and others are important to acknowledge, validate, and involve in the problem-solving process.
 

Question #3: If you were Ms. S’s hospitalist, what would you do?

Dr. Khawaja: As the hospitalist caring for Ms. S, I would use the “four boxes” model as a helpful, clinically relevant and systematic approach to managing ethical concerns.²

This “four boxes” model gives us a practical framework to address these ethical principles by asking questions in four domains.

Medical indications: What is the nature of her current illness, and is it reversible or not? What is the probability of success of treatment options like mechanical ventilation? Are there adverse effects of treatment?

Patient preferences: Since Ms. S lacks capacity, does her daughter understand the benefits and burdens of treatment? What are the goals of treatment? Prolonging life? Minimizing discomfort? Spending time with loved ones? What burdens would the patient be willing to endure to reach her goals?

Quality of life: What would the patient’s quality of life be with and without the treatments?

Contextual features: My priorities would be building a relationship of trust with Ms. S’s daughter – by educating her about her mother’s clinical status, addressing her concerns and questions, and supporting her as we work through patient-centered decisions about what is best for her mother. Honest communication is a must, even if it means acknowledging uncertainties about the course of disease and prognosis.

These are not easy decisions for surrogates to make. They should be given time to process information and to make what they believe are the best decisions for their loved ones. It is critical for clinicians to provide honest and complete clinical information and to avoid value judgments, bias, or unreasonable time pressure. While one-on-one conversations are central, I find that multidisciplinary meetings allow all stakeholders to ask and answer vital questions and ideally to reach consensus in treatment planning.

Dr. Chase: In caring for Ms. S, I would use a structured approach to discussions with her daughter, such as the “SPIKES” protocol.³ Using open ended questions, I would ask about the patient’s and her daughter’s goals, values, and fears and provide support about the responsibility for shared-decision making and the difficulty of uncertainty. Reflecting statements can help in confirming understanding and showing attention (e.g. “I hear that avoiding discomfort would be important to your mother.”)

I find it helpful to emphasize my commitment to honesty and non-abandonment (a common fear among patients and families). By offering to provide recommendations about both disease-directed and palliative, comfort-focused interventions, the patient’s daughter has an opportunity to engage voluntarily in discussion. When asked about care that may have marginal benefit, I suggest time-limited trials.⁴ I do not offer non-beneficial treatments and if asked about such treatments, I note the underlying motive and why the treatment is not feasible (“I see that you are hoping that your mother will live longer, but I am concerned that tube feeding will not help because…”), offer preferable alternatives, and leave space for questions and emotions. It is important not to force a premature resolution of the situation through unilateral or coercive decisions⁵ (i.e., going off service does not mean I have to wrap up the existential crisis which is occurring.) A broader challenge is the grief and other emotions which accompany illness and death. I can neither prevent death nor grief, but I can offer my professional guidance and provide a supportive space for the patient and family to experience this transition. By acknowledging this, I center myself with the patient and family and we can work together toward a common goal of providing compassionate and ethical care.

Dr. Chase is associate professor, Department of Family and Community Medicine, University of California San Francisco; and co-chair, Ethics Committee, San Francisco General Hospital. Dr. Khawaja is assistant professor, Department of Internal Medicine, Baylor College of Medicine, Houston, and a member of the Ethics Committee of the Society of General Internal Medicine.

References

1. Sulmasy DP, Snyder L. Substituted interests and best judgments: an integrated model of surrogate decision making. JAMA. 2010 Nov 3;304(17):1946-7. doi: 10.1001/jama.2010.159.

2. Jonsen AR, Siegler M, Winslade WJ. Clinical ethics: A practical approach to ethical decisions in clinical medicine. 6th ed. New York: McGraw Hill Medical; 2006.

3. Baile WF, et al. SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer. Oncologist. 2000;5(4):302–311. doi: 10.1634/theoncologist.5-4-302.

4. Chang DW, et al. Evaluation of time-limited trials among critically ill patients with advanced medical illnesses and reduction of nonbeneficial ICU treatments. JAMA Intern Med. 2021;181(6):786–794. doi: 10.1001/jamainternmed.2021.1000.

5. Sedig, L. What’s the role of autonomy in patient-and family-centered care when patients and family members don’t agree? AMA J Ethics. 2016;18(1):12-17. doi: 10.1001/journalofethics.2017.18.1.ecas2-1601.

Editor’s note: In this article, we present an archetypal ethics challenge in hospital medicine. The authors, members of the SHM’s Ethics Special Interest Group and clinical ethics consultants at their respective hospitals, will comment on the questions and practical approaches for hospitalists.

Ms. S, an 82-year-old woman with severe dementia, was initially hospitalized in the ICU with acute on chronic respiratory failure. Prior to admission, Ms. S lived with her daughter, who is her primary caregiver. Ms. S is able to say her daughter’s name, and answer “yes” and “no” to simple questions. She is bed bound, incontinent of urine and feces, and dependent on her daughter for all ADLs.

This admission, Ms. S has been re-intubated 4 times for recurrent respiratory failure. The nursing staff are distressed that she is suffering physically. Her daughter requests to continue all intensive, life-prolonging treatment including mechanical ventilation and artificial nutrition.

During sign out, your colleague remarks that his grandmother was in a similar situation and that his family chose to pursue comfort care. He questions whether Ms. S has any quality of life and asks if you think further intensive care is futile.

On your first day caring for Ms. S, you contact her primary care provider. Her PCP reports that Ms. S and her daughter completed an advance directive (AD) 10 years ago which documents a preference for all life prolonging treatment.
 

Question #1: What are the ethical challenges?

Dr. Chase: In caring for Ms. S, we face a common ethical challenge: how to respect the patient’s prior preferences (autonomy) when the currently requested treatments have diminishing benefits (beneficence) and escalating harms (non-maleficence). Life-prolonging care can have diminishing returns at the end of life. Ms. S’s loss of decision-making capacity adds a layer of complexity. Her AD was completed when she was able to consider decisions about her care, and she might make different decisions in her current state of health. Shared decision-making with a surrogate can be complicated by a surrogate’s anxiety with making life-altering decisions or their desire to avoid guilt or loneliness. Health care professionals face the limits of scientific knowledge in delivering accurate prognostic estimates, probabilities of recovery, and likelihood of benefit from interventions. In addition to the guideposts of ethical principles, some hospitals have policies which advise clinicians to avoid non-beneficial care.

Such situations are emotionally intense and can trigger distress among patients, families, caregivers and health care professionals. Conscious and unconscious bias about a patient’s perceived quality of life undermines equity and can play a role in our recommendations for patients of advanced age, with cognitive impairment, and those who live with a disability.
 

Question #2: How might you meet the patient’s medical needs in line with her goals?

Dr. Khawaja: In order to provide care consistent with the patient’s goals, the first step is to clarify these goals with Ms. S’s surrogate decision-maker, her daughter. In a previously autonomous but presently incapacitated patient, the previously expressed preferences in the form of a written AD should be respected. However, the AD is only a set of preferences completed at a particular time, not medical orders. The clinician and surrogate must consider how to apply the AD to the current clinical circumstances. The clinician should verify that the clinical circumstances specified in the AD have been met and evaluate if the patient’s preferences have changed since she originally completed the AD.

Surrogates are asked to use a Substituted Judgement Standard (i.e., what would the patient choose in this situation if known). This may differ from what the surrogate wants. If not known, surrogates are asked to use the Best Interest Standard (i.e., what would bring the most net benefit to the patient by weighing benefits and risks of treatment options). I often ask the surrogate, “Tell us about your loved one.” Or, “Knowing your loved one, what do you think would be the most important for her right now?”¹

I would also caution against bias in judging quality of life in patients with dementia, and using the term “futility,” as these concepts are inherently subjective. In general, when a colleague raises the issue of futility, I begin by asking, “…futile to achieve what goal?” That can help clarify some of the disagreement as some goals can be accomplished while others cannot.

Finally, I work to include other members of our team in these discussions. The distress of nurses, social workers, and others are important to acknowledge, validate, and involve in the problem-solving process.
 

Question #3: If you were Ms. S’s hospitalist, what would you do?

Dr. Khawaja: As the hospitalist caring for Ms. S, I would use the “four boxes” model as a helpful, clinically relevant and systematic approach to managing ethical concerns.²

This “four boxes” model gives us a practical framework to address these ethical principles by asking questions in four domains.

Medical indications: What is the nature of her current illness, and is it reversible or not? What is the probability of success of treatment options like mechanical ventilation? Are there adverse effects of treatment?

Patient preferences: Since Ms. S lacks capacity, does her daughter understand the benefits and burdens of treatment? What are the goals of treatment? Prolonging life? Minimizing discomfort? Spending time with loved ones? What burdens would the patient be willing to endure to reach her goals?

Quality of life: What would the patient’s quality of life be with and without the treatments?

Contextual features: My priorities would be building a relationship of trust with Ms. S’s daughter – by educating her about her mother’s clinical status, addressing her concerns and questions, and supporting her as we work through patient-centered decisions about what is best for her mother. Honest communication is a must, even if it means acknowledging uncertainties about the course of disease and prognosis.

These are not easy decisions for surrogates to make. They should be given time to process information and to make what they believe are the best decisions for their loved ones. It is critical for clinicians to provide honest and complete clinical information and to avoid value judgments, bias, or unreasonable time pressure. While one-on-one conversations are central, I find that multidisciplinary meetings allow all stakeholders to ask and answer vital questions and ideally to reach consensus in treatment planning.

Dr. Chase: In caring for Ms. S, I would use a structured approach to discussions with her daughter, such as the “SPIKES” protocol.³ Using open ended questions, I would ask about the patient’s and her daughter’s goals, values, and fears and provide support about the responsibility for shared-decision making and the difficulty of uncertainty. Reflecting statements can help in confirming understanding and showing attention (e.g. “I hear that avoiding discomfort would be important to your mother.”)

I find it helpful to emphasize my commitment to honesty and non-abandonment (a common fear among patients and families). By offering to provide recommendations about both disease-directed and palliative, comfort-focused interventions, the patient’s daughter has an opportunity to engage voluntarily in discussion. When asked about care that may have marginal benefit, I suggest time-limited trials.⁴ I do not offer non-beneficial treatments and if asked about such treatments, I note the underlying motive and why the treatment is not feasible (“I see that you are hoping that your mother will live longer, but I am concerned that tube feeding will not help because…”), offer preferable alternatives, and leave space for questions and emotions. It is important not to force a premature resolution of the situation through unilateral or coercive decisions⁵ (i.e., going off service does not mean I have to wrap up the existential crisis which is occurring.) A broader challenge is the grief and other emotions which accompany illness and death. I can neither prevent death nor grief, but I can offer my professional guidance and provide a supportive space for the patient and family to experience this transition. By acknowledging this, I center myself with the patient and family and we can work together toward a common goal of providing compassionate and ethical care.

Dr. Chase is associate professor, Department of Family and Community Medicine, University of California San Francisco; and co-chair, Ethics Committee, San Francisco General Hospital. Dr. Khawaja is assistant professor, Department of Internal Medicine, Baylor College of Medicine, Houston, and a member of the Ethics Committee of the Society of General Internal Medicine.

References

1. Sulmasy DP, Snyder L. Substituted interests and best judgments: an integrated model of surrogate decision making. JAMA. 2010 Nov 3;304(17):1946-7. doi: 10.1001/jama.2010.159.

2. Jonsen AR, Siegler M, Winslade WJ. Clinical ethics: A practical approach to ethical decisions in clinical medicine. 6th ed. New York: McGraw Hill Medical; 2006.

3. Baile WF, et al. SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer. Oncologist. 2000;5(4):302–311. doi: 10.1634/theoncologist.5-4-302.

4. Chang DW, et al. Evaluation of time-limited trials among critically ill patients with advanced medical illnesses and reduction of nonbeneficial ICU treatments. JAMA Intern Med. 2021;181(6):786–794. doi: 10.1001/jamainternmed.2021.1000.

5. Sedig, L. What’s the role of autonomy in patient-and family-centered care when patients and family members don’t agree? AMA J Ethics. 2016;18(1):12-17. doi: 10.1001/journalofethics.2017.18.1.ecas2-1601.

Editor’s note: In this article, we present an archetypal ethics challenge in hospital medicine. The authors, members of the SHM’s Ethics Special Interest Group and clinical ethics consultants at their respective hospitals, will comment on the questions and practical approaches for hospitalists.

Ms. S, an 82-year-old woman with severe dementia, was initially hospitalized in the ICU with acute on chronic respiratory failure. Prior to admission, Ms. S lived with her daughter, who is her primary caregiver. Ms. S is able to say her daughter’s name, and answer “yes” and “no” to simple questions. She is bed bound, incontinent of urine and feces, and dependent on her daughter for all ADLs.

This admission, Ms. S has been re-intubated 4 times for recurrent respiratory failure. The nursing staff are distressed that she is suffering physically. Her daughter requests to continue all intensive, life-prolonging treatment including mechanical ventilation and artificial nutrition.

During sign out, your colleague remarks that his grandmother was in a similar situation and that his family chose to pursue comfort care. He questions whether Ms. S has any quality of life and asks if you think further intensive care is futile.

On your first day caring for Ms. S, you contact her primary care provider. Her PCP reports that Ms. S and her daughter completed an advance directive (AD) 10 years ago which documents a preference for all life prolonging treatment.
 

Question #1: What are the ethical challenges?

Dr. Chase: In caring for Ms. S, we face a common ethical challenge: how to respect the patient’s prior preferences (autonomy) when the currently requested treatments have diminishing benefits (beneficence) and escalating harms (non-maleficence). Life-prolonging care can have diminishing returns at the end of life. Ms. S’s loss of decision-making capacity adds a layer of complexity. Her AD was completed when she was able to consider decisions about her care, and she might make different decisions in her current state of health. Shared decision-making with a surrogate can be complicated by a surrogate’s anxiety with making life-altering decisions or their desire to avoid guilt or loneliness. Health care professionals face the limits of scientific knowledge in delivering accurate prognostic estimates, probabilities of recovery, and likelihood of benefit from interventions. In addition to the guideposts of ethical principles, some hospitals have policies which advise clinicians to avoid non-beneficial care.

Such situations are emotionally intense and can trigger distress among patients, families, caregivers and health care professionals. Conscious and unconscious bias about a patient’s perceived quality of life undermines equity and can play a role in our recommendations for patients of advanced age, with cognitive impairment, and those who live with a disability.
 

Question #2: How might you meet the patient’s medical needs in line with her goals?

Dr. Khawaja: In order to provide care consistent with the patient’s goals, the first step is to clarify these goals with Ms. S’s surrogate decision-maker, her daughter. In a previously autonomous but presently incapacitated patient, the previously expressed preferences in the form of a written AD should be respected. However, the AD is only a set of preferences completed at a particular time, not medical orders. The clinician and surrogate must consider how to apply the AD to the current clinical circumstances. The clinician should verify that the clinical circumstances specified in the AD have been met and evaluate if the patient’s preferences have changed since she originally completed the AD.

Surrogates are asked to use a Substituted Judgement Standard (i.e., what would the patient choose in this situation if known). This may differ from what the surrogate wants. If not known, surrogates are asked to use the Best Interest Standard (i.e., what would bring the most net benefit to the patient by weighing benefits and risks of treatment options). I often ask the surrogate, “Tell us about your loved one.” Or, “Knowing your loved one, what do you think would be the most important for her right now?”¹

I would also caution against bias in judging quality of life in patients with dementia, and using the term “futility,” as these concepts are inherently subjective. In general, when a colleague raises the issue of futility, I begin by asking, “…futile to achieve what goal?” That can help clarify some of the disagreement as some goals can be accomplished while others cannot.

Finally, I work to include other members of our team in these discussions. The distress of nurses, social workers, and others are important to acknowledge, validate, and involve in the problem-solving process.
 

Question #3: If you were Ms. S’s hospitalist, what would you do?

Dr. Khawaja: As the hospitalist caring for Ms. S, I would use the “four boxes” model as a helpful, clinically relevant and systematic approach to managing ethical concerns.²

This “four boxes” model gives us a practical framework to address these ethical principles by asking questions in four domains.

Medical indications: What is the nature of her current illness, and is it reversible or not? What is the probability of success of treatment options like mechanical ventilation? Are there adverse effects of treatment?

Patient preferences: Since Ms. S lacks capacity, does her daughter understand the benefits and burdens of treatment? What are the goals of treatment? Prolonging life? Minimizing discomfort? Spending time with loved ones? What burdens would the patient be willing to endure to reach her goals?

Quality of life: What would the patient’s quality of life be with and without the treatments?

Contextual features: My priorities would be building a relationship of trust with Ms. S’s daughter – by educating her about her mother’s clinical status, addressing her concerns and questions, and supporting her as we work through patient-centered decisions about what is best for her mother. Honest communication is a must, even if it means acknowledging uncertainties about the course of disease and prognosis.

These are not easy decisions for surrogates to make. They should be given time to process information and to make what they believe are the best decisions for their loved ones. It is critical for clinicians to provide honest and complete clinical information and to avoid value judgments, bias, or unreasonable time pressure. While one-on-one conversations are central, I find that multidisciplinary meetings allow all stakeholders to ask and answer vital questions and ideally to reach consensus in treatment planning.

Dr. Chase: In caring for Ms. S, I would use a structured approach to discussions with her daughter, such as the “SPIKES” protocol.³ Using open ended questions, I would ask about the patient’s and her daughter’s goals, values, and fears and provide support about the responsibility for shared-decision making and the difficulty of uncertainty. Reflecting statements can help in confirming understanding and showing attention (e.g. “I hear that avoiding discomfort would be important to your mother.”)

I find it helpful to emphasize my commitment to honesty and non-abandonment (a common fear among patients and families). By offering to provide recommendations about both disease-directed and palliative, comfort-focused interventions, the patient’s daughter has an opportunity to engage voluntarily in discussion. When asked about care that may have marginal benefit, I suggest time-limited trials.⁴ I do not offer non-beneficial treatments and if asked about such treatments, I note the underlying motive and why the treatment is not feasible (“I see that you are hoping that your mother will live longer, but I am concerned that tube feeding will not help because…”), offer preferable alternatives, and leave space for questions and emotions. It is important not to force a premature resolution of the situation through unilateral or coercive decisions⁵ (i.e., going off service does not mean I have to wrap up the existential crisis which is occurring.) A broader challenge is the grief and other emotions which accompany illness and death. I can neither prevent death nor grief, but I can offer my professional guidance and provide a supportive space for the patient and family to experience this transition. By acknowledging this, I center myself with the patient and family and we can work together toward a common goal of providing compassionate and ethical care.

Dr. Chase is associate professor, Department of Family and Community Medicine, University of California San Francisco; and co-chair, Ethics Committee, San Francisco General Hospital. Dr. Khawaja is assistant professor, Department of Internal Medicine, Baylor College of Medicine, Houston, and a member of the Ethics Committee of the Society of General Internal Medicine.

References

1. Sulmasy DP, Snyder L. Substituted interests and best judgments: an integrated model of surrogate decision making. JAMA. 2010 Nov 3;304(17):1946-7. doi: 10.1001/jama.2010.159.

2. Jonsen AR, Siegler M, Winslade WJ. Clinical ethics: A practical approach to ethical decisions in clinical medicine. 6th ed. New York: McGraw Hill Medical; 2006.

3. Baile WF, et al. SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer. Oncologist. 2000;5(4):302–311. doi: 10.1634/theoncologist.5-4-302.

4. Chang DW, et al. Evaluation of time-limited trials among critically ill patients with advanced medical illnesses and reduction of nonbeneficial ICU treatments. JAMA Intern Med. 2021;181(6):786–794. doi: 10.1001/jamainternmed.2021.1000.

5. Sedig, L. What’s the role of autonomy in patient-and family-centered care when patients and family members don’t agree? AMA J Ethics. 2016;18(1):12-17. doi: 10.1001/journalofethics.2017.18.1.ecas2-1601.

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

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

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

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

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

Complications or risk factors?

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

Dr. O. Joseph Bienvenu

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

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

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

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

Risks to mental health

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

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

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

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

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

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

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

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

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

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

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

Complications or risk factors?

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

Dr. O. Joseph Bienvenu

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

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

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

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

Risks to mental health

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

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

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

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

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

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

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

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

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

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

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

Complications or risk factors?

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

Dr. O. Joseph Bienvenu

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

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

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

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

Risks to mental health

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

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

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

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

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

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

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.

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.

Editor’s note: This article has been provided by The Doctors Company, the exclusively endorsed medical malpractice carrier for the Society of Hospital Medicine.

The Doctors Company

On April 5, 2021, a requirement of the 21st Century Cures Act went into effect: Patients must be able to access information in their EHRs “without delay.” (This requirement does not apply to paper records.) The Cures Act prohibition against information blocking, often referred to as an “open notes” provision, provides patients with transparency in the outcomes of their health care via convenient access to information in their EHR, which can positively or negatively impact the patient-doctor relationship.

Patient access to records is not new, and neither is the Cures Act, which dates to 2016. What is new is the requirement that patients have electronic records access that is fast and easy. This requirement is expected to result in more patients – still a small proportion overall, but more patients – accessing additional EHR information, including providers’ notes.

The requirement to provide patients with EHR access raises questions for health care practices. Some questions are logistical, and some are relational. Concerns include the potential for increased time for patient education, or patient requests for changes to their records that the clinician cannot support.

Health care providers should understand the good, bad, and ugly implications of the Cures Act open notes provisions so they can meet the requirements and reap their benefits, while avoiding the potential for fines or sanctions based on noncompliance, or other negative impacts.
 

Good news about open notes

Many patients feel better about their provider after reading a note. Positive effects on the patient-provider relationship may be most significant among vulnerable patients, such as those with fewer years of formal education.

Further, open notes have positive impacts on patient engagement and understanding. Patients report that reading notes is a way to better understand and feel more in control of their health care. They also say it builds trust with their provider. The nonprofit organization OpenNotes (not a part of the Cures Act) cites helping laypeople maintain trust in scientific medicine as one benefit of the transparency created by the Cures Act open notes provisions.
 

Bad news about open notes

Concerns about open notes mainly revolve around the potential for conflicts with patients and potential time conflicts.

Concerns include:

• Timing: The originally planned implementation date for the open notes provisions in the Cures Act was November 2020. Because of the COVID-19 pandemic, this was pushed back to April 2021. However, many providers and practices are still feeling the pandemic’s effects, leading to the question: “Will new demands never end?”
• Uncertainty about the documentation process: Most patients will not understand clinical shorthand, and providers may need added time for explanation. Providers are wondering: “How can I make my notes comprehensible to patients while still writing them quickly?”
• Technology: Some EHR vendors are still racing to provide services that allow practices to remain in compliance with the Cures Act. It may be necessary for a provider to call their EHR vendor and say: “What are you doing to ensure my interoperability compliance?” Meanwhile, secure drop box options for records requests provide a workaround.

Ugly news about open notes

Some patient requests for record amendment are legitimate and easily handled. Some patients, however, will request removal of material they find embarrassing, even though it is accurate.

More frequent requests for records changes from patients could increase already weighty administrative burdens on providers. Worse, some of these requests will be for changes providers cannot support, and making time for careful conversations with patients and providing written responses for requests that are rejected will be a challenge. Inevitably, some of these conversations will not go well, whether through the patient feeling the provider did not adequately respond to their concerns, or through the patient insisting on unreasonable demands. These negative relationship outcomes will add emotional stress on both the patient and the provider, as well as a reputational threat to providers from angry patients posting negative reviews online.

More tangibly, noncompliance with the open notes requirement carries the potential for fines, penalties, and/or sanctions from medical boards. The specifics of potential penalties are not yet known – there are more changes coming with the Cures Act.
 

Making changes in open notes

Patients will ask providers to amend their medical records. Be familiar with what the patient has the right to ask, what the provider can grant and/or refuse, and how to amend notes.

Here are some highlights:

• Patients have the right to request amendments to their medical records: HIPAA requires a signed, dated request from the patient regarding what they want changed and why.
• Providers have the right to determine whether the requested amendment will be made: The provider must respond, in writing, within 60 days of receipt of the patient’s request.
• Common reasons to deny a patient’s request include that the provider who received the request did not create the record entry, or that the medical record is accurate as is.
• The patient’s request and the provider’s response both become part of the patient’s medical record.

Strategies for success

When composing notes, certain simple strategies will raise the odds that notes will be well understood and well received. Beyond being clear and succinct, strategies for success include composing at least a portion of the note as instructions directly addressed to the patient – “Start taking lisinopril and check your blood pressure twice a week” versus “Initiated lisinopril and instructed her to check her blood pressure twice a week” – and providing a list of commonly used medical terms and abbreviations.

For an in-depth review of strategies for success when composing notes, see “12 Strategies for Success With Open Notes in Healthcare: The Cures Act.”
 

Exceptions

Unless an exception applies, clinical notes must not be blocked, but the Cures Act allows for a fairly long list of specific, well-delineated exceptions. For instance, a record can be blocked if a provider believes that viewing a note presents a substantial risk of harm to the physical safety of the patient or someone else. The Cures Act also recognizes exemptions that apply to certain caregiving situations, such as when parents attempt to access confidential parts of an adolescent child’s records.

For information regarding exceptions to open notes, please see “What Open Notes Exceptions Does the Cures Act Allow?”
 

Seeing open notes as part of high-touch, high-value care

While many physicians and other providers have anticipated open notes with dread, most outcomes so far have been positive. Patients have reacted well to clarity. They have used open notes as a tool to improve their own understanding of and adherence to care instructions. When patients have noted valid issues or miscommunications, they have appreciated being able to quickly clear them up. More than an administrative burden, open notes present an opportunity to improve documentation, patient-provider relationships, and patient safety. By improving patient adherence to treatment plans, open notes have the potential to improve provider satisfaction, as well.

Chad Anguilm, MBA, is vice president, in-practice technology services, Medical Advantage, part of TDC Group. Richard F. Cahill, JD, is vice president and associate general counsel, The Doctors Company, part of TDC Group. Kathleen Stillwell, MPA/HSA, RN, is senior patient safety risk manager, The Doctors Company, part of TDC Group.

Editor’s note: This article has been provided by The Doctors Company, the exclusively endorsed medical malpractice carrier for the Society of Hospital Medicine.

The Doctors Company

On April 5, 2021, a requirement of the 21st Century Cures Act went into effect: Patients must be able to access information in their EHRs “without delay.” (This requirement does not apply to paper records.) The Cures Act prohibition against information blocking, often referred to as an “open notes” provision, provides patients with transparency in the outcomes of their health care via convenient access to information in their EHR, which can positively or negatively impact the patient-doctor relationship.

Patient access to records is not new, and neither is the Cures Act, which dates to 2016. What is new is the requirement that patients have electronic records access that is fast and easy. This requirement is expected to result in more patients – still a small proportion overall, but more patients – accessing additional EHR information, including providers’ notes.

The requirement to provide patients with EHR access raises questions for health care practices. Some questions are logistical, and some are relational. Concerns include the potential for increased time for patient education, or patient requests for changes to their records that the clinician cannot support.

Health care providers should understand the good, bad, and ugly implications of the Cures Act open notes provisions so they can meet the requirements and reap their benefits, while avoiding the potential for fines or sanctions based on noncompliance, or other negative impacts.
 

Good news about open notes

Many patients feel better about their provider after reading a note. Positive effects on the patient-provider relationship may be most significant among vulnerable patients, such as those with fewer years of formal education.

Further, open notes have positive impacts on patient engagement and understanding. Patients report that reading notes is a way to better understand and feel more in control of their health care. They also say it builds trust with their provider. The nonprofit organization OpenNotes (not a part of the Cures Act) cites helping laypeople maintain trust in scientific medicine as one benefit of the transparency created by the Cures Act open notes provisions.
 

Bad news about open notes

Concerns about open notes mainly revolve around the potential for conflicts with patients and potential time conflicts.

Concerns include:

• Timing: The originally planned implementation date for the open notes provisions in the Cures Act was November 2020. Because of the COVID-19 pandemic, this was pushed back to April 2021. However, many providers and practices are still feeling the pandemic’s effects, leading to the question: “Will new demands never end?”
• Uncertainty about the documentation process: Most patients will not understand clinical shorthand, and providers may need added time for explanation. Providers are wondering: “How can I make my notes comprehensible to patients while still writing them quickly?”
• Technology: Some EHR vendors are still racing to provide services that allow practices to remain in compliance with the Cures Act. It may be necessary for a provider to call their EHR vendor and say: “What are you doing to ensure my interoperability compliance?” Meanwhile, secure drop box options for records requests provide a workaround.

Ugly news about open notes

Some patient requests for record amendment are legitimate and easily handled. Some patients, however, will request removal of material they find embarrassing, even though it is accurate.

More frequent requests for records changes from patients could increase already weighty administrative burdens on providers. Worse, some of these requests will be for changes providers cannot support, and making time for careful conversations with patients and providing written responses for requests that are rejected will be a challenge. Inevitably, some of these conversations will not go well, whether through the patient feeling the provider did not adequately respond to their concerns, or through the patient insisting on unreasonable demands. These negative relationship outcomes will add emotional stress on both the patient and the provider, as well as a reputational threat to providers from angry patients posting negative reviews online.

More tangibly, noncompliance with the open notes requirement carries the potential for fines, penalties, and/or sanctions from medical boards. The specifics of potential penalties are not yet known – there are more changes coming with the Cures Act.
 

Making changes in open notes

Patients will ask providers to amend their medical records. Be familiar with what the patient has the right to ask, what the provider can grant and/or refuse, and how to amend notes.

Here are some highlights:

• Patients have the right to request amendments to their medical records: HIPAA requires a signed, dated request from the patient regarding what they want changed and why.
• Providers have the right to determine whether the requested amendment will be made: The provider must respond, in writing, within 60 days of receipt of the patient’s request.
• Common reasons to deny a patient’s request include that the provider who received the request did not create the record entry, or that the medical record is accurate as is.
• The patient’s request and the provider’s response both become part of the patient’s medical record.

Strategies for success

When composing notes, certain simple strategies will raise the odds that notes will be well understood and well received. Beyond being clear and succinct, strategies for success include composing at least a portion of the note as instructions directly addressed to the patient – “Start taking lisinopril and check your blood pressure twice a week” versus “Initiated lisinopril and instructed her to check her blood pressure twice a week” – and providing a list of commonly used medical terms and abbreviations.

For an in-depth review of strategies for success when composing notes, see “12 Strategies for Success With Open Notes in Healthcare: The Cures Act.”
 

Exceptions

Unless an exception applies, clinical notes must not be blocked, but the Cures Act allows for a fairly long list of specific, well-delineated exceptions. For instance, a record can be blocked if a provider believes that viewing a note presents a substantial risk of harm to the physical safety of the patient or someone else. The Cures Act also recognizes exemptions that apply to certain caregiving situations, such as when parents attempt to access confidential parts of an adolescent child’s records.

For information regarding exceptions to open notes, please see “What Open Notes Exceptions Does the Cures Act Allow?”
 

Seeing open notes as part of high-touch, high-value care

While many physicians and other providers have anticipated open notes with dread, most outcomes so far have been positive. Patients have reacted well to clarity. They have used open notes as a tool to improve their own understanding of and adherence to care instructions. When patients have noted valid issues or miscommunications, they have appreciated being able to quickly clear them up. More than an administrative burden, open notes present an opportunity to improve documentation, patient-provider relationships, and patient safety. By improving patient adherence to treatment plans, open notes have the potential to improve provider satisfaction, as well.

Chad Anguilm, MBA, is vice president, in-practice technology services, Medical Advantage, part of TDC Group. Richard F. Cahill, JD, is vice president and associate general counsel, The Doctors Company, part of TDC Group. Kathleen Stillwell, MPA/HSA, RN, is senior patient safety risk manager, The Doctors Company, part of TDC Group.

Editor’s note: This article has been provided by The Doctors Company, the exclusively endorsed medical malpractice carrier for the Society of Hospital Medicine.

The Doctors Company

On April 5, 2021, a requirement of the 21st Century Cures Act went into effect: Patients must be able to access information in their EHRs “without delay.” (This requirement does not apply to paper records.) The Cures Act prohibition against information blocking, often referred to as an “open notes” provision, provides patients with transparency in the outcomes of their health care via convenient access to information in their EHR, which can positively or negatively impact the patient-doctor relationship.

Patient access to records is not new, and neither is the Cures Act, which dates to 2016. What is new is the requirement that patients have electronic records access that is fast and easy. This requirement is expected to result in more patients – still a small proportion overall, but more patients – accessing additional EHR information, including providers’ notes.

The requirement to provide patients with EHR access raises questions for health care practices. Some questions are logistical, and some are relational. Concerns include the potential for increased time for patient education, or patient requests for changes to their records that the clinician cannot support.

Health care providers should understand the good, bad, and ugly implications of the Cures Act open notes provisions so they can meet the requirements and reap their benefits, while avoiding the potential for fines or sanctions based on noncompliance, or other negative impacts.
 

Good news about open notes

Many patients feel better about their provider after reading a note. Positive effects on the patient-provider relationship may be most significant among vulnerable patients, such as those with fewer years of formal education.

Further, open notes have positive impacts on patient engagement and understanding. Patients report that reading notes is a way to better understand and feel more in control of their health care. They also say it builds trust with their provider. The nonprofit organization OpenNotes (not a part of the Cures Act) cites helping laypeople maintain trust in scientific medicine as one benefit of the transparency created by the Cures Act open notes provisions.
 

Bad news about open notes

Concerns about open notes mainly revolve around the potential for conflicts with patients and potential time conflicts.

Concerns include:

• Timing: The originally planned implementation date for the open notes provisions in the Cures Act was November 2020. Because of the COVID-19 pandemic, this was pushed back to April 2021. However, many providers and practices are still feeling the pandemic’s effects, leading to the question: “Will new demands never end?”
• Uncertainty about the documentation process: Most patients will not understand clinical shorthand, and providers may need added time for explanation. Providers are wondering: “How can I make my notes comprehensible to patients while still writing them quickly?”
• Technology: Some EHR vendors are still racing to provide services that allow practices to remain in compliance with the Cures Act. It may be necessary for a provider to call their EHR vendor and say: “What are you doing to ensure my interoperability compliance?” Meanwhile, secure drop box options for records requests provide a workaround.

Ugly news about open notes

Some patient requests for record amendment are legitimate and easily handled. Some patients, however, will request removal of material they find embarrassing, even though it is accurate.

More frequent requests for records changes from patients could increase already weighty administrative burdens on providers. Worse, some of these requests will be for changes providers cannot support, and making time for careful conversations with patients and providing written responses for requests that are rejected will be a challenge. Inevitably, some of these conversations will not go well, whether through the patient feeling the provider did not adequately respond to their concerns, or through the patient insisting on unreasonable demands. These negative relationship outcomes will add emotional stress on both the patient and the provider, as well as a reputational threat to providers from angry patients posting negative reviews online.

More tangibly, noncompliance with the open notes requirement carries the potential for fines, penalties, and/or sanctions from medical boards. The specifics of potential penalties are not yet known – there are more changes coming with the Cures Act.
 

Making changes in open notes

Patients will ask providers to amend their medical records. Be familiar with what the patient has the right to ask, what the provider can grant and/or refuse, and how to amend notes.

Here are some highlights:

• Patients have the right to request amendments to their medical records: HIPAA requires a signed, dated request from the patient regarding what they want changed and why.
• Providers have the right to determine whether the requested amendment will be made: The provider must respond, in writing, within 60 days of receipt of the patient’s request.
• Common reasons to deny a patient’s request include that the provider who received the request did not create the record entry, or that the medical record is accurate as is.
• The patient’s request and the provider’s response both become part of the patient’s medical record.

Strategies for success

When composing notes, certain simple strategies will raise the odds that notes will be well understood and well received. Beyond being clear and succinct, strategies for success include composing at least a portion of the note as instructions directly addressed to the patient – “Start taking lisinopril and check your blood pressure twice a week” versus “Initiated lisinopril and instructed her to check her blood pressure twice a week” – and providing a list of commonly used medical terms and abbreviations.

For an in-depth review of strategies for success when composing notes, see “12 Strategies for Success With Open Notes in Healthcare: The Cures Act.”
 

Exceptions

Unless an exception applies, clinical notes must not be blocked, but the Cures Act allows for a fairly long list of specific, well-delineated exceptions. For instance, a record can be blocked if a provider believes that viewing a note presents a substantial risk of harm to the physical safety of the patient or someone else. The Cures Act also recognizes exemptions that apply to certain caregiving situations, such as when parents attempt to access confidential parts of an adolescent child’s records.

For information regarding exceptions to open notes, please see “What Open Notes Exceptions Does the Cures Act Allow?”
 

Seeing open notes as part of high-touch, high-value care

While many physicians and other providers have anticipated open notes with dread, most outcomes so far have been positive. Patients have reacted well to clarity. They have used open notes as a tool to improve their own understanding of and adherence to care instructions. When patients have noted valid issues or miscommunications, they have appreciated being able to quickly clear them up. More than an administrative burden, open notes present an opportunity to improve documentation, patient-provider relationships, and patient safety. By improving patient adherence to treatment plans, open notes have the potential to improve provider satisfaction, as well.

Chad Anguilm, MBA, is vice president, in-practice technology services, Medical Advantage, part of TDC Group. Richard F. Cahill, JD, is vice president and associate general counsel, The Doctors Company, part of TDC Group. Kathleen Stillwell, MPA/HSA, RN, is senior patient safety risk manager, The Doctors Company, part of TDC Group.

The American Society for Clinical Pathology (ASCP), which represents over 100,000 pathologists and medical laboratory professionals, has called for a nationwide vaccination mandate. It is the first medical specialty society to do so, ASCP chief executive officer Blair Holladay, PhD, said in an interview.

However, the American Lung Association this week said it supports President Biden’s call for businesses to require their employees to be vaccinated. In addition, more than 50 medical societies, including ASCP, recently said they support vaccination mandates for health care workers.

In a position statement released Wednesday, ASCP recommended that every eligible American be vaccinated. “The U.S. Food and Drug Administration is soon expected to fully approve at least one COVID-19 vaccine, and when it does, we urge that vaccination requirements become the norm,” the society said.

Second, ASCP noted that at least 16 states have enacted some form of a ban on COVID-19 vaccine mandates or related requirements. These include blocking employment-based mandates, school vaccination or mask requirements, and vaccine passport requirements.

“These laws prolong the pandemic and threaten the health and safety of every American. They should be repealed or overturned immediately,” the association stated.

Third, ASCP said, it supports the guidance of the Centers for Disease Control and Prevention that masks should be worn indoors in public places in areas of substantial or high COVID-19 transmission.

“Before more people die, our elected leaders need to take serious and aggressive action to ensure that Americans get vaccinated, so we can end the pandemic, end patient and family suffering, end the fatalities, and get back to the lives we had before COVID-19,” the statement concluded.
 

Laboratories have to focus on COVID again

In his interview, Dr. Holladay noted that the eruption of the Delta variant across the country has again forced laboratories to focus on COVID-19 testing at the expense of necessary tests related to other diseases.

“Because 7 of 10 medical decisions depend on the laboratory, anything that interferes with that interferes with the needs of patient care, including preventive, chronic, and acute care services,” he said.

This is a major reason, he said, for ASCP to support a national vaccination mandate. “People have postponed treatment because of the inability to access medical care [for other conditions],” he noted. The same is true for preventive or diagnostic care such as biopsies for breast cancer and colonoscopies, he added.

“In many parts of the country, the throughput of COVID tests made it difficult for us to focus on tests for other acute conditions. It overwhelmed the laboratory personnel in terms of the number of tests being run.”
 

Returning to the ‘dark days’

This was a significant issue in the earlier part of the pandemic, Dr. Holladay recalled. The shortage of non-COVID lab capacity eased in the spring and early summer of 2021, when COVID-19 vaccines became widely available.

“But with the Delta variant, we’re going back to those dark days and creating the same bottleneck that we saw in the beginning,” he said.

Although the situation is worse in some states than others, Dr. Holladay added, some of the hardest-hit states like Florida and Texas have very large populations.

“This is not just about doctors, nurses, pathologists, and laboratory personnel being exhausted,” commented Kimberly Sanford, MD, president of ASCP, in a press release. “Laboratory medicine is absolutely necessary for accurate and timely diagnosis of disease, infection control, and effective treatment planning. It is an essential part of the health care system and often overwhelmed by the increasing number of coronavirus tests requiring immediate analysis.

“Such testing takes time and disproportionately consumes scarce equipment and other resources. It means those with cancer and other life-threatening conditions face serious delays in diagnosis and treatment. It delays medical diagnoses, erects barriers to preventative care, and prevents us from focusing on the significant health care needs of the population at large.”

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

The American Society for Clinical Pathology (ASCP), which represents over 100,000 pathologists and medical laboratory professionals, has called for a nationwide vaccination mandate. It is the first medical specialty society to do so, ASCP chief executive officer Blair Holladay, PhD, said in an interview.

However, the American Lung Association this week said it supports President Biden’s call for businesses to require their employees to be vaccinated. In addition, more than 50 medical societies, including ASCP, recently said they support vaccination mandates for health care workers.

In a position statement released Wednesday, ASCP recommended that every eligible American be vaccinated. “The U.S. Food and Drug Administration is soon expected to fully approve at least one COVID-19 vaccine, and when it does, we urge that vaccination requirements become the norm,” the society said.

Second, ASCP noted that at least 16 states have enacted some form of a ban on COVID-19 vaccine mandates or related requirements. These include blocking employment-based mandates, school vaccination or mask requirements, and vaccine passport requirements.

“These laws prolong the pandemic and threaten the health and safety of every American. They should be repealed or overturned immediately,” the association stated.

Third, ASCP said, it supports the guidance of the Centers for Disease Control and Prevention that masks should be worn indoors in public places in areas of substantial or high COVID-19 transmission.

“Before more people die, our elected leaders need to take serious and aggressive action to ensure that Americans get vaccinated, so we can end the pandemic, end patient and family suffering, end the fatalities, and get back to the lives we had before COVID-19,” the statement concluded.
 

Laboratories have to focus on COVID again

In his interview, Dr. Holladay noted that the eruption of the Delta variant across the country has again forced laboratories to focus on COVID-19 testing at the expense of necessary tests related to other diseases.

“Because 7 of 10 medical decisions depend on the laboratory, anything that interferes with that interferes with the needs of patient care, including preventive, chronic, and acute care services,” he said.

This is a major reason, he said, for ASCP to support a national vaccination mandate. “People have postponed treatment because of the inability to access medical care [for other conditions],” he noted. The same is true for preventive or diagnostic care such as biopsies for breast cancer and colonoscopies, he added.

“In many parts of the country, the throughput of COVID tests made it difficult for us to focus on tests for other acute conditions. It overwhelmed the laboratory personnel in terms of the number of tests being run.”
 

Returning to the ‘dark days’

This was a significant issue in the earlier part of the pandemic, Dr. Holladay recalled. The shortage of non-COVID lab capacity eased in the spring and early summer of 2021, when COVID-19 vaccines became widely available.

“But with the Delta variant, we’re going back to those dark days and creating the same bottleneck that we saw in the beginning,” he said.

Although the situation is worse in some states than others, Dr. Holladay added, some of the hardest-hit states like Florida and Texas have very large populations.

“This is not just about doctors, nurses, pathologists, and laboratory personnel being exhausted,” commented Kimberly Sanford, MD, president of ASCP, in a press release. “Laboratory medicine is absolutely necessary for accurate and timely diagnosis of disease, infection control, and effective treatment planning. It is an essential part of the health care system and often overwhelmed by the increasing number of coronavirus tests requiring immediate analysis.

“Such testing takes time and disproportionately consumes scarce equipment and other resources. It means those with cancer and other life-threatening conditions face serious delays in diagnosis and treatment. It delays medical diagnoses, erects barriers to preventative care, and prevents us from focusing on the significant health care needs of the population at large.”

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

The American Society for Clinical Pathology (ASCP), which represents over 100,000 pathologists and medical laboratory professionals, has called for a nationwide vaccination mandate. It is the first medical specialty society to do so, ASCP chief executive officer Blair Holladay, PhD, said in an interview.

However, the American Lung Association this week said it supports President Biden’s call for businesses to require their employees to be vaccinated. In addition, more than 50 medical societies, including ASCP, recently said they support vaccination mandates for health care workers.

In a position statement released Wednesday, ASCP recommended that every eligible American be vaccinated. “The U.S. Food and Drug Administration is soon expected to fully approve at least one COVID-19 vaccine, and when it does, we urge that vaccination requirements become the norm,” the society said.

Second, ASCP noted that at least 16 states have enacted some form of a ban on COVID-19 vaccine mandates or related requirements. These include blocking employment-based mandates, school vaccination or mask requirements, and vaccine passport requirements.

“These laws prolong the pandemic and threaten the health and safety of every American. They should be repealed or overturned immediately,” the association stated.

Third, ASCP said, it supports the guidance of the Centers for Disease Control and Prevention that masks should be worn indoors in public places in areas of substantial or high COVID-19 transmission.

“Before more people die, our elected leaders need to take serious and aggressive action to ensure that Americans get vaccinated, so we can end the pandemic, end patient and family suffering, end the fatalities, and get back to the lives we had before COVID-19,” the statement concluded.
 

Laboratories have to focus on COVID again

In his interview, Dr. Holladay noted that the eruption of the Delta variant across the country has again forced laboratories to focus on COVID-19 testing at the expense of necessary tests related to other diseases.

“Because 7 of 10 medical decisions depend on the laboratory, anything that interferes with that interferes with the needs of patient care, including preventive, chronic, and acute care services,” he said.

This is a major reason, he said, for ASCP to support a national vaccination mandate. “People have postponed treatment because of the inability to access medical care [for other conditions],” he noted. The same is true for preventive or diagnostic care such as biopsies for breast cancer and colonoscopies, he added.

“In many parts of the country, the throughput of COVID tests made it difficult for us to focus on tests for other acute conditions. It overwhelmed the laboratory personnel in terms of the number of tests being run.”
 

Returning to the ‘dark days’

This was a significant issue in the earlier part of the pandemic, Dr. Holladay recalled. The shortage of non-COVID lab capacity eased in the spring and early summer of 2021, when COVID-19 vaccines became widely available.

“But with the Delta variant, we’re going back to those dark days and creating the same bottleneck that we saw in the beginning,” he said.

Although the situation is worse in some states than others, Dr. Holladay added, some of the hardest-hit states like Florida and Texas have very large populations.

“This is not just about doctors, nurses, pathologists, and laboratory personnel being exhausted,” commented Kimberly Sanford, MD, president of ASCP, in a press release. “Laboratory medicine is absolutely necessary for accurate and timely diagnosis of disease, infection control, and effective treatment planning. It is an essential part of the health care system and often overwhelmed by the increasing number of coronavirus tests requiring immediate analysis.

“Such testing takes time and disproportionately consumes scarce equipment and other resources. It means those with cancer and other life-threatening conditions face serious delays in diagnosis and treatment. It delays medical diagnoses, erects barriers to preventative care, and prevents us from focusing on the significant health care needs of the population at large.”

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

At the end of 2021, Nadia Nadim will join the tens of thousands of medical students who will exchange their short white coats for the long ones of practicing physicians. Unlike other future doctors, this soon-to-be reconstructive surgeon has also been wearing a uniform that’s more than white. She has donned brightly colored red, purple, or blue jerseys as a striker for teams in the U.S. National Women’s Soccer League and the Danish National football team.

The 33-year-old found her way into medicine after a harrowing childhood. Following the murder of her father by the Taliban, Nadia, her mother, and her four sisters fled Afghanistan in fear for their lives. They sought refuge in Denmark, where Nadia first discovered football [soccer] and a growing call to become a humanitarian activist. Just one semester away from becoming a doctor, and still sustaining a demanding professional football schedule, this news organization spoke with her about her remarkable story.

This interview has been edited for length and clarity.

Question: Would you mind telling us a bit about your background and your journey into medicine?

Nadia: I was born in Afghanistan and was raised there until I was 10 years old. Then we had to flee the country because of war. We came to Denmark at the start of sixth grade. At that point, I didn’t really understand the language. I didn’t understand a lot of things. The only thing I kind of knew was math because my mom was teaching us at home.

My mom had always emphasized the importance of education. She said that it can get you out of any situation in your life. If you’re having problems or are in poverty or whatever, education is the key. She was the first kid in her family to get education. No one before her ever went to school, especially not girls.

My mom wanted to become a doctor, but then she got married and her plans changed. She always had this dream and then wanted one of her kids to become a doctor. When I heard that I was like: “Hell no, I’m not gonna. I’m not gonna fulfill your dreams.” My older sister wanted to become a doctor, and I was like: “I’m not gonna become a doctor. I’m gonna do something else. I’m gonna try to become rich.”

I remember in ninth grade, we had this one week where you get to choose what you want to do. I chose to go to the clinic close to our house, not because I had the biggest interest but because it was close and I could sleep in longer.

The week that I was there, I was really surprised. I thought: “Wow, this is really cool to be in the hospital.” I saw some cosmetic operations and eye surgeries. I could see myself in that environment. I love the fact the doctors are able to help people, especially the ones who are really in need. I thought “Maybe I should give this a go.”

So I signed up (for medical school). I got in. I didn’t tell my mom. I told her that I applied to business school and was accepted. She’s was half-heartedly saying: “Oh, I’m so proud of you!” She didn’t really mean it.

I remember being in the first semester and thinking: “I’ve chosen so right.” I loved everything about med school, from the blood to the conversations that you have with your patients. I love it.

Obviously, football is a big part of your life as well. How have you balanced medical training with your work as an athlete on a global stage?

It hasn’t been easy. I did my bachelor’s degree as normal as everyone else because it was possible for me to be in school from 7 a.m. to 3 p.m. My football training was at 6 p.m. It was possible but also really tough.

We have these huge exams in Denmark where you are literally tested on six, seven, or eight big subjects. The failure rate is really high. I was selected for the Danish national team. The time for my exam was literally the same time that I was about to go to camp. I remember there was this lady ... I explained my problem, and she said: “Well, I’m sorry, this is it. You have to make a choice. No one can play football and be a doctor, so I guess you have to make a choice.” I wanted to prove her wrong.

What advice would you have for students who may be in such similar situations, in which they have a counselor or an advisor who isn’t very supportive?

I think there’s always two ways: Either you’re gonna listen and be like “okay, this is it. I give up.” Or, if you’re really passionate about it, you’re gonna go the hard way, which is that you do your thing and then slowly everything is gonna go your way.

I think it’s just about being strong enough to “do you.” I think that’s important. Don’t just give up easily just because you’ve been told: ‘We’ve never done this before. It’s impossible.’ I don’t believe that [impossible] is something that exists. I think if you want to do something, there’s always a way. You just have to find it.

I have never taken no for an answer, I guess. But it’s not gonna be easy.

Given all that is on your plate, how do you avoid burnout?

I love doing active stuff. I have a lot of hobbies. I also enjoy just chilling. If my football allows it, and I’m fresh, I love to do stuff outside like tennis, basketball, and swimming.

I love to watch Bollywood movies, just because I speak Hindi. They have something a bit magical around them, like fairy tale movies. I love to watch Korean dramas. I think I’m always interested in other cultures.

You also have a lot of other projects in the works. Could you tell us briefly about some that you’re currently working on?

One of the things that is really close to my heart and I’m passionate about is volunteer work. You know, the humanitarian organizations that do so much in the world. I’ve been on the receiving hand on the other side. I know that a little tiny help can have a huge impact on your character and your future. That’s probably also one of the reasons I want to be a doctor.

One of the organizations that I work with is the Danish Refugee Council. I have visited refugee camps around the world. I’ve been in Jordan and Kenya, and also Denmark. I’m also ambassador for [United Nations Educational, Scientific, and Cultural Organization] UNESCO’s education for girls. Because, again, I think education is the key to a lot of the problems we do face right now.

For instance, let’s say racism, which is a huge thing. You could probably decrease that by educating people. Ignorance, I think, is a huge factor, the fear that you see among a lot of people because of Islam. It’s just people being ignorant. They don’t know. They just assume or they see a certain group and think that they are the representation for the entire population. All of this ends with education.

If you could educate people, I think a lot of problems would disappear or at least get better. So yeah, I am really busy. But whenever I have a bit of time, I try to use it on making a change.

I started by saying that my mom said education is very important. I think that’s something that my entire family has taken to. My oldest [sister] is a doctor, and then I have two nurses in the family, my youngest sisters. I think a goal is to have a clinic all together.

At the end of 2021, Nadia Nadim will join the tens of thousands of medical students who will exchange their short white coats for the long ones of practicing physicians. Unlike other future doctors, this soon-to-be reconstructive surgeon has also been wearing a uniform that’s more than white. She has donned brightly colored red, purple, or blue jerseys as a striker for teams in the U.S. National Women’s Soccer League and the Danish National football team.

The 33-year-old found her way into medicine after a harrowing childhood. Following the murder of her father by the Taliban, Nadia, her mother, and her four sisters fled Afghanistan in fear for their lives. They sought refuge in Denmark, where Nadia first discovered football [soccer] and a growing call to become a humanitarian activist. Just one semester away from becoming a doctor, and still sustaining a demanding professional football schedule, this news organization spoke with her about her remarkable story.

This interview has been edited for length and clarity.

Question: Would you mind telling us a bit about your background and your journey into medicine?

Nadia: I was born in Afghanistan and was raised there until I was 10 years old. Then we had to flee the country because of war. We came to Denmark at the start of sixth grade. At that point, I didn’t really understand the language. I didn’t understand a lot of things. The only thing I kind of knew was math because my mom was teaching us at home.

My mom had always emphasized the importance of education. She said that it can get you out of any situation in your life. If you’re having problems or are in poverty or whatever, education is the key. She was the first kid in her family to get education. No one before her ever went to school, especially not girls.

My mom wanted to become a doctor, but then she got married and her plans changed. She always had this dream and then wanted one of her kids to become a doctor. When I heard that I was like: “Hell no, I’m not gonna. I’m not gonna fulfill your dreams.” My older sister wanted to become a doctor, and I was like: “I’m not gonna become a doctor. I’m gonna do something else. I’m gonna try to become rich.”

I remember in ninth grade, we had this one week where you get to choose what you want to do. I chose to go to the clinic close to our house, not because I had the biggest interest but because it was close and I could sleep in longer.

The week that I was there, I was really surprised. I thought: “Wow, this is really cool to be in the hospital.” I saw some cosmetic operations and eye surgeries. I could see myself in that environment. I love the fact the doctors are able to help people, especially the ones who are really in need. I thought “Maybe I should give this a go.”

So I signed up (for medical school). I got in. I didn’t tell my mom. I told her that I applied to business school and was accepted. She’s was half-heartedly saying: “Oh, I’m so proud of you!” She didn’t really mean it.

I remember being in the first semester and thinking: “I’ve chosen so right.” I loved everything about med school, from the blood to the conversations that you have with your patients. I love it.

Obviously, football is a big part of your life as well. How have you balanced medical training with your work as an athlete on a global stage?

It hasn’t been easy. I did my bachelor’s degree as normal as everyone else because it was possible for me to be in school from 7 a.m. to 3 p.m. My football training was at 6 p.m. It was possible but also really tough.

We have these huge exams in Denmark where you are literally tested on six, seven, or eight big subjects. The failure rate is really high. I was selected for the Danish national team. The time for my exam was literally the same time that I was about to go to camp. I remember there was this lady ... I explained my problem, and she said: “Well, I’m sorry, this is it. You have to make a choice. No one can play football and be a doctor, so I guess you have to make a choice.” I wanted to prove her wrong.

What advice would you have for students who may be in such similar situations, in which they have a counselor or an advisor who isn’t very supportive?

I think there’s always two ways: Either you’re gonna listen and be like “okay, this is it. I give up.” Or, if you’re really passionate about it, you’re gonna go the hard way, which is that you do your thing and then slowly everything is gonna go your way.

I think it’s just about being strong enough to “do you.” I think that’s important. Don’t just give up easily just because you’ve been told: ‘We’ve never done this before. It’s impossible.’ I don’t believe that [impossible] is something that exists. I think if you want to do something, there’s always a way. You just have to find it.

I have never taken no for an answer, I guess. But it’s not gonna be easy.

Given all that is on your plate, how do you avoid burnout?

I love doing active stuff. I have a lot of hobbies. I also enjoy just chilling. If my football allows it, and I’m fresh, I love to do stuff outside like tennis, basketball, and swimming.

I love to watch Bollywood movies, just because I speak Hindi. They have something a bit magical around them, like fairy tale movies. I love to watch Korean dramas. I think I’m always interested in other cultures.

You also have a lot of other projects in the works. Could you tell us briefly about some that you’re currently working on?

One of the things that is really close to my heart and I’m passionate about is volunteer work. You know, the humanitarian organizations that do so much in the world. I’ve been on the receiving hand on the other side. I know that a little tiny help can have a huge impact on your character and your future. That’s probably also one of the reasons I want to be a doctor.

One of the organizations that I work with is the Danish Refugee Council. I have visited refugee camps around the world. I’ve been in Jordan and Kenya, and also Denmark. I’m also ambassador for [United Nations Educational, Scientific, and Cultural Organization] UNESCO’s education for girls. Because, again, I think education is the key to a lot of the problems we do face right now.

For instance, let’s say racism, which is a huge thing. You could probably decrease that by educating people. Ignorance, I think, is a huge factor, the fear that you see among a lot of people because of Islam. It’s just people being ignorant. They don’t know. They just assume or they see a certain group and think that they are the representation for the entire population. All of this ends with education.

If you could educate people, I think a lot of problems would disappear or at least get better. So yeah, I am really busy. But whenever I have a bit of time, I try to use it on making a change.

I started by saying that my mom said education is very important. I think that’s something that my entire family has taken to. My oldest [sister] is a doctor, and then I have two nurses in the family, my youngest sisters. I think a goal is to have a clinic all together.

At the end of 2021, Nadia Nadim will join the tens of thousands of medical students who will exchange their short white coats for the long ones of practicing physicians. Unlike other future doctors, this soon-to-be reconstructive surgeon has also been wearing a uniform that’s more than white. She has donned brightly colored red, purple, or blue jerseys as a striker for teams in the U.S. National Women’s Soccer League and the Danish National football team.

The 33-year-old found her way into medicine after a harrowing childhood. Following the murder of her father by the Taliban, Nadia, her mother, and her four sisters fled Afghanistan in fear for their lives. They sought refuge in Denmark, where Nadia first discovered football [soccer] and a growing call to become a humanitarian activist. Just one semester away from becoming a doctor, and still sustaining a demanding professional football schedule, this news organization spoke with her about her remarkable story.

This interview has been edited for length and clarity.

Question: Would you mind telling us a bit about your background and your journey into medicine?

Nadia: I was born in Afghanistan and was raised there until I was 10 years old. Then we had to flee the country because of war. We came to Denmark at the start of sixth grade. At that point, I didn’t really understand the language. I didn’t understand a lot of things. The only thing I kind of knew was math because my mom was teaching us at home.

My mom had always emphasized the importance of education. She said that it can get you out of any situation in your life. If you’re having problems or are in poverty or whatever, education is the key. She was the first kid in her family to get education. No one before her ever went to school, especially not girls.

My mom wanted to become a doctor, but then she got married and her plans changed. She always had this dream and then wanted one of her kids to become a doctor. When I heard that I was like: “Hell no, I’m not gonna. I’m not gonna fulfill your dreams.” My older sister wanted to become a doctor, and I was like: “I’m not gonna become a doctor. I’m gonna do something else. I’m gonna try to become rich.”

I remember in ninth grade, we had this one week where you get to choose what you want to do. I chose to go to the clinic close to our house, not because I had the biggest interest but because it was close and I could sleep in longer.

The week that I was there, I was really surprised. I thought: “Wow, this is really cool to be in the hospital.” I saw some cosmetic operations and eye surgeries. I could see myself in that environment. I love the fact the doctors are able to help people, especially the ones who are really in need. I thought “Maybe I should give this a go.”

So I signed up (for medical school). I got in. I didn’t tell my mom. I told her that I applied to business school and was accepted. She’s was half-heartedly saying: “Oh, I’m so proud of you!” She didn’t really mean it.

I remember being in the first semester and thinking: “I’ve chosen so right.” I loved everything about med school, from the blood to the conversations that you have with your patients. I love it.

Obviously, football is a big part of your life as well. How have you balanced medical training with your work as an athlete on a global stage?

It hasn’t been easy. I did my bachelor’s degree as normal as everyone else because it was possible for me to be in school from 7 a.m. to 3 p.m. My football training was at 6 p.m. It was possible but also really tough.

We have these huge exams in Denmark where you are literally tested on six, seven, or eight big subjects. The failure rate is really high. I was selected for the Danish national team. The time for my exam was literally the same time that I was about to go to camp. I remember there was this lady ... I explained my problem, and she said: “Well, I’m sorry, this is it. You have to make a choice. No one can play football and be a doctor, so I guess you have to make a choice.” I wanted to prove her wrong.

What advice would you have for students who may be in such similar situations, in which they have a counselor or an advisor who isn’t very supportive?

I think there’s always two ways: Either you’re gonna listen and be like “okay, this is it. I give up.” Or, if you’re really passionate about it, you’re gonna go the hard way, which is that you do your thing and then slowly everything is gonna go your way.

I think it’s just about being strong enough to “do you.” I think that’s important. Don’t just give up easily just because you’ve been told: ‘We’ve never done this before. It’s impossible.’ I don’t believe that [impossible] is something that exists. I think if you want to do something, there’s always a way. You just have to find it.

I have never taken no for an answer, I guess. But it’s not gonna be easy.

Given all that is on your plate, how do you avoid burnout?

I love doing active stuff. I have a lot of hobbies. I also enjoy just chilling. If my football allows it, and I’m fresh, I love to do stuff outside like tennis, basketball, and swimming.

I love to watch Bollywood movies, just because I speak Hindi. They have something a bit magical around them, like fairy tale movies. I love to watch Korean dramas. I think I’m always interested in other cultures.

You also have a lot of other projects in the works. Could you tell us briefly about some that you’re currently working on?

One of the things that is really close to my heart and I’m passionate about is volunteer work. You know, the humanitarian organizations that do so much in the world. I’ve been on the receiving hand on the other side. I know that a little tiny help can have a huge impact on your character and your future. That’s probably also one of the reasons I want to be a doctor.

One of the organizations that I work with is the Danish Refugee Council. I have visited refugee camps around the world. I’ve been in Jordan and Kenya, and also Denmark. I’m also ambassador for [United Nations Educational, Scientific, and Cultural Organization] UNESCO’s education for girls. Because, again, I think education is the key to a lot of the problems we do face right now.

For instance, let’s say racism, which is a huge thing. You could probably decrease that by educating people. Ignorance, I think, is a huge factor, the fear that you see among a lot of people because of Islam. It’s just people being ignorant. They don’t know. They just assume or they see a certain group and think that they are the representation for the entire population. All of this ends with education.

If you could educate people, I think a lot of problems would disappear or at least get better. So yeah, I am really busy. But whenever I have a bit of time, I try to use it on making a change.

I started by saying that my mom said education is very important. I think that’s something that my entire family has taken to. My oldest [sister] is a doctor, and then I have two nurses in the family, my youngest sisters. I think a goal is to have a clinic all together.

The current pandemic is forcing changes throughout the health care industry. Telehealth is witnessing a surge. Hospitals are struggling without elective care, and remarkably, physicians are being laid off during a time of crisis. While some states have a surplus work force, other states go begging, and they lock the system up with delays in the processing of applications.

Considering the prevalence of noncompete clauses and a schism in state-to-state processing of complaints, patients are suffering and dying under an antiquated system. The Federation of State Medical Boards doesn’t seem to add to the solution, but instead confounds the problem with new directives. The time is nigh for the federal government to eliminate state medical licensure and replace it with a national medical license for all physicians and health care professionals.

Because physicians’ training requirements don’t vary from state to state, it makes sense. We must take national standardized exams to qualify. Locum tenens physicians must maintain licensure in as many states as they practice; this creates an unnecessary burden and expense, when there is a better alternative. Some states have arranged reciprocity licensure with other states. This is commendable but doesn’t go far enough to manage national shortages in rural areas.

Under a national licensing system, physicians and other health care professionals would not only be free to travel anywhere in the United States to practice, they can count on consistent and equal management of their license. The federal government can track regional overages and shortages and redirect physicians and other medical professionals with incentives to areas in need.

The FSMB claims that there is interstate continuity among state medical boards, but the data don’t support this.

Why is this the case? Each medical board fails to manage their charges equally. Often, action taken by one state board when reported to another state board can cause a review and readjudication. This occasionally results in the overturning of a reprimand or suspension because of differences in legislation.

Yet the physician or health care professional must bear the burden of the notification against their license. Once again, the FSMB claims there is interstate continuity in disciplinary actions, but the data do not support this.

Once someone brings a complaint against a health professional, which in this health care climate is inevitable, the medical board must institute an investigation. Even if it has no merit, the process must go forward. Under a national system, a consistent approach to dismiss and investigate issues and complaints might expedite the process. This eliminates inefficiency and delays in clearance of charges.

A report in 2006 identified fragmentation and discontinuities in the way each state medical board manages a physician or other health care personnel’s complaints. The number of hands involved in the process varies and is often onerous and redundant. Several sources may request the same information, tying it up as it moves through an inefficient and uncooperative system. With the increase in internal politics since then, this only compounds rather than improves the problem.

Yet the benefit of national licensure is not just for the health care personnel but also for insurance companies that must register and screen physicians as they move from region to region. In each state, the physician must repeat the accreditation process, delaying reimbursements and denying care. Hospitals also must repeat the credentialing task as well. This, although the physician or health care worker has a clean record with the same company or the same hospital system in their original state.

Perhaps data from one insurance group or hospital in another state get lost or altered in transfer, but under national licensing, this would not be possible. Furthermore, the current system limits the individual professional’s input. By nationalizing, record corrections would go through a federal database rather than state data banks that don’t sync.

This already partially exists with the National Practitioner Identifier. But we can take it one step further. Through nationalization, we could institute a fairer system of reporting where both the professional’s and the complainant’s summary is included. One might argue the National Physician Data Bank performs this function, but in fact, it merely reflects state assessments – which again vary.

The infrastructure is already in place to transition from a state to national system with facilities and records kept in each state’s medical board. It would simply be a matter of replacing state personnel with federal employees who all work from the same script. A national medical license simply makes sense for all parties. It reduces discontinuity and increases efficiency. A national medical license empowers the individual rather than institutions, yet benefits both.

The time is nigh to nationally certify and set physicians free, reduce paperwork and needless fees, and eliminate state supremacy.  


Dr. Raymond is an emergency physician based in Hickory, N.C., and Muckendorf an der Donau, Austria.

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

The current pandemic is forcing changes throughout the health care industry. Telehealth is witnessing a surge. Hospitals are struggling without elective care, and remarkably, physicians are being laid off during a time of crisis. While some states have a surplus work force, other states go begging, and they lock the system up with delays in the processing of applications.

Considering the prevalence of noncompete clauses and a schism in state-to-state processing of complaints, patients are suffering and dying under an antiquated system. The Federation of State Medical Boards doesn’t seem to add to the solution, but instead confounds the problem with new directives. The time is nigh for the federal government to eliminate state medical licensure and replace it with a national medical license for all physicians and health care professionals.

Because physicians’ training requirements don’t vary from state to state, it makes sense. We must take national standardized exams to qualify. Locum tenens physicians must maintain licensure in as many states as they practice; this creates an unnecessary burden and expense, when there is a better alternative. Some states have arranged reciprocity licensure with other states. This is commendable but doesn’t go far enough to manage national shortages in rural areas.

Under a national licensing system, physicians and other health care professionals would not only be free to travel anywhere in the United States to practice, they can count on consistent and equal management of their license. The federal government can track regional overages and shortages and redirect physicians and other medical professionals with incentives to areas in need.

The FSMB claims that there is interstate continuity among state medical boards, but the data don’t support this.

Why is this the case? Each medical board fails to manage their charges equally. Often, action taken by one state board when reported to another state board can cause a review and readjudication. This occasionally results in the overturning of a reprimand or suspension because of differences in legislation.

Yet the physician or health care professional must bear the burden of the notification against their license. Once again, the FSMB claims there is interstate continuity in disciplinary actions, but the data do not support this.

Once someone brings a complaint against a health professional, which in this health care climate is inevitable, the medical board must institute an investigation. Even if it has no merit, the process must go forward. Under a national system, a consistent approach to dismiss and investigate issues and complaints might expedite the process. This eliminates inefficiency and delays in clearance of charges.

A report in 2006 identified fragmentation and discontinuities in the way each state medical board manages a physician or other health care personnel’s complaints. The number of hands involved in the process varies and is often onerous and redundant. Several sources may request the same information, tying it up as it moves through an inefficient and uncooperative system. With the increase in internal politics since then, this only compounds rather than improves the problem.

Yet the benefit of national licensure is not just for the health care personnel but also for insurance companies that must register and screen physicians as they move from region to region. In each state, the physician must repeat the accreditation process, delaying reimbursements and denying care. Hospitals also must repeat the credentialing task as well. This, although the physician or health care worker has a clean record with the same company or the same hospital system in their original state.

Perhaps data from one insurance group or hospital in another state get lost or altered in transfer, but under national licensing, this would not be possible. Furthermore, the current system limits the individual professional’s input. By nationalizing, record corrections would go through a federal database rather than state data banks that don’t sync.

This already partially exists with the National Practitioner Identifier. But we can take it one step further. Through nationalization, we could institute a fairer system of reporting where both the professional’s and the complainant’s summary is included. One might argue the National Physician Data Bank performs this function, but in fact, it merely reflects state assessments – which again vary.

The infrastructure is already in place to transition from a state to national system with facilities and records kept in each state’s medical board. It would simply be a matter of replacing state personnel with federal employees who all work from the same script. A national medical license simply makes sense for all parties. It reduces discontinuity and increases efficiency. A national medical license empowers the individual rather than institutions, yet benefits both.

The time is nigh to nationally certify and set physicians free, reduce paperwork and needless fees, and eliminate state supremacy.  


Dr. Raymond is an emergency physician based in Hickory, N.C., and Muckendorf an der Donau, Austria.

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

The current pandemic is forcing changes throughout the health care industry. Telehealth is witnessing a surge. Hospitals are struggling without elective care, and remarkably, physicians are being laid off during a time of crisis. While some states have a surplus work force, other states go begging, and they lock the system up with delays in the processing of applications.

Considering the prevalence of noncompete clauses and a schism in state-to-state processing of complaints, patients are suffering and dying under an antiquated system. The Federation of State Medical Boards doesn’t seem to add to the solution, but instead confounds the problem with new directives. The time is nigh for the federal government to eliminate state medical licensure and replace it with a national medical license for all physicians and health care professionals.

Because physicians’ training requirements don’t vary from state to state, it makes sense. We must take national standardized exams to qualify. Locum tenens physicians must maintain licensure in as many states as they practice; this creates an unnecessary burden and expense, when there is a better alternative. Some states have arranged reciprocity licensure with other states. This is commendable but doesn’t go far enough to manage national shortages in rural areas.

Under a national licensing system, physicians and other health care professionals would not only be free to travel anywhere in the United States to practice, they can count on consistent and equal management of their license. The federal government can track regional overages and shortages and redirect physicians and other medical professionals with incentives to areas in need.

The FSMB claims that there is interstate continuity among state medical boards, but the data don’t support this.

Why is this the case? Each medical board fails to manage their charges equally. Often, action taken by one state board when reported to another state board can cause a review and readjudication. This occasionally results in the overturning of a reprimand or suspension because of differences in legislation.

Yet the physician or health care professional must bear the burden of the notification against their license. Once again, the FSMB claims there is interstate continuity in disciplinary actions, but the data do not support this.

Once someone brings a complaint against a health professional, which in this health care climate is inevitable, the medical board must institute an investigation. Even if it has no merit, the process must go forward. Under a national system, a consistent approach to dismiss and investigate issues and complaints might expedite the process. This eliminates inefficiency and delays in clearance of charges.

A report in 2006 identified fragmentation and discontinuities in the way each state medical board manages a physician or other health care personnel’s complaints. The number of hands involved in the process varies and is often onerous and redundant. Several sources may request the same information, tying it up as it moves through an inefficient and uncooperative system. With the increase in internal politics since then, this only compounds rather than improves the problem.

Yet the benefit of national licensure is not just for the health care personnel but also for insurance companies that must register and screen physicians as they move from region to region. In each state, the physician must repeat the accreditation process, delaying reimbursements and denying care. Hospitals also must repeat the credentialing task as well. This, although the physician or health care worker has a clean record with the same company or the same hospital system in their original state.

Perhaps data from one insurance group or hospital in another state get lost or altered in transfer, but under national licensing, this would not be possible. Furthermore, the current system limits the individual professional’s input. By nationalizing, record corrections would go through a federal database rather than state data banks that don’t sync.

This already partially exists with the National Practitioner Identifier. But we can take it one step further. Through nationalization, we could institute a fairer system of reporting where both the professional’s and the complainant’s summary is included. One might argue the National Physician Data Bank performs this function, but in fact, it merely reflects state assessments – which again vary.

The infrastructure is already in place to transition from a state to national system with facilities and records kept in each state’s medical board. It would simply be a matter of replacing state personnel with federal employees who all work from the same script. A national medical license simply makes sense for all parties. It reduces discontinuity and increases efficiency. A national medical license empowers the individual rather than institutions, yet benefits both.

The time is nigh to nationally certify and set physicians free, reduce paperwork and needless fees, and eliminate state supremacy.  


Dr. Raymond is an emergency physician based in Hickory, N.C., and Muckendorf an der Donau, Austria.

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

Anaplasmosis prevalence in New York state nearly quadrupled statewide from 2010 to 2018, new research suggests, increasing by more than eightfold in the region surrounding Albany, the state capital. The proportion of ticks carrying Anaplasma phagocytophilum, the bacterium that causes the tick-borne disease, also increased during the study period. 

Although not as well-recognized as Lyme disease, anaplasmosis is one of the most common tickborne diseases in the United States. The bacterial disease is primarily transmitted to humans by the bites of blacklegged ticks infected with A. phagocytophilum, and often causes fever, headache, muscle aches, and chills. If treatment is delayed – or if a patient has underlying medical conditions – anaplasmosis can lead to difficulty breathing, bleeding problems, organ failure, and even death.

Since anaplasmosis become a nationally notifiable disease in 1999, cases have increased 16-fold in the United States, from 351 cases in 2000 to a high of 5,762 cases in 2017, according to data from the Centers for Disease Control and Prevention. Just eight states – Vermont, Maine, Rhode Island, Minnesota, Massachusetts, Wisconsin, New Hampshire, and New York – make up 90% of reported cases.

“While Lyme disease remains the most common tick-borne illness reported in New York state, anaplasmosis continues to account for a growing proportion of our tick-borne disease cases each year,” Melissa Prusinski, a research scientist at the New York State Department of Health and author of the study, told this news organization in an email. “It is critically important to investigate the environmental and epidemiological drivers facilitating this increase to better understand why and how risk for this serious illness is increasing.” The results were published in Emerging Infectious Diseases.

For the study, investigators analyzed human anaplasmosis cases reported to the New York State Department of Health from 2010-2018. They also included data from tick collection and pathogen testing in order to determine whether the prevalence of A. phagocytophilum in ticks increased along with cases. All New York State counties were included in the study, apart from the five boroughs of New York City: Manhattan, Brooklyn, the Bronx, Queens, and Staten Island.

There were 5,146 reported anaplasmosis cases in New York, with annual case numbers peaking at 1,112 in 2017. Researchers reported a dip in cases in 2018, a trend that was also seen nationally. Anaplasmosis incidence surged in the area surrounding Albany, increasing 8.4-fold from 4.3 cases per 100,000 people in 2010 to 36.3 cases per 100,000 persons in 2018.

Ms. Prusinski noted that the rapid increase in and around this inland hot spot is unlike the gradual spread of Lyme disease and other tick-borne illnesses like babesiosis, which spreads from coastal areas both northward and westward across New York. The research team also found that the incidence of ticks infected with A. phagocytophilum nearly doubled statewide and increased fourfold – from 2.9% to 12% – between 2010 and 2018 in the Albany area.

This increase in cases could be the result, at least in part, of more robust testing efforts over time, said Susan Elias, PhD, of the Vector-Borne Disease Laboratory at the Maine Medical Center Research Institute in Scarborough. She was not involved with the recently published study. “The more you look for something, the more you find,” she said. For example, she added, a 602% surge in anaplasmosis cases in Maine from 2013-2017 occurred alongside a 10-fold increase in use of tick-borne disease panels that test for multiple pathogens.

Ms. Prusinski agreed that increased testing at least partially explains the surge of cases in New York, but she did not have data on how many tick-borne disease panels were used to diagnose cases in the state.

Proliferation of A. phagocytophilum in tick populations could also partially explain this dramatic increase in cases. With the suburbanization of America, “we have basically laid out a buffet” for ticks, Dr. Elias said. Patches of forest and yards create edge habitats where ticks, and the small mammals they feed on, thrive. “Then, once you have a large expanding blacklegged tick population, it makes it easier for the pathogens and carriers to amplify,” she added.

While the study did not differentiate between a variant of A. phagocytophilum associated with small mammals that causes illness and another found in white-tailed deer that is nonpathogenic, Ms. Prusinski suspects that the infectious variant is likely more prevalent and is circulating in animals and ticks in and around Albany. Research is ongoing to see if this could help explain the spread of disease in this anaplasmosis hotspot.

“The unique geographic pattern of anaplasmosis spread in New York state and elsewhere leads to many further questions about the vector ecology and epidemiology of this emerging tick-borne illness,” Ms. Prusinski added. “Learning all we can about this dynamic disease system will help us better identify at-risk populations and may lead to novel ways to prevent anaplasmosis.”

Dr. Elias and Ms. Prusinski disclosed no relevant financial relationships.

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

Anaplasmosis prevalence in New York state nearly quadrupled statewide from 2010 to 2018, new research suggests, increasing by more than eightfold in the region surrounding Albany, the state capital. The proportion of ticks carrying Anaplasma phagocytophilum, the bacterium that causes the tick-borne disease, also increased during the study period. 

Although not as well-recognized as Lyme disease, anaplasmosis is one of the most common tickborne diseases in the United States. The bacterial disease is primarily transmitted to humans by the bites of blacklegged ticks infected with A. phagocytophilum, and often causes fever, headache, muscle aches, and chills. If treatment is delayed – or if a patient has underlying medical conditions – anaplasmosis can lead to difficulty breathing, bleeding problems, organ failure, and even death.

Since anaplasmosis become a nationally notifiable disease in 1999, cases have increased 16-fold in the United States, from 351 cases in 2000 to a high of 5,762 cases in 2017, according to data from the Centers for Disease Control and Prevention. Just eight states – Vermont, Maine, Rhode Island, Minnesota, Massachusetts, Wisconsin, New Hampshire, and New York – make up 90% of reported cases.

“While Lyme disease remains the most common tick-borne illness reported in New York state, anaplasmosis continues to account for a growing proportion of our tick-borne disease cases each year,” Melissa Prusinski, a research scientist at the New York State Department of Health and author of the study, told this news organization in an email. “It is critically important to investigate the environmental and epidemiological drivers facilitating this increase to better understand why and how risk for this serious illness is increasing.” The results were published in Emerging Infectious Diseases.

For the study, investigators analyzed human anaplasmosis cases reported to the New York State Department of Health from 2010-2018. They also included data from tick collection and pathogen testing in order to determine whether the prevalence of A. phagocytophilum in ticks increased along with cases. All New York State counties were included in the study, apart from the five boroughs of New York City: Manhattan, Brooklyn, the Bronx, Queens, and Staten Island.

There were 5,146 reported anaplasmosis cases in New York, with annual case numbers peaking at 1,112 in 2017. Researchers reported a dip in cases in 2018, a trend that was also seen nationally. Anaplasmosis incidence surged in the area surrounding Albany, increasing 8.4-fold from 4.3 cases per 100,000 people in 2010 to 36.3 cases per 100,000 persons in 2018.

Ms. Prusinski noted that the rapid increase in and around this inland hot spot is unlike the gradual spread of Lyme disease and other tick-borne illnesses like babesiosis, which spreads from coastal areas both northward and westward across New York. The research team also found that the incidence of ticks infected with A. phagocytophilum nearly doubled statewide and increased fourfold – from 2.9% to 12% – between 2010 and 2018 in the Albany area.

This increase in cases could be the result, at least in part, of more robust testing efforts over time, said Susan Elias, PhD, of the Vector-Borne Disease Laboratory at the Maine Medical Center Research Institute in Scarborough. She was not involved with the recently published study. “The more you look for something, the more you find,” she said. For example, she added, a 602% surge in anaplasmosis cases in Maine from 2013-2017 occurred alongside a 10-fold increase in use of tick-borne disease panels that test for multiple pathogens.

Ms. Prusinski agreed that increased testing at least partially explains the surge of cases in New York, but she did not have data on how many tick-borne disease panels were used to diagnose cases in the state.

Proliferation of A. phagocytophilum in tick populations could also partially explain this dramatic increase in cases. With the suburbanization of America, “we have basically laid out a buffet” for ticks, Dr. Elias said. Patches of forest and yards create edge habitats where ticks, and the small mammals they feed on, thrive. “Then, once you have a large expanding blacklegged tick population, it makes it easier for the pathogens and carriers to amplify,” she added.

While the study did not differentiate between a variant of A. phagocytophilum associated with small mammals that causes illness and another found in white-tailed deer that is nonpathogenic, Ms. Prusinski suspects that the infectious variant is likely more prevalent and is circulating in animals and ticks in and around Albany. Research is ongoing to see if this could help explain the spread of disease in this anaplasmosis hotspot.

“The unique geographic pattern of anaplasmosis spread in New York state and elsewhere leads to many further questions about the vector ecology and epidemiology of this emerging tick-borne illness,” Ms. Prusinski added. “Learning all we can about this dynamic disease system will help us better identify at-risk populations and may lead to novel ways to prevent anaplasmosis.”

Dr. Elias and Ms. Prusinski disclosed no relevant financial relationships.

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

Anaplasmosis prevalence in New York state nearly quadrupled statewide from 2010 to 2018, new research suggests, increasing by more than eightfold in the region surrounding Albany, the state capital. The proportion of ticks carrying Anaplasma phagocytophilum, the bacterium that causes the tick-borne disease, also increased during the study period. 

Although not as well-recognized as Lyme disease, anaplasmosis is one of the most common tickborne diseases in the United States. The bacterial disease is primarily transmitted to humans by the bites of blacklegged ticks infected with A. phagocytophilum, and often causes fever, headache, muscle aches, and chills. If treatment is delayed – or if a patient has underlying medical conditions – anaplasmosis can lead to difficulty breathing, bleeding problems, organ failure, and even death.

Since anaplasmosis become a nationally notifiable disease in 1999, cases have increased 16-fold in the United States, from 351 cases in 2000 to a high of 5,762 cases in 2017, according to data from the Centers for Disease Control and Prevention. Just eight states – Vermont, Maine, Rhode Island, Minnesota, Massachusetts, Wisconsin, New Hampshire, and New York – make up 90% of reported cases.

“While Lyme disease remains the most common tick-borne illness reported in New York state, anaplasmosis continues to account for a growing proportion of our tick-borne disease cases each year,” Melissa Prusinski, a research scientist at the New York State Department of Health and author of the study, told this news organization in an email. “It is critically important to investigate the environmental and epidemiological drivers facilitating this increase to better understand why and how risk for this serious illness is increasing.” The results were published in Emerging Infectious Diseases.

For the study, investigators analyzed human anaplasmosis cases reported to the New York State Department of Health from 2010-2018. They also included data from tick collection and pathogen testing in order to determine whether the prevalence of A. phagocytophilum in ticks increased along with cases. All New York State counties were included in the study, apart from the five boroughs of New York City: Manhattan, Brooklyn, the Bronx, Queens, and Staten Island.

There were 5,146 reported anaplasmosis cases in New York, with annual case numbers peaking at 1,112 in 2017. Researchers reported a dip in cases in 2018, a trend that was also seen nationally. Anaplasmosis incidence surged in the area surrounding Albany, increasing 8.4-fold from 4.3 cases per 100,000 people in 2010 to 36.3 cases per 100,000 persons in 2018.

Ms. Prusinski noted that the rapid increase in and around this inland hot spot is unlike the gradual spread of Lyme disease and other tick-borne illnesses like babesiosis, which spreads from coastal areas both northward and westward across New York. The research team also found that the incidence of ticks infected with A. phagocytophilum nearly doubled statewide and increased fourfold – from 2.9% to 12% – between 2010 and 2018 in the Albany area.

This increase in cases could be the result, at least in part, of more robust testing efforts over time, said Susan Elias, PhD, of the Vector-Borne Disease Laboratory at the Maine Medical Center Research Institute in Scarborough. She was not involved with the recently published study. “The more you look for something, the more you find,” she said. For example, she added, a 602% surge in anaplasmosis cases in Maine from 2013-2017 occurred alongside a 10-fold increase in use of tick-borne disease panels that test for multiple pathogens.

Ms. Prusinski agreed that increased testing at least partially explains the surge of cases in New York, but she did not have data on how many tick-borne disease panels were used to diagnose cases in the state.

Proliferation of A. phagocytophilum in tick populations could also partially explain this dramatic increase in cases. With the suburbanization of America, “we have basically laid out a buffet” for ticks, Dr. Elias said. Patches of forest and yards create edge habitats where ticks, and the small mammals they feed on, thrive. “Then, once you have a large expanding blacklegged tick population, it makes it easier for the pathogens and carriers to amplify,” she added.

While the study did not differentiate between a variant of A. phagocytophilum associated with small mammals that causes illness and another found in white-tailed deer that is nonpathogenic, Ms. Prusinski suspects that the infectious variant is likely more prevalent and is circulating in animals and ticks in and around Albany. Research is ongoing to see if this could help explain the spread of disease in this anaplasmosis hotspot.

“The unique geographic pattern of anaplasmosis spread in New York state and elsewhere leads to many further questions about the vector ecology and epidemiology of this emerging tick-borne illness,” Ms. Prusinski added. “Learning all we can about this dynamic disease system will help us better identify at-risk populations and may lead to novel ways to prevent anaplasmosis.”

Dr. Elias and Ms. Prusinski disclosed no relevant financial relationships.

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