Federal Practitioner

Lung cancer is the second most frequently diagnosed cancer among US veterans and the leading cause of cancer death.¹ Clinical trials have shown that annual screening of high-risk persons with low-dose computed tomography (LDCT) can reduce the risk of dying of lung cancer.² In 2011, the National Lung Screening Trial (NLST) reported that over a 3-year period, annual LDCT screening reduced the risk of dying of lung cancer by 20% compared with chest radiograph screening.³ Lung cancer screening (LCS), however, was associated with harms, including false-positive results, complications from invasive diagnostic procedures, incidental findings, overdiagnosis, and radiation exposure.

The US Preventive Services Task Force (USPSTF) began recommending annual screening of high-risk persons after publication of the NLST results.⁴ The Veterans Health Administration (VHA) recommended implementing LCS in 2017.⁵ Guidelines, however, have consistently highlighted the complexity of the decision and the importance of engaging patients in thorough discussions about the potential benefits and harms of screening (shared decision making [SDM]). The Centers for Medicare and Medicaid Services (CMS) has issued coverage determinations mandating that eligible patients undergo a counseling visit that uses a decision aid to support SDM for LCS and addresses tobacco use.^6,7 However, primary care practitioners (PCPs) face many challenges in delivering SDM, including a lack of awareness of clinical trial results and screening guidelines, competing clinical demands, being untrained in SDM, and not having educational resources.⁸ Patients in rural locations face travel burdens in attending counseling visits.⁹

We conducted a pilot study to address concerns with delivering SDM for LCS to veterans. We implemented a centralized screening model in which veterans were referred by clinicians to a trained decision coach who conducted telephone visits to discuss the initial LCS decision, addressed tobacco cessation, and placed LDCT orders. We evaluated the outcomes of this telemedicine visit by using decision quality metrics and tracking LCS uptake, referrals for tobacco cessation, and clinical outcomes. The University of Iowa Institutional Review Board considered this study to be a quality improvement project and waived informed consent and HIPAA (Health Insurance Portability and Accountability Act) authorization requirements.

Implementation

We implemented the LCS program at the Iowa City Veterans Affairs Health Care System (ICVAHCS), which has both resident and staff clinicians, and 2 community-based outpatient clinics (Coralville, Cedar Rapids) with staff clinicians. The pilot study, conducted from November 2020 through July 2022, was led by a multidisciplinary team that included a nurse, primary care physician, pulmonologist, and radiologist. The team conducted online presentations to educate PCPs about the epidemiology of lung cancer, results of screening trials, LCS guidelines, the rationale for a centralized model of SDM, and the ICVAHCS screening protocols.

Screening Referrals

When the study began in 2020, we used the 2015 USPSTF criteria for annual LCS: individuals aged 55 to 80 years with a 30 pack-year smoking history and current tobacco user or who had quit within 15 years.⁴ We lowered the starting age to 50 years and the pack-year requirement to 20 after the USPSTF issued updated guidelines in 2021.¹⁰ Clinicians were notified about potentially eligible patients through the US Department of Veterans Affairs (VA) Computerized Personal Record System (CPRS) reminders or by the nurse program coordinator (NPC) who reviewed health records of patients with upcoming appointments. If the clinician determined that screening was appropriate, they ordered an LCS consult. The NPC called the veteran to confirm eligibility, mailed a decision aid, and scheduled a telephone visit to conduct SDM. We used the VA decision aid developed for the LCS demonstration project conducted at 8 academic VA medical centers between 2013 and 2017.¹¹

Shared Decision-Making Telephone Visit

The NPC adapted a telephone script developed for a Cancer Prevention and Research Institute of Texas–funded project conducted by 2 coauthors (RJV and LML).¹² The NPC asked about receipt/review of the decision aid, described the screening process, and addressed benefits and potential harms of screening. The NPC also offered smoking cessation interventions for veterans who were currently smoking, including referrals to the VA patient aligned care team clinical pharmacist for management of tobacco cessation or to the national VA Quit Line. The encounter ended by assessing the veteran’s understanding of screening issues and eliciting the veteran’s preferences for LDCT and willingness to adhere with the LCS program.

LDCT Imaging

The NPC placed LDCT orders for veterans interested in screening and alerted the referring clinician to sign the order. Veterans who agreed to be screened were placed in an LCS dashboard developed by the Veterans Integrated Services Network (VISN) 23 LCS program that was used as a patient management tool. The dashboard allowed the NPC to track patients, ensuring that veterans were being scheduled for and completing initial and follow-up testing. Radiologists used the Lung-RADS (Lung Imaging Reporting and Data System) to categorize LDCT results (1, normal; 2, benign nodule; 3, probably benign nodule; 4, suspicious nodule).¹³ Veterans with Lung-RADS 1 or 2 results were scheduled for an annual LDCT (if they remained eligible). Veterans with Lung-RADS 3 results were scheduled for a 6-month follow-up CT. The screening program sent electronic consults to pulmonary for veterans with Lung-RADS 4 to determine whether they should undergo additional imaging or be evaluated in the pulmonary clinic.

Evaluating Shared Decision Making

We audio taped and transcribed randomly selected SDM encounters to assess fidelity with the 2016 CMS required discussion elements for counseling about lung cancer, including the benefit of reducing lung cancer mortality; the potential for harms from false alarms, incidental findings, overdiagnosis, and radiation exposure; the need for annual screening; the importance of smoking cessation; and the possibility of undergoing follow-up testing and diagnostic procedures. An investigator coded the transcripts to assess for the presence of each required element and scored the encounter from 0 to 7.

We also surveyed veterans completing SDM, using a convenience sampling strategy to evaluate knowledge, the quality of the SDM process, and decisional conflict. Initially, we sent mailed surveys to subjects to be completed 1 week after the SDM visit. To increase the response rate, we subsequently called patients to complete the surveys by telephone 1 week after the SDM visit.

We used the validated LCS-12 knowledge measure to assess awareness of lung cancer risks, screening eligibility, and the benefits and harms of screening.¹⁴ We evaluated the quality of the SDM visit by using the 3-item CollaboRATE scale (Table 1).¹⁵

Clinical Outcomes

We used the screening dashboard and CPRS to track clinical outcomes, including screening uptake, referrals for tobacco cessation, appropriate (screening or diagnostic) follow-up testing, and cancer diagnoses. We used descriptive statistics to characterize demographic data and survey responses.

Initial Findings

We conducted 105 SDM telephone visits from November 2020 through July 2022 (Table 2).

We surveyed 47 of the veterans completing SDM visits (45%) and received 37 completed surveys (79%). All respondents were male, mean age 61.9 years, 89% White, 38% married/partnered, 70% rural, 65% currently smoking, with a mean 44.8 pack-years smoking history. On average, veterans answered 6.3 (53%) of knowledge questions correctly (Table 3).

Implementing SDM

The NPC’s field notes indicated that many veterans did not perceive any need to discuss the screening decision and believed that their PCP had referred them just for screening. However, they reported having cursory discussions with their PCP, being told that only their history of heavy tobacco use meant they should be screened. For veterans who had not read the decision aid, the NPC attempted to summarize benefits and harms. However, the discussions were often inadequate because the veterans were not interested in receiving information, particularly numerical data, or indicated that they had limited time for the call.

Seventy-two (69%) of the veterans who met with the NPC were currently smoking. Tobacco cessation counseling was offered to 66; 29 were referred to the VA Quit Line, 10 were referred to the tobacco cessation pharmacist, and the NPC contacted the PCPs for 9 patients who wanted prescriptions for nicotine replacement therapy.

After the SDM visit, 91 veterans (87%) agreed to screening. By the end of the study period, 73 veterans (80%) completed testing. Most veterans had Lung-RADS 1 or 2 results, 11 (1%) had a Lung-RADS 3, and 7 (10%) had a Lung-RADS 4. All 9 veterans with Lung-RADS 3 results and at least 6 months of follow-up underwent repeat imaging within 4 to 13 months (median, 7). All veterans with a Lung-RADS 4 result were referred to pulmonary. One patient was diagnosed with an early-stage non–small cell lung cancer.

We identified several problems with LDCT coding. Radiologists did not consistently use Lung-RADS when interpreting screening LDCTs; some used the Fleischner lung nodule criteria.¹⁸ We also found discordant readings for abnormal LDCTs, where the assigned Lung-RADS score was not consistent with the nodule description in the radiology report.

Discussion

Efforts to implement LCS with a telemedicine SDM intervention were mixed. An NPC-led SDM phone call was successfully incorporated into the clinical workflow. Most veterans identified as being eligible for screening participated in the counseling visit and underwent screening. However, they were often reluctant to engage in SDM, feeling that their clinician had already recommended screening and that there was no need for further discussion. Unfortunately, many veterans had not received or reviewed the decision aid and were not interested in receiving information about benefits and harms. Because we relied on telephone calls, we could not share visual information in real time.

Overall, the surveys indicated that most veterans were very satisfied with the quality of the discussion and reported feeling no decisional conflict. However, based on the NPC’s field notes and audio recordings, we believe that the responses may have reflected earlier discussions with the PCP that reportedly emphasized only the veteran’s eligibility for screening. The fidelity assessments indicated that the NPC consistently addressed the harms and benefits of screening.

Nonetheless, the performance on knowledge measures was uneven. Veterans were generally aware of harms, including false alarms, overdiagnosis, radiation exposure, and incidental findings. They did not, however, appreciate when screening should stop. They also underestimated the risks of developing lung cancer and the portion of that risk attributable to tobacco use, and overestimated the benefits of screening. These results suggest that the veterans, at least those who completed the surveys, may not be making well-informed decisions.

Our findings echo those of other VA investigators in finding knowledge deficits among screened veterans, including being unaware that LDCT was for LCS, believing that screening could prevent cancer, receiving little information about screening harms, and feeling that negative tests meant they were among the “lucky ones” who would avoid harm from continued smoking.^19,20

The VA is currently implementing centralized screening models with the Lung Precision Oncology Program and the VA partnership to increase access to lung screening (VA-PALS).⁵ The centralized model, which readily supports the tracking, monitoring, and reporting needs of a screening program, also has advantages in delivering SDM because counselors have been trained in SDM, are more familiar with LCS evidence and processes, can better incorporate decision tools, and do not face the same time constraints as clinicians.²¹ However, studies have shown that most patients have already decided to be screened when they show up for the SDM visit.²² In contrast, about one-third of patients in primary care settings who receive decision support chose not to be screened.^23,24 We found that 13% of our patients decided against screening after a telephone discussion, suggesting that a virtually conducted SDM visit can meaningfully support decision making. Telemedicine also may reduce health inequities in centralized models arising from patients having limited access to screening centers.

Our results suggest that PCPs referring patients to a centralized program, even for virtual visits, should frame the decision to initiate LCS as SDM, where an informed patient is being supported in making a decision consistent with their values and preferences. Furthermore, engaging patients in SDM should not be construed as endorsing screening. When centralized support is less available, individual clinics may need to provide SDM, perhaps using a nonclinician decision coach if clinicians lack the time to lead the discussions. Decision coaches have been effectively used to increase patients’ knowledge about the benefits and harms of screening.¹² Regardless of the program model, PCPs will also be responsible for determining whether patients are healthy enough to undergo invasive diagnostic testing and treatment and ensuring that tobacco use is addressed.

SDM delivered in any setting will be enhanced by ensuring that patients are provided with decision aids before a counseling visit. This will help them better understand the benefits and harms of screening and the need to elicit values. The discussion can then focus on areas of concern or questions raised by reviewing the decision aid. The clinician and patient could also use a decision aid during either a face-to-face or video clinical encounter to facilitate SDM. A Cochrane review has shown that using decision aids for people facing screening decisions increases knowledge, reduces decisional conflict, and effectively elicits values and preferences.²⁵ Providing high-quality decision support is a patient-centered approach that respects a patient’s autonomy and may promote health equity and improve adherence.

We recognized the importance of having a multidisciplinary team, involving primary care, radiology, pulmonary, and nursing, with a shared understanding of the screening processes. These are essential features for a high-quality screening program where eligible veterans are readily identified and receive prompt and appropriate follow-up. Radiologists need to use Lung-RADS categories consistently and appropriately when reading LDCTs. This may require ongoing educational efforts, particularly given the new CMS guidelines accepting nonsubspecialist chest readers.⁷ Additionally, fellows and board-eligible residents may interpret images in academic settings and at VA facilities. The program needs to work closely with the pulmonary service to ensure that Lung-RADS 4 patients are promptly assessed. Radiologists and pulmonologists should calibrate the application of Lung-RADS categories to pulmonary nodules through jointly participating in meetings to review selected cases.

Challenges and Limitations

We faced some notable implementation challenges. The COVID-19 pandemic was extremely disruptive to LCS as it was to all health care. In addition, screening workflow processes were hampered by a lack of clinical reminders, which ideally would trigger for clinicians based on the tobacco history. The absence of this reminder meant that numerous patients were found to be ineligible for screening. We have a long-standing lung nodule clinic, and clinicians were confused about whether to order a surveillance imaging for an incidental nodule or a screening LDCT.

The radiology service was able to update order sets in CPRS to help guide clinicians in distinguishing indications and prerequisites for enrolling in LCS. This helped reduce the number of inappropriate orders and crossover orders between the VISN nodule tracking program and the LCS program.

Our results were preliminary and based on a small sample. We did not survey all veterans who underwent SDM, though the response rate was 79% and patient characteristics were similar to the larger cohort. Our results were potentially subject to selection bias, which could inflate the positive responses about decision quality and decisional conflict. However, the knowledge deficits are likely to be valid and suggest a need to better inform eligible veterans about the benefits and harms of screening. We did not have sufficient follow-up time to determine whether veterans were adherent to annual screenings. We showed that almost all those with abnormal imaging results completed diagnostic evaluations and/or were evaluated by pulmonary. As the program matures, we will be able to track outcomes related to cancer diagnoses and treatment.

Conclusions

A centralized LCS program was able to deliver SDM and enroll veterans in a screening program. While veterans were confident in their decision to screen and felt that they participated in decision making, knowledge testing indicated important deficits. Furthermore, we observed that many veterans did not meaningfully engage in SDM. Clinicians will need to frame the decision as patient centered at the time of referral, highlight the role of the NPC and importance of SDM, and be able to provide adequate decision support. The SDM visits can be enhanced by ensuring that veterans are able to review decision aids. Telemedicine is an acceptable and effective approach for supporting screening discussions, particularly for rural veterans.²⁶

Acknowledgments

The authors thank the following individuals for their contributions to the study: John Paul Hornbeck, program support specialist; Kelly Miell, PhD; Bradley Mecham, PhD; Christopher C. Richards, MA; Bailey Noble, NP; Rebecca Barnhart, program analyst.

Lung cancer is the second most frequently diagnosed cancer among US veterans and the leading cause of cancer death.¹ Clinical trials have shown that annual screening of high-risk persons with low-dose computed tomography (LDCT) can reduce the risk of dying of lung cancer.² In 2011, the National Lung Screening Trial (NLST) reported that over a 3-year period, annual LDCT screening reduced the risk of dying of lung cancer by 20% compared with chest radiograph screening.³ Lung cancer screening (LCS), however, was associated with harms, including false-positive results, complications from invasive diagnostic procedures, incidental findings, overdiagnosis, and radiation exposure.

The US Preventive Services Task Force (USPSTF) began recommending annual screening of high-risk persons after publication of the NLST results.⁴ The Veterans Health Administration (VHA) recommended implementing LCS in 2017.⁵ Guidelines, however, have consistently highlighted the complexity of the decision and the importance of engaging patients in thorough discussions about the potential benefits and harms of screening (shared decision making [SDM]). The Centers for Medicare and Medicaid Services (CMS) has issued coverage determinations mandating that eligible patients undergo a counseling visit that uses a decision aid to support SDM for LCS and addresses tobacco use.^6,7 However, primary care practitioners (PCPs) face many challenges in delivering SDM, including a lack of awareness of clinical trial results and screening guidelines, competing clinical demands, being untrained in SDM, and not having educational resources.⁸ Patients in rural locations face travel burdens in attending counseling visits.⁹

We conducted a pilot study to address concerns with delivering SDM for LCS to veterans. We implemented a centralized screening model in which veterans were referred by clinicians to a trained decision coach who conducted telephone visits to discuss the initial LCS decision, addressed tobacco cessation, and placed LDCT orders. We evaluated the outcomes of this telemedicine visit by using decision quality metrics and tracking LCS uptake, referrals for tobacco cessation, and clinical outcomes. The University of Iowa Institutional Review Board considered this study to be a quality improvement project and waived informed consent and HIPAA (Health Insurance Portability and Accountability Act) authorization requirements.

Implementation

We implemented the LCS program at the Iowa City Veterans Affairs Health Care System (ICVAHCS), which has both resident and staff clinicians, and 2 community-based outpatient clinics (Coralville, Cedar Rapids) with staff clinicians. The pilot study, conducted from November 2020 through July 2022, was led by a multidisciplinary team that included a nurse, primary care physician, pulmonologist, and radiologist. The team conducted online presentations to educate PCPs about the epidemiology of lung cancer, results of screening trials, LCS guidelines, the rationale for a centralized model of SDM, and the ICVAHCS screening protocols.

Screening Referrals

When the study began in 2020, we used the 2015 USPSTF criteria for annual LCS: individuals aged 55 to 80 years with a 30 pack-year smoking history and current tobacco user or who had quit within 15 years.⁴ We lowered the starting age to 50 years and the pack-year requirement to 20 after the USPSTF issued updated guidelines in 2021.¹⁰ Clinicians were notified about potentially eligible patients through the US Department of Veterans Affairs (VA) Computerized Personal Record System (CPRS) reminders or by the nurse program coordinator (NPC) who reviewed health records of patients with upcoming appointments. If the clinician determined that screening was appropriate, they ordered an LCS consult. The NPC called the veteran to confirm eligibility, mailed a decision aid, and scheduled a telephone visit to conduct SDM. We used the VA decision aid developed for the LCS demonstration project conducted at 8 academic VA medical centers between 2013 and 2017.¹¹

Shared Decision-Making Telephone Visit

The NPC adapted a telephone script developed for a Cancer Prevention and Research Institute of Texas–funded project conducted by 2 coauthors (RJV and LML).¹² The NPC asked about receipt/review of the decision aid, described the screening process, and addressed benefits and potential harms of screening. The NPC also offered smoking cessation interventions for veterans who were currently smoking, including referrals to the VA patient aligned care team clinical pharmacist for management of tobacco cessation or to the national VA Quit Line. The encounter ended by assessing the veteran’s understanding of screening issues and eliciting the veteran’s preferences for LDCT and willingness to adhere with the LCS program.

LDCT Imaging

The NPC placed LDCT orders for veterans interested in screening and alerted the referring clinician to sign the order. Veterans who agreed to be screened were placed in an LCS dashboard developed by the Veterans Integrated Services Network (VISN) 23 LCS program that was used as a patient management tool. The dashboard allowed the NPC to track patients, ensuring that veterans were being scheduled for and completing initial and follow-up testing. Radiologists used the Lung-RADS (Lung Imaging Reporting and Data System) to categorize LDCT results (1, normal; 2, benign nodule; 3, probably benign nodule; 4, suspicious nodule).¹³ Veterans with Lung-RADS 1 or 2 results were scheduled for an annual LDCT (if they remained eligible). Veterans with Lung-RADS 3 results were scheduled for a 6-month follow-up CT. The screening program sent electronic consults to pulmonary for veterans with Lung-RADS 4 to determine whether they should undergo additional imaging or be evaluated in the pulmonary clinic.

Evaluating Shared Decision Making

We audio taped and transcribed randomly selected SDM encounters to assess fidelity with the 2016 CMS required discussion elements for counseling about lung cancer, including the benefit of reducing lung cancer mortality; the potential for harms from false alarms, incidental findings, overdiagnosis, and radiation exposure; the need for annual screening; the importance of smoking cessation; and the possibility of undergoing follow-up testing and diagnostic procedures. An investigator coded the transcripts to assess for the presence of each required element and scored the encounter from 0 to 7.

We also surveyed veterans completing SDM, using a convenience sampling strategy to evaluate knowledge, the quality of the SDM process, and decisional conflict. Initially, we sent mailed surveys to subjects to be completed 1 week after the SDM visit. To increase the response rate, we subsequently called patients to complete the surveys by telephone 1 week after the SDM visit.

We used the validated LCS-12 knowledge measure to assess awareness of lung cancer risks, screening eligibility, and the benefits and harms of screening.¹⁴ We evaluated the quality of the SDM visit by using the 3-item CollaboRATE scale (Table 1).¹⁵

Clinical Outcomes

We used the screening dashboard and CPRS to track clinical outcomes, including screening uptake, referrals for tobacco cessation, appropriate (screening or diagnostic) follow-up testing, and cancer diagnoses. We used descriptive statistics to characterize demographic data and survey responses.

Initial Findings

We conducted 105 SDM telephone visits from November 2020 through July 2022 (Table 2).

We surveyed 47 of the veterans completing SDM visits (45%) and received 37 completed surveys (79%). All respondents were male, mean age 61.9 years, 89% White, 38% married/partnered, 70% rural, 65% currently smoking, with a mean 44.8 pack-years smoking history. On average, veterans answered 6.3 (53%) of knowledge questions correctly (Table 3).

Implementing SDM

The NPC’s field notes indicated that many veterans did not perceive any need to discuss the screening decision and believed that their PCP had referred them just for screening. However, they reported having cursory discussions with their PCP, being told that only their history of heavy tobacco use meant they should be screened. For veterans who had not read the decision aid, the NPC attempted to summarize benefits and harms. However, the discussions were often inadequate because the veterans were not interested in receiving information, particularly numerical data, or indicated that they had limited time for the call.

Seventy-two (69%) of the veterans who met with the NPC were currently smoking. Tobacco cessation counseling was offered to 66; 29 were referred to the VA Quit Line, 10 were referred to the tobacco cessation pharmacist, and the NPC contacted the PCPs for 9 patients who wanted prescriptions for nicotine replacement therapy.

After the SDM visit, 91 veterans (87%) agreed to screening. By the end of the study period, 73 veterans (80%) completed testing. Most veterans had Lung-RADS 1 or 2 results, 11 (1%) had a Lung-RADS 3, and 7 (10%) had a Lung-RADS 4. All 9 veterans with Lung-RADS 3 results and at least 6 months of follow-up underwent repeat imaging within 4 to 13 months (median, 7). All veterans with a Lung-RADS 4 result were referred to pulmonary. One patient was diagnosed with an early-stage non–small cell lung cancer.

We identified several problems with LDCT coding. Radiologists did not consistently use Lung-RADS when interpreting screening LDCTs; some used the Fleischner lung nodule criteria.¹⁸ We also found discordant readings for abnormal LDCTs, where the assigned Lung-RADS score was not consistent with the nodule description in the radiology report.

Discussion

Efforts to implement LCS with a telemedicine SDM intervention were mixed. An NPC-led SDM phone call was successfully incorporated into the clinical workflow. Most veterans identified as being eligible for screening participated in the counseling visit and underwent screening. However, they were often reluctant to engage in SDM, feeling that their clinician had already recommended screening and that there was no need for further discussion. Unfortunately, many veterans had not received or reviewed the decision aid and were not interested in receiving information about benefits and harms. Because we relied on telephone calls, we could not share visual information in real time.

Overall, the surveys indicated that most veterans were very satisfied with the quality of the discussion and reported feeling no decisional conflict. However, based on the NPC’s field notes and audio recordings, we believe that the responses may have reflected earlier discussions with the PCP that reportedly emphasized only the veteran’s eligibility for screening. The fidelity assessments indicated that the NPC consistently addressed the harms and benefits of screening.

Nonetheless, the performance on knowledge measures was uneven. Veterans were generally aware of harms, including false alarms, overdiagnosis, radiation exposure, and incidental findings. They did not, however, appreciate when screening should stop. They also underestimated the risks of developing lung cancer and the portion of that risk attributable to tobacco use, and overestimated the benefits of screening. These results suggest that the veterans, at least those who completed the surveys, may not be making well-informed decisions.

Our findings echo those of other VA investigators in finding knowledge deficits among screened veterans, including being unaware that LDCT was for LCS, believing that screening could prevent cancer, receiving little information about screening harms, and feeling that negative tests meant they were among the “lucky ones” who would avoid harm from continued smoking.^19,20

The VA is currently implementing centralized screening models with the Lung Precision Oncology Program and the VA partnership to increase access to lung screening (VA-PALS).⁵ The centralized model, which readily supports the tracking, monitoring, and reporting needs of a screening program, also has advantages in delivering SDM because counselors have been trained in SDM, are more familiar with LCS evidence and processes, can better incorporate decision tools, and do not face the same time constraints as clinicians.²¹ However, studies have shown that most patients have already decided to be screened when they show up for the SDM visit.²² In contrast, about one-third of patients in primary care settings who receive decision support chose not to be screened.^23,24 We found that 13% of our patients decided against screening after a telephone discussion, suggesting that a virtually conducted SDM visit can meaningfully support decision making. Telemedicine also may reduce health inequities in centralized models arising from patients having limited access to screening centers.

Our results suggest that PCPs referring patients to a centralized program, even for virtual visits, should frame the decision to initiate LCS as SDM, where an informed patient is being supported in making a decision consistent with their values and preferences. Furthermore, engaging patients in SDM should not be construed as endorsing screening. When centralized support is less available, individual clinics may need to provide SDM, perhaps using a nonclinician decision coach if clinicians lack the time to lead the discussions. Decision coaches have been effectively used to increase patients’ knowledge about the benefits and harms of screening.¹² Regardless of the program model, PCPs will also be responsible for determining whether patients are healthy enough to undergo invasive diagnostic testing and treatment and ensuring that tobacco use is addressed.

SDM delivered in any setting will be enhanced by ensuring that patients are provided with decision aids before a counseling visit. This will help them better understand the benefits and harms of screening and the need to elicit values. The discussion can then focus on areas of concern or questions raised by reviewing the decision aid. The clinician and patient could also use a decision aid during either a face-to-face or video clinical encounter to facilitate SDM. A Cochrane review has shown that using decision aids for people facing screening decisions increases knowledge, reduces decisional conflict, and effectively elicits values and preferences.²⁵ Providing high-quality decision support is a patient-centered approach that respects a patient’s autonomy and may promote health equity and improve adherence.

We recognized the importance of having a multidisciplinary team, involving primary care, radiology, pulmonary, and nursing, with a shared understanding of the screening processes. These are essential features for a high-quality screening program where eligible veterans are readily identified and receive prompt and appropriate follow-up. Radiologists need to use Lung-RADS categories consistently and appropriately when reading LDCTs. This may require ongoing educational efforts, particularly given the new CMS guidelines accepting nonsubspecialist chest readers.⁷ Additionally, fellows and board-eligible residents may interpret images in academic settings and at VA facilities. The program needs to work closely with the pulmonary service to ensure that Lung-RADS 4 patients are promptly assessed. Radiologists and pulmonologists should calibrate the application of Lung-RADS categories to pulmonary nodules through jointly participating in meetings to review selected cases.

Challenges and Limitations

We faced some notable implementation challenges. The COVID-19 pandemic was extremely disruptive to LCS as it was to all health care. In addition, screening workflow processes were hampered by a lack of clinical reminders, which ideally would trigger for clinicians based on the tobacco history. The absence of this reminder meant that numerous patients were found to be ineligible for screening. We have a long-standing lung nodule clinic, and clinicians were confused about whether to order a surveillance imaging for an incidental nodule or a screening LDCT.

The radiology service was able to update order sets in CPRS to help guide clinicians in distinguishing indications and prerequisites for enrolling in LCS. This helped reduce the number of inappropriate orders and crossover orders between the VISN nodule tracking program and the LCS program.

Our results were preliminary and based on a small sample. We did not survey all veterans who underwent SDM, though the response rate was 79% and patient characteristics were similar to the larger cohort. Our results were potentially subject to selection bias, which could inflate the positive responses about decision quality and decisional conflict. However, the knowledge deficits are likely to be valid and suggest a need to better inform eligible veterans about the benefits and harms of screening. We did not have sufficient follow-up time to determine whether veterans were adherent to annual screenings. We showed that almost all those with abnormal imaging results completed diagnostic evaluations and/or were evaluated by pulmonary. As the program matures, we will be able to track outcomes related to cancer diagnoses and treatment.

Conclusions

A centralized LCS program was able to deliver SDM and enroll veterans in a screening program. While veterans were confident in their decision to screen and felt that they participated in decision making, knowledge testing indicated important deficits. Furthermore, we observed that many veterans did not meaningfully engage in SDM. Clinicians will need to frame the decision as patient centered at the time of referral, highlight the role of the NPC and importance of SDM, and be able to provide adequate decision support. The SDM visits can be enhanced by ensuring that veterans are able to review decision aids. Telemedicine is an acceptable and effective approach for supporting screening discussions, particularly for rural veterans.²⁶

Acknowledgments

The authors thank the following individuals for their contributions to the study: John Paul Hornbeck, program support specialist; Kelly Miell, PhD; Bradley Mecham, PhD; Christopher C. Richards, MA; Bailey Noble, NP; Rebecca Barnhart, program analyst.

Lung cancer is the second most frequently diagnosed cancer among US veterans and the leading cause of cancer death.¹ Clinical trials have shown that annual screening of high-risk persons with low-dose computed tomography (LDCT) can reduce the risk of dying of lung cancer.² In 2011, the National Lung Screening Trial (NLST) reported that over a 3-year period, annual LDCT screening reduced the risk of dying of lung cancer by 20% compared with chest radiograph screening.³ Lung cancer screening (LCS), however, was associated with harms, including false-positive results, complications from invasive diagnostic procedures, incidental findings, overdiagnosis, and radiation exposure.

The US Preventive Services Task Force (USPSTF) began recommending annual screening of high-risk persons after publication of the NLST results.⁴ The Veterans Health Administration (VHA) recommended implementing LCS in 2017.⁵ Guidelines, however, have consistently highlighted the complexity of the decision and the importance of engaging patients in thorough discussions about the potential benefits and harms of screening (shared decision making [SDM]). The Centers for Medicare and Medicaid Services (CMS) has issued coverage determinations mandating that eligible patients undergo a counseling visit that uses a decision aid to support SDM for LCS and addresses tobacco use.^6,7 However, primary care practitioners (PCPs) face many challenges in delivering SDM, including a lack of awareness of clinical trial results and screening guidelines, competing clinical demands, being untrained in SDM, and not having educational resources.⁸ Patients in rural locations face travel burdens in attending counseling visits.⁹

We conducted a pilot study to address concerns with delivering SDM for LCS to veterans. We implemented a centralized screening model in which veterans were referred by clinicians to a trained decision coach who conducted telephone visits to discuss the initial LCS decision, addressed tobacco cessation, and placed LDCT orders. We evaluated the outcomes of this telemedicine visit by using decision quality metrics and tracking LCS uptake, referrals for tobacco cessation, and clinical outcomes. The University of Iowa Institutional Review Board considered this study to be a quality improvement project and waived informed consent and HIPAA (Health Insurance Portability and Accountability Act) authorization requirements.

Implementation

We implemented the LCS program at the Iowa City Veterans Affairs Health Care System (ICVAHCS), which has both resident and staff clinicians, and 2 community-based outpatient clinics (Coralville, Cedar Rapids) with staff clinicians. The pilot study, conducted from November 2020 through July 2022, was led by a multidisciplinary team that included a nurse, primary care physician, pulmonologist, and radiologist. The team conducted online presentations to educate PCPs about the epidemiology of lung cancer, results of screening trials, LCS guidelines, the rationale for a centralized model of SDM, and the ICVAHCS screening protocols.

Screening Referrals

When the study began in 2020, we used the 2015 USPSTF criteria for annual LCS: individuals aged 55 to 80 years with a 30 pack-year smoking history and current tobacco user or who had quit within 15 years.⁴ We lowered the starting age to 50 years and the pack-year requirement to 20 after the USPSTF issued updated guidelines in 2021.¹⁰ Clinicians were notified about potentially eligible patients through the US Department of Veterans Affairs (VA) Computerized Personal Record System (CPRS) reminders or by the nurse program coordinator (NPC) who reviewed health records of patients with upcoming appointments. If the clinician determined that screening was appropriate, they ordered an LCS consult. The NPC called the veteran to confirm eligibility, mailed a decision aid, and scheduled a telephone visit to conduct SDM. We used the VA decision aid developed for the LCS demonstration project conducted at 8 academic VA medical centers between 2013 and 2017.¹¹

Shared Decision-Making Telephone Visit

The NPC adapted a telephone script developed for a Cancer Prevention and Research Institute of Texas–funded project conducted by 2 coauthors (RJV and LML).¹² The NPC asked about receipt/review of the decision aid, described the screening process, and addressed benefits and potential harms of screening. The NPC also offered smoking cessation interventions for veterans who were currently smoking, including referrals to the VA patient aligned care team clinical pharmacist for management of tobacco cessation or to the national VA Quit Line. The encounter ended by assessing the veteran’s understanding of screening issues and eliciting the veteran’s preferences for LDCT and willingness to adhere with the LCS program.

LDCT Imaging

The NPC placed LDCT orders for veterans interested in screening and alerted the referring clinician to sign the order. Veterans who agreed to be screened were placed in an LCS dashboard developed by the Veterans Integrated Services Network (VISN) 23 LCS program that was used as a patient management tool. The dashboard allowed the NPC to track patients, ensuring that veterans were being scheduled for and completing initial and follow-up testing. Radiologists used the Lung-RADS (Lung Imaging Reporting and Data System) to categorize LDCT results (1, normal; 2, benign nodule; 3, probably benign nodule; 4, suspicious nodule).¹³ Veterans with Lung-RADS 1 or 2 results were scheduled for an annual LDCT (if they remained eligible). Veterans with Lung-RADS 3 results were scheduled for a 6-month follow-up CT. The screening program sent electronic consults to pulmonary for veterans with Lung-RADS 4 to determine whether they should undergo additional imaging or be evaluated in the pulmonary clinic.

Evaluating Shared Decision Making

We audio taped and transcribed randomly selected SDM encounters to assess fidelity with the 2016 CMS required discussion elements for counseling about lung cancer, including the benefit of reducing lung cancer mortality; the potential for harms from false alarms, incidental findings, overdiagnosis, and radiation exposure; the need for annual screening; the importance of smoking cessation; and the possibility of undergoing follow-up testing and diagnostic procedures. An investigator coded the transcripts to assess for the presence of each required element and scored the encounter from 0 to 7.

We also surveyed veterans completing SDM, using a convenience sampling strategy to evaluate knowledge, the quality of the SDM process, and decisional conflict. Initially, we sent mailed surveys to subjects to be completed 1 week after the SDM visit. To increase the response rate, we subsequently called patients to complete the surveys by telephone 1 week after the SDM visit.

We used the validated LCS-12 knowledge measure to assess awareness of lung cancer risks, screening eligibility, and the benefits and harms of screening.¹⁴ We evaluated the quality of the SDM visit by using the 3-item CollaboRATE scale (Table 1).¹⁵

Clinical Outcomes

We used the screening dashboard and CPRS to track clinical outcomes, including screening uptake, referrals for tobacco cessation, appropriate (screening or diagnostic) follow-up testing, and cancer diagnoses. We used descriptive statistics to characterize demographic data and survey responses.

Initial Findings

We conducted 105 SDM telephone visits from November 2020 through July 2022 (Table 2).

We surveyed 47 of the veterans completing SDM visits (45%) and received 37 completed surveys (79%). All respondents were male, mean age 61.9 years, 89% White, 38% married/partnered, 70% rural, 65% currently smoking, with a mean 44.8 pack-years smoking history. On average, veterans answered 6.3 (53%) of knowledge questions correctly (Table 3).

Implementing SDM

The NPC’s field notes indicated that many veterans did not perceive any need to discuss the screening decision and believed that their PCP had referred them just for screening. However, they reported having cursory discussions with their PCP, being told that only their history of heavy tobacco use meant they should be screened. For veterans who had not read the decision aid, the NPC attempted to summarize benefits and harms. However, the discussions were often inadequate because the veterans were not interested in receiving information, particularly numerical data, or indicated that they had limited time for the call.

Seventy-two (69%) of the veterans who met with the NPC were currently smoking. Tobacco cessation counseling was offered to 66; 29 were referred to the VA Quit Line, 10 were referred to the tobacco cessation pharmacist, and the NPC contacted the PCPs for 9 patients who wanted prescriptions for nicotine replacement therapy.

After the SDM visit, 91 veterans (87%) agreed to screening. By the end of the study period, 73 veterans (80%) completed testing. Most veterans had Lung-RADS 1 or 2 results, 11 (1%) had a Lung-RADS 3, and 7 (10%) had a Lung-RADS 4. All 9 veterans with Lung-RADS 3 results and at least 6 months of follow-up underwent repeat imaging within 4 to 13 months (median, 7). All veterans with a Lung-RADS 4 result were referred to pulmonary. One patient was diagnosed with an early-stage non–small cell lung cancer.

We identified several problems with LDCT coding. Radiologists did not consistently use Lung-RADS when interpreting screening LDCTs; some used the Fleischner lung nodule criteria.¹⁸ We also found discordant readings for abnormal LDCTs, where the assigned Lung-RADS score was not consistent with the nodule description in the radiology report.

Discussion

Efforts to implement LCS with a telemedicine SDM intervention were mixed. An NPC-led SDM phone call was successfully incorporated into the clinical workflow. Most veterans identified as being eligible for screening participated in the counseling visit and underwent screening. However, they were often reluctant to engage in SDM, feeling that their clinician had already recommended screening and that there was no need for further discussion. Unfortunately, many veterans had not received or reviewed the decision aid and were not interested in receiving information about benefits and harms. Because we relied on telephone calls, we could not share visual information in real time.

Overall, the surveys indicated that most veterans were very satisfied with the quality of the discussion and reported feeling no decisional conflict. However, based on the NPC’s field notes and audio recordings, we believe that the responses may have reflected earlier discussions with the PCP that reportedly emphasized only the veteran’s eligibility for screening. The fidelity assessments indicated that the NPC consistently addressed the harms and benefits of screening.

Nonetheless, the performance on knowledge measures was uneven. Veterans were generally aware of harms, including false alarms, overdiagnosis, radiation exposure, and incidental findings. They did not, however, appreciate when screening should stop. They also underestimated the risks of developing lung cancer and the portion of that risk attributable to tobacco use, and overestimated the benefits of screening. These results suggest that the veterans, at least those who completed the surveys, may not be making well-informed decisions.

Our findings echo those of other VA investigators in finding knowledge deficits among screened veterans, including being unaware that LDCT was for LCS, believing that screening could prevent cancer, receiving little information about screening harms, and feeling that negative tests meant they were among the “lucky ones” who would avoid harm from continued smoking.^19,20

The VA is currently implementing centralized screening models with the Lung Precision Oncology Program and the VA partnership to increase access to lung screening (VA-PALS).⁵ The centralized model, which readily supports the tracking, monitoring, and reporting needs of a screening program, also has advantages in delivering SDM because counselors have been trained in SDM, are more familiar with LCS evidence and processes, can better incorporate decision tools, and do not face the same time constraints as clinicians.²¹ However, studies have shown that most patients have already decided to be screened when they show up for the SDM visit.²² In contrast, about one-third of patients in primary care settings who receive decision support chose not to be screened.^23,24 We found that 13% of our patients decided against screening after a telephone discussion, suggesting that a virtually conducted SDM visit can meaningfully support decision making. Telemedicine also may reduce health inequities in centralized models arising from patients having limited access to screening centers.

Our results suggest that PCPs referring patients to a centralized program, even for virtual visits, should frame the decision to initiate LCS as SDM, where an informed patient is being supported in making a decision consistent with their values and preferences. Furthermore, engaging patients in SDM should not be construed as endorsing screening. When centralized support is less available, individual clinics may need to provide SDM, perhaps using a nonclinician decision coach if clinicians lack the time to lead the discussions. Decision coaches have been effectively used to increase patients’ knowledge about the benefits and harms of screening.¹² Regardless of the program model, PCPs will also be responsible for determining whether patients are healthy enough to undergo invasive diagnostic testing and treatment and ensuring that tobacco use is addressed.

SDM delivered in any setting will be enhanced by ensuring that patients are provided with decision aids before a counseling visit. This will help them better understand the benefits and harms of screening and the need to elicit values. The discussion can then focus on areas of concern or questions raised by reviewing the decision aid. The clinician and patient could also use a decision aid during either a face-to-face or video clinical encounter to facilitate SDM. A Cochrane review has shown that using decision aids for people facing screening decisions increases knowledge, reduces decisional conflict, and effectively elicits values and preferences.²⁵ Providing high-quality decision support is a patient-centered approach that respects a patient’s autonomy and may promote health equity and improve adherence.

We recognized the importance of having a multidisciplinary team, involving primary care, radiology, pulmonary, and nursing, with a shared understanding of the screening processes. These are essential features for a high-quality screening program where eligible veterans are readily identified and receive prompt and appropriate follow-up. Radiologists need to use Lung-RADS categories consistently and appropriately when reading LDCTs. This may require ongoing educational efforts, particularly given the new CMS guidelines accepting nonsubspecialist chest readers.⁷ Additionally, fellows and board-eligible residents may interpret images in academic settings and at VA facilities. The program needs to work closely with the pulmonary service to ensure that Lung-RADS 4 patients are promptly assessed. Radiologists and pulmonologists should calibrate the application of Lung-RADS categories to pulmonary nodules through jointly participating in meetings to review selected cases.

Challenges and Limitations

We faced some notable implementation challenges. The COVID-19 pandemic was extremely disruptive to LCS as it was to all health care. In addition, screening workflow processes were hampered by a lack of clinical reminders, which ideally would trigger for clinicians based on the tobacco history. The absence of this reminder meant that numerous patients were found to be ineligible for screening. We have a long-standing lung nodule clinic, and clinicians were confused about whether to order a surveillance imaging for an incidental nodule or a screening LDCT.

The radiology service was able to update order sets in CPRS to help guide clinicians in distinguishing indications and prerequisites for enrolling in LCS. This helped reduce the number of inappropriate orders and crossover orders between the VISN nodule tracking program and the LCS program.

Our results were preliminary and based on a small sample. We did not survey all veterans who underwent SDM, though the response rate was 79% and patient characteristics were similar to the larger cohort. Our results were potentially subject to selection bias, which could inflate the positive responses about decision quality and decisional conflict. However, the knowledge deficits are likely to be valid and suggest a need to better inform eligible veterans about the benefits and harms of screening. We did not have sufficient follow-up time to determine whether veterans were adherent to annual screenings. We showed that almost all those with abnormal imaging results completed diagnostic evaluations and/or were evaluated by pulmonary. As the program matures, we will be able to track outcomes related to cancer diagnoses and treatment.

Conclusions

A centralized LCS program was able to deliver SDM and enroll veterans in a screening program. While veterans were confident in their decision to screen and felt that they participated in decision making, knowledge testing indicated important deficits. Furthermore, we observed that many veterans did not meaningfully engage in SDM. Clinicians will need to frame the decision as patient centered at the time of referral, highlight the role of the NPC and importance of SDM, and be able to provide adequate decision support. The SDM visits can be enhanced by ensuring that veterans are able to review decision aids. Telemedicine is an acceptable and effective approach for supporting screening discussions, particularly for rural veterans.²⁶

Acknowledgments

The authors thank the following individuals for their contributions to the study: John Paul Hornbeck, program support specialist; Kelly Miell, PhD; Bradley Mecham, PhD; Christopher C. Richards, MA; Bailey Noble, NP; Rebecca Barnhart, program analyst.

P ruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). The exact pathophysiology of PV-associated pruritus is poorly understood. The itch sensation may arise from a central phenomenon without skin itch receptor involvement, as is seen in opioid-induced pruritus, or peripherally via unmyelinated C fibers. Various interventions have been used with mixed results for symptom management in this patient population.¹

Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and fluoxetine, have historically demonstrated some efficacy in treating PV-associated pruritus.² Alongside SSRIs, phlebotomy, antihistamines, phototherapy, interferon a, and myelosuppressive medications also comprise the various current treatment options. In addition to lacking efficacy, antihistamines can cause somnolence, constipation, and xerostomia.^3,4 Phlebotomy and cytoreductive therapy are often effective in controlling erythrocytosis but fail to alleviate the disabling pruritus.^1,5,6 More recently, suboptimal symptom alleviation has prompted the discovery of agents that target the mammalian target of rapamycin (mTOR) and Janus kinase 2 (Jak2) pathways.¹

Naltrexone is an opioid antagonist shown to suppress pruritus in various dermatologic pathologies involving histamine-independent pathways.^3,7,8 A systematic search strategy identified 34 studies on PV-associated pruritus, its pathophysiology and interventions, and naltrexone as a therapeutic agent. Only 1 study in the literature has described the use of naltrexone for uremic and cholestatic pruritus.⁹ We describe the successful use of naltrexone monotherapy for the treatment of pruritus in a patient with PV.

Case Presentation

A 40-year-old man with Jak2-positive PV treated with ruxolitinib presented to the outpatient Michael E. DeBakey Veterans Affairs Medical Center Supportive Care Clinic in Houston, Texas, for severe refractory pruritus. Wheals manifested in pruritic regions of the patient’s skin without gross excoriations or erythema. Pruritus reportedly began diffusely across the posterior torso. Through the rapid progression of an episode lasting 30 to 45 minutes, the lesions and pruritus would spread to the anterior torso, extend to the upper extremities bilaterally, and finally descend to the lower extremities bilaterally. A persistent sensation of heat or warmth on the patient’s skin was present, and periodically, this would culminate in a burning sensation comparable to “lying flat on one’s back directly on a hornet’s nest…[followed by] a million stings” that was inconsistent with erythromelalgia given the absence of erythema. The intensity of the pruritic episodes was subjectively also described as “enough to make [him] want to jump off the roof of a building…[causing] moments of deep, deep frustration…[and] the worst of all the symptoms one may encounter because of [PV].”

Pruritus was exacerbated by sweating, heat, contact with any liquids on the skin, and sunburns, which doubled the intensity. The patient reported minimal, temporary relief with cannabidiol and cold fabric or air on his skin. His current regimen and nonpharmacologic efforts provided no relief and included oatmeal baths, cornstarch after showers, and patting instead of rubbing the skin with topical products. Trials with nonprescription diphenhydramine, loratadine, and calamine and zinc were not successful. He had not pursued phototherapy due to time limitations and travel constraints. He had a history of phlebotomies and hydroxyurea use, which he preferred to avoid and discontinued 1 year before presentation.

Despite improving hematocrit (< 45% goal) and platelet counts with ruxolitinib, the patient reported worsening pruritus that significantly impaired quality of life. His sleep and social and physical activities were hindered, preventing him from working. The patient’s active medications also included low-dose aspirin, sertraline, hydroxyzine, triamcinolone acetonide, and pregabalin for sciatica. Given persistent symptoms despite multimodal therapy and lifestyle modifications, the patient was started on naltrexone 25 mg daily, which provided immediate relief of symptoms. He continues to have adequate symptom control 2 years after naltrexone initiation.

Literature Review

A systematic search strategy was developed with the assistance of a medical librarian in Medline Ovid, using both Medical Subject Heading (MeSH) terms and synonymous keywords. The strategy was then translated to Embase, Web of Science, and Cochrane to extract publications investigating PV, pruritus, and/or naltrexone therapy. All searches were conducted on July 18, 2022, and the results of the literature review were as follows: 2 results from Medline Ovid; 34 results from Embase (2 were duplicates of Medline Ovid results); 3 results from Web of Science (all of which were duplicates of Medline Ovid or Embase results); and 0 results from Cochrane (Figure).

Discussion

Although pruritus is a common and often excruciating manifestation of PV, its pathophysiology remains unclear. Some patients with decreasing or newly normal hematocrit and hemoglobin levels have paradoxically experienced an intensification of their pruritus, which introduces erythropoietin signaling pathways as a potential mechanism of the symptom.⁸ However, iron replacement therapy for patients with exacerbated pruritus after phlebotomies has not demonstrated consistent relief of pruritus.⁸ Normalization of platelet levels also has not been historically associated with improvement of pruritus.^8,9 It has been hypothesized that cells harboring Jak2 mutations at any stage of the hematopoietic pathway mature and accumulate to cause pruritus in PV.⁹ This theory has been foundational in the development of drugs with activity against cells expressing Jak2 mutations and interventions targeting histamine-releasing mast cells.^9-11

The effective use of naltrexone in our patient suggests that histamine may not be the most effective or sole therapeutic target against pruritus in PV. Naltrexone targets opioid receptors in all layers of the epidermis, affecting cell adhesion and keratinocyte production, and exhibits anti-inflammatory effects through interactions with nonopioid receptors, including Toll-like receptor 4.¹² The efficacy of oral naltrexone has been documented in patients with pruritus associated with immune checkpoint inhibitors, psoriasis, eczema, lichen simplex chronicus, prurigo nodularis, cholestasis, uremia, and multiple rheumatologic diseases.^{3,4,7-9,12-14} Opioid pathways also may be involved in peripheral and/or central processing of pruritus associated with PV.

Importantly, patients who are potential candidates for naltrexone therapy should be notified and advised of the risk of drug interactions with opioids, which could lead to symptoms of opioid withdrawal. Other common adverse effects of naltrexone include hepatotoxicity (especially in patients with a history of significant alcohol consumption), abdominal pain, nausea, arthralgias, myalgias, insomnia, headaches, fatigue, and anxiety.¹² Therefore, it is integral to screen patients for opioid dependence and determine their baseline liver function. Patients should be monitored following naltrexone initiation to determine whether the drug is an appropriate and effective intervention against PV-associated pruritus.

CONCLUSIONS

This case study demonstrates that naltrexone may be a safe, effective, nonsedating, and cost-efficient oral alternative for refractory PV-associated pruritus. Future directions involve consideration of case series or randomized clinical trials investigating the efficacy of naltrexone in treating PV-associated pruritus. Further research is also warranted to better understand the pathophysiology of this symptom of PV to enhance and potentially expand medical management for patients.

Acknowledgments

The authors thank Amy Sisson (The Texas Medical Center Library) for her guidance and support in the literature review methodology.

P ruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). The exact pathophysiology of PV-associated pruritus is poorly understood. The itch sensation may arise from a central phenomenon without skin itch receptor involvement, as is seen in opioid-induced pruritus, or peripherally via unmyelinated C fibers. Various interventions have been used with mixed results for symptom management in this patient population.¹

Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and fluoxetine, have historically demonstrated some efficacy in treating PV-associated pruritus.² Alongside SSRIs, phlebotomy, antihistamines, phototherapy, interferon a, and myelosuppressive medications also comprise the various current treatment options. In addition to lacking efficacy, antihistamines can cause somnolence, constipation, and xerostomia.^3,4 Phlebotomy and cytoreductive therapy are often effective in controlling erythrocytosis but fail to alleviate the disabling pruritus.^1,5,6 More recently, suboptimal symptom alleviation has prompted the discovery of agents that target the mammalian target of rapamycin (mTOR) and Janus kinase 2 (Jak2) pathways.¹

Naltrexone is an opioid antagonist shown to suppress pruritus in various dermatologic pathologies involving histamine-independent pathways.^3,7,8 A systematic search strategy identified 34 studies on PV-associated pruritus, its pathophysiology and interventions, and naltrexone as a therapeutic agent. Only 1 study in the literature has described the use of naltrexone for uremic and cholestatic pruritus.⁹ We describe the successful use of naltrexone monotherapy for the treatment of pruritus in a patient with PV.

Case Presentation

A 40-year-old man with Jak2-positive PV treated with ruxolitinib presented to the outpatient Michael E. DeBakey Veterans Affairs Medical Center Supportive Care Clinic in Houston, Texas, for severe refractory pruritus. Wheals manifested in pruritic regions of the patient’s skin without gross excoriations or erythema. Pruritus reportedly began diffusely across the posterior torso. Through the rapid progression of an episode lasting 30 to 45 minutes, the lesions and pruritus would spread to the anterior torso, extend to the upper extremities bilaterally, and finally descend to the lower extremities bilaterally. A persistent sensation of heat or warmth on the patient’s skin was present, and periodically, this would culminate in a burning sensation comparable to “lying flat on one’s back directly on a hornet’s nest…[followed by] a million stings” that was inconsistent with erythromelalgia given the absence of erythema. The intensity of the pruritic episodes was subjectively also described as “enough to make [him] want to jump off the roof of a building…[causing] moments of deep, deep frustration…[and] the worst of all the symptoms one may encounter because of [PV].”

Pruritus was exacerbated by sweating, heat, contact with any liquids on the skin, and sunburns, which doubled the intensity. The patient reported minimal, temporary relief with cannabidiol and cold fabric or air on his skin. His current regimen and nonpharmacologic efforts provided no relief and included oatmeal baths, cornstarch after showers, and patting instead of rubbing the skin with topical products. Trials with nonprescription diphenhydramine, loratadine, and calamine and zinc were not successful. He had not pursued phototherapy due to time limitations and travel constraints. He had a history of phlebotomies and hydroxyurea use, which he preferred to avoid and discontinued 1 year before presentation.

Despite improving hematocrit (< 45% goal) and platelet counts with ruxolitinib, the patient reported worsening pruritus that significantly impaired quality of life. His sleep and social and physical activities were hindered, preventing him from working. The patient’s active medications also included low-dose aspirin, sertraline, hydroxyzine, triamcinolone acetonide, and pregabalin for sciatica. Given persistent symptoms despite multimodal therapy and lifestyle modifications, the patient was started on naltrexone 25 mg daily, which provided immediate relief of symptoms. He continues to have adequate symptom control 2 years after naltrexone initiation.

Literature Review

A systematic search strategy was developed with the assistance of a medical librarian in Medline Ovid, using both Medical Subject Heading (MeSH) terms and synonymous keywords. The strategy was then translated to Embase, Web of Science, and Cochrane to extract publications investigating PV, pruritus, and/or naltrexone therapy. All searches were conducted on July 18, 2022, and the results of the literature review were as follows: 2 results from Medline Ovid; 34 results from Embase (2 were duplicates of Medline Ovid results); 3 results from Web of Science (all of which were duplicates of Medline Ovid or Embase results); and 0 results from Cochrane (Figure).

Discussion

Although pruritus is a common and often excruciating manifestation of PV, its pathophysiology remains unclear. Some patients with decreasing or newly normal hematocrit and hemoglobin levels have paradoxically experienced an intensification of their pruritus, which introduces erythropoietin signaling pathways as a potential mechanism of the symptom.⁸ However, iron replacement therapy for patients with exacerbated pruritus after phlebotomies has not demonstrated consistent relief of pruritus.⁸ Normalization of platelet levels also has not been historically associated with improvement of pruritus.^8,9 It has been hypothesized that cells harboring Jak2 mutations at any stage of the hematopoietic pathway mature and accumulate to cause pruritus in PV.⁹ This theory has been foundational in the development of drugs with activity against cells expressing Jak2 mutations and interventions targeting histamine-releasing mast cells.^9-11

The effective use of naltrexone in our patient suggests that histamine may not be the most effective or sole therapeutic target against pruritus in PV. Naltrexone targets opioid receptors in all layers of the epidermis, affecting cell adhesion and keratinocyte production, and exhibits anti-inflammatory effects through interactions with nonopioid receptors, including Toll-like receptor 4.¹² The efficacy of oral naltrexone has been documented in patients with pruritus associated with immune checkpoint inhibitors, psoriasis, eczema, lichen simplex chronicus, prurigo nodularis, cholestasis, uremia, and multiple rheumatologic diseases.^{3,4,7-9,12-14} Opioid pathways also may be involved in peripheral and/or central processing of pruritus associated with PV.

Importantly, patients who are potential candidates for naltrexone therapy should be notified and advised of the risk of drug interactions with opioids, which could lead to symptoms of opioid withdrawal. Other common adverse effects of naltrexone include hepatotoxicity (especially in patients with a history of significant alcohol consumption), abdominal pain, nausea, arthralgias, myalgias, insomnia, headaches, fatigue, and anxiety.¹² Therefore, it is integral to screen patients for opioid dependence and determine their baseline liver function. Patients should be monitored following naltrexone initiation to determine whether the drug is an appropriate and effective intervention against PV-associated pruritus.

CONCLUSIONS

This case study demonstrates that naltrexone may be a safe, effective, nonsedating, and cost-efficient oral alternative for refractory PV-associated pruritus. Future directions involve consideration of case series or randomized clinical trials investigating the efficacy of naltrexone in treating PV-associated pruritus. Further research is also warranted to better understand the pathophysiology of this symptom of PV to enhance and potentially expand medical management for patients.

Acknowledgments

The authors thank Amy Sisson (The Texas Medical Center Library) for her guidance and support in the literature review methodology.

P ruritus is a characteristic and often debilitating clinical manifestation reported by about 50% of patients with polycythemia vera (PV). The exact pathophysiology of PV-associated pruritus is poorly understood. The itch sensation may arise from a central phenomenon without skin itch receptor involvement, as is seen in opioid-induced pruritus, or peripherally via unmyelinated C fibers. Various interventions have been used with mixed results for symptom management in this patient population.¹

Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine and fluoxetine, have historically demonstrated some efficacy in treating PV-associated pruritus.² Alongside SSRIs, phlebotomy, antihistamines, phototherapy, interferon a, and myelosuppressive medications also comprise the various current treatment options. In addition to lacking efficacy, antihistamines can cause somnolence, constipation, and xerostomia.^3,4 Phlebotomy and cytoreductive therapy are often effective in controlling erythrocytosis but fail to alleviate the disabling pruritus.^1,5,6 More recently, suboptimal symptom alleviation has prompted the discovery of agents that target the mammalian target of rapamycin (mTOR) and Janus kinase 2 (Jak2) pathways.¹

Naltrexone is an opioid antagonist shown to suppress pruritus in various dermatologic pathologies involving histamine-independent pathways.^3,7,8 A systematic search strategy identified 34 studies on PV-associated pruritus, its pathophysiology and interventions, and naltrexone as a therapeutic agent. Only 1 study in the literature has described the use of naltrexone for uremic and cholestatic pruritus.⁹ We describe the successful use of naltrexone monotherapy for the treatment of pruritus in a patient with PV.

Case Presentation

A 40-year-old man with Jak2-positive PV treated with ruxolitinib presented to the outpatient Michael E. DeBakey Veterans Affairs Medical Center Supportive Care Clinic in Houston, Texas, for severe refractory pruritus. Wheals manifested in pruritic regions of the patient’s skin without gross excoriations or erythema. Pruritus reportedly began diffusely across the posterior torso. Through the rapid progression of an episode lasting 30 to 45 minutes, the lesions and pruritus would spread to the anterior torso, extend to the upper extremities bilaterally, and finally descend to the lower extremities bilaterally. A persistent sensation of heat or warmth on the patient’s skin was present, and periodically, this would culminate in a burning sensation comparable to “lying flat on one’s back directly on a hornet’s nest…[followed by] a million stings” that was inconsistent with erythromelalgia given the absence of erythema. The intensity of the pruritic episodes was subjectively also described as “enough to make [him] want to jump off the roof of a building…[causing] moments of deep, deep frustration…[and] the worst of all the symptoms one may encounter because of [PV].”

Pruritus was exacerbated by sweating, heat, contact with any liquids on the skin, and sunburns, which doubled the intensity. The patient reported minimal, temporary relief with cannabidiol and cold fabric or air on his skin. His current regimen and nonpharmacologic efforts provided no relief and included oatmeal baths, cornstarch after showers, and patting instead of rubbing the skin with topical products. Trials with nonprescription diphenhydramine, loratadine, and calamine and zinc were not successful. He had not pursued phototherapy due to time limitations and travel constraints. He had a history of phlebotomies and hydroxyurea use, which he preferred to avoid and discontinued 1 year before presentation.

Despite improving hematocrit (< 45% goal) and platelet counts with ruxolitinib, the patient reported worsening pruritus that significantly impaired quality of life. His sleep and social and physical activities were hindered, preventing him from working. The patient’s active medications also included low-dose aspirin, sertraline, hydroxyzine, triamcinolone acetonide, and pregabalin for sciatica. Given persistent symptoms despite multimodal therapy and lifestyle modifications, the patient was started on naltrexone 25 mg daily, which provided immediate relief of symptoms. He continues to have adequate symptom control 2 years after naltrexone initiation.

Literature Review

A systematic search strategy was developed with the assistance of a medical librarian in Medline Ovid, using both Medical Subject Heading (MeSH) terms and synonymous keywords. The strategy was then translated to Embase, Web of Science, and Cochrane to extract publications investigating PV, pruritus, and/or naltrexone therapy. All searches were conducted on July 18, 2022, and the results of the literature review were as follows: 2 results from Medline Ovid; 34 results from Embase (2 were duplicates of Medline Ovid results); 3 results from Web of Science (all of which were duplicates of Medline Ovid or Embase results); and 0 results from Cochrane (Figure).

Discussion

Although pruritus is a common and often excruciating manifestation of PV, its pathophysiology remains unclear. Some patients with decreasing or newly normal hematocrit and hemoglobin levels have paradoxically experienced an intensification of their pruritus, which introduces erythropoietin signaling pathways as a potential mechanism of the symptom.⁸ However, iron replacement therapy for patients with exacerbated pruritus after phlebotomies has not demonstrated consistent relief of pruritus.⁸ Normalization of platelet levels also has not been historically associated with improvement of pruritus.^8,9 It has been hypothesized that cells harboring Jak2 mutations at any stage of the hematopoietic pathway mature and accumulate to cause pruritus in PV.⁹ This theory has been foundational in the development of drugs with activity against cells expressing Jak2 mutations and interventions targeting histamine-releasing mast cells.^9-11

The effective use of naltrexone in our patient suggests that histamine may not be the most effective or sole therapeutic target against pruritus in PV. Naltrexone targets opioid receptors in all layers of the epidermis, affecting cell adhesion and keratinocyte production, and exhibits anti-inflammatory effects through interactions with nonopioid receptors, including Toll-like receptor 4.¹² The efficacy of oral naltrexone has been documented in patients with pruritus associated with immune checkpoint inhibitors, psoriasis, eczema, lichen simplex chronicus, prurigo nodularis, cholestasis, uremia, and multiple rheumatologic diseases.^{3,4,7-9,12-14} Opioid pathways also may be involved in peripheral and/or central processing of pruritus associated with PV.

Importantly, patients who are potential candidates for naltrexone therapy should be notified and advised of the risk of drug interactions with opioids, which could lead to symptoms of opioid withdrawal. Other common adverse effects of naltrexone include hepatotoxicity (especially in patients with a history of significant alcohol consumption), abdominal pain, nausea, arthralgias, myalgias, insomnia, headaches, fatigue, and anxiety.¹² Therefore, it is integral to screen patients for opioid dependence and determine their baseline liver function. Patients should be monitored following naltrexone initiation to determine whether the drug is an appropriate and effective intervention against PV-associated pruritus.

CONCLUSIONS

This case study demonstrates that naltrexone may be a safe, effective, nonsedating, and cost-efficient oral alternative for refractory PV-associated pruritus. Future directions involve consideration of case series or randomized clinical trials investigating the efficacy of naltrexone in treating PV-associated pruritus. Further research is also warranted to better understand the pathophysiology of this symptom of PV to enhance and potentially expand medical management for patients.

Acknowledgments

The authors thank Amy Sisson (The Texas Medical Center Library) for her guidance and support in the literature review methodology.

Drinking alcohol around the time of a breast cancer diagnosis may not have effects on prognosis that is mediated by body mass index (BMI), an analysis of data from a prospective cohort study suggests.

Kaiser Permanente

The study appears to show that drinking up to one serving of alcohol daily, including wine, beer, and liquor, was not associated with any specific outcomes after breast cancer diagnosis. The authors say these findings could have implications for developing more specific guidelines on alcohol use as it relates to the prevention of death and recurrence for cancer survivors.

Among 3,659 women followed for a mean of 11.2 years after a breast cancer diagnosis, overall alcohol consumption in the months before and up to 6 months after diagnosis was not associated with recurrence or mortality after adjusting for numerous factors such as age at diagnosis, cancer stage, socioeconomic details, smoking history, and preexisting conditions.

However, women with obesity (body mass index of 30 kg/m² or greater) had a lower risk of mortality with increasing alcohol consumption for occasional drinking of 2 or more alcohol servings per week (hazard ratio, 0.71), and regular drinking of at least one alcohol serving daily (HR, 0.77), in a dose-response manner, Marilyn L. Kwan, PhD, and colleagues found.

Dr. Kwan is a senior research scientist at Kaiser Permanente Northern California Division of Research, Oakland.

Women with BMI less than 30 kg/m² did not have a higher risk of mortality but a nonsignificant increase in the risk of recurrence was observed for those who consumed alcohol occasionally (HR, 1.29) and regularly (HR, 1.19), the investigators reported.

The findings were published online in Cancer.

Women included in the current study were participants in the Pathways Study and were diagnosed with stage I-IV breast cancer between 2003 and 2015. During follow-up, 524 recurrences and 834 deaths occurred, including 369 breast cancer-specific deaths, 314 cardiovascular disease-specific deaths, and 151 deaths from other health problems.

Alcohol consumption was assessed for the 6 months prior to cohort entry, which occurred at an average of about 2 months after diagnosis, as well as 6 months later – at an average of about 8 months after diagnosis – using a food-frequency questionnaire.

Compared with nondrinkers (36.9%), drinkers were more likely younger, more educated, and current or past smokers, the investigators noted.

“This profile appears counterintuitive yet might reflect a healthier lifestyle contributing to better overall survival. Furthermore, higher levels of alcohol consumption could lead to improvement in insulin sensitivity and reduction in insulin-like growth factor-1,” they speculated, noting that reduced fasting insulin concentrations and lower insulin-like growth factor-1 levels are linked with a decreased risk of type 2 diabetes, cardiovascular disease, and cancer.

“Many women with a history of breast cancer are interested in how to improve their prognosis and survival by making lifestyle changes after diagnosis,” they wrote, explaining the rationale for the study. “Current cancer prevention guidelines recommend avoiding alcohol intake or limiting consumption to no more than one drink per day for women. However, no specific guideline exists for cancer survivors other than following the cancer prevention guidelines to reduce the risk of a second cancer.”

High-quality studies on the impact of alcohol consumption on breast cancer prognosis are lacking, they added.

“Given that consuming alcohol is a potentially modifiable lifestyle factor after breast cancer diagnosis, further confirmation is warranted in other large prospective studies of breast cancer survivors with detailed exposure assessment and focus on body size,” they concluded.

The group is the first to report this finding in obese women, and they “strongly believe more research is needed to see if the same association is seen in other studies,” Dr. Kwan told this news organization.

“After a cancer diagnosis, many patients are motivated to make lifestyle changes,” she said. “That often includes adding exercise to their daily routine and eating a healthier diet. Our study findings suggest that doctors can tell patients that having up to a glass of alcohol a day is not likely to increase their risk of a breast cancer recurrence.”

This study was funded by the National Cancer Institute. The authors reported having no disclosures.
 

Drinking alcohol around the time of a breast cancer diagnosis may not have effects on prognosis that is mediated by body mass index (BMI), an analysis of data from a prospective cohort study suggests.

Kaiser Permanente

The study appears to show that drinking up to one serving of alcohol daily, including wine, beer, and liquor, was not associated with any specific outcomes after breast cancer diagnosis. The authors say these findings could have implications for developing more specific guidelines on alcohol use as it relates to the prevention of death and recurrence for cancer survivors.

Among 3,659 women followed for a mean of 11.2 years after a breast cancer diagnosis, overall alcohol consumption in the months before and up to 6 months after diagnosis was not associated with recurrence or mortality after adjusting for numerous factors such as age at diagnosis, cancer stage, socioeconomic details, smoking history, and preexisting conditions.

However, women with obesity (body mass index of 30 kg/m² or greater) had a lower risk of mortality with increasing alcohol consumption for occasional drinking of 2 or more alcohol servings per week (hazard ratio, 0.71), and regular drinking of at least one alcohol serving daily (HR, 0.77), in a dose-response manner, Marilyn L. Kwan, PhD, and colleagues found.

Dr. Kwan is a senior research scientist at Kaiser Permanente Northern California Division of Research, Oakland.

Women with BMI less than 30 kg/m² did not have a higher risk of mortality but a nonsignificant increase in the risk of recurrence was observed for those who consumed alcohol occasionally (HR, 1.29) and regularly (HR, 1.19), the investigators reported.

The findings were published online in Cancer.

Women included in the current study were participants in the Pathways Study and were diagnosed with stage I-IV breast cancer between 2003 and 2015. During follow-up, 524 recurrences and 834 deaths occurred, including 369 breast cancer-specific deaths, 314 cardiovascular disease-specific deaths, and 151 deaths from other health problems.

Alcohol consumption was assessed for the 6 months prior to cohort entry, which occurred at an average of about 2 months after diagnosis, as well as 6 months later – at an average of about 8 months after diagnosis – using a food-frequency questionnaire.

Compared with nondrinkers (36.9%), drinkers were more likely younger, more educated, and current or past smokers, the investigators noted.

“This profile appears counterintuitive yet might reflect a healthier lifestyle contributing to better overall survival. Furthermore, higher levels of alcohol consumption could lead to improvement in insulin sensitivity and reduction in insulin-like growth factor-1,” they speculated, noting that reduced fasting insulin concentrations and lower insulin-like growth factor-1 levels are linked with a decreased risk of type 2 diabetes, cardiovascular disease, and cancer.

“Many women with a history of breast cancer are interested in how to improve their prognosis and survival by making lifestyle changes after diagnosis,” they wrote, explaining the rationale for the study. “Current cancer prevention guidelines recommend avoiding alcohol intake or limiting consumption to no more than one drink per day for women. However, no specific guideline exists for cancer survivors other than following the cancer prevention guidelines to reduce the risk of a second cancer.”

High-quality studies on the impact of alcohol consumption on breast cancer prognosis are lacking, they added.

“Given that consuming alcohol is a potentially modifiable lifestyle factor after breast cancer diagnosis, further confirmation is warranted in other large prospective studies of breast cancer survivors with detailed exposure assessment and focus on body size,” they concluded.

The group is the first to report this finding in obese women, and they “strongly believe more research is needed to see if the same association is seen in other studies,” Dr. Kwan told this news organization.

“After a cancer diagnosis, many patients are motivated to make lifestyle changes,” she said. “That often includes adding exercise to their daily routine and eating a healthier diet. Our study findings suggest that doctors can tell patients that having up to a glass of alcohol a day is not likely to increase their risk of a breast cancer recurrence.”

This study was funded by the National Cancer Institute. The authors reported having no disclosures.
 

Drinking alcohol around the time of a breast cancer diagnosis may not have effects on prognosis that is mediated by body mass index (BMI), an analysis of data from a prospective cohort study suggests.

Kaiser Permanente

The study appears to show that drinking up to one serving of alcohol daily, including wine, beer, and liquor, was not associated with any specific outcomes after breast cancer diagnosis. The authors say these findings could have implications for developing more specific guidelines on alcohol use as it relates to the prevention of death and recurrence for cancer survivors.

Among 3,659 women followed for a mean of 11.2 years after a breast cancer diagnosis, overall alcohol consumption in the months before and up to 6 months after diagnosis was not associated with recurrence or mortality after adjusting for numerous factors such as age at diagnosis, cancer stage, socioeconomic details, smoking history, and preexisting conditions.

However, women with obesity (body mass index of 30 kg/m² or greater) had a lower risk of mortality with increasing alcohol consumption for occasional drinking of 2 or more alcohol servings per week (hazard ratio, 0.71), and regular drinking of at least one alcohol serving daily (HR, 0.77), in a dose-response manner, Marilyn L. Kwan, PhD, and colleagues found.

Dr. Kwan is a senior research scientist at Kaiser Permanente Northern California Division of Research, Oakland.

Women with BMI less than 30 kg/m² did not have a higher risk of mortality but a nonsignificant increase in the risk of recurrence was observed for those who consumed alcohol occasionally (HR, 1.29) and regularly (HR, 1.19), the investigators reported.

The findings were published online in Cancer.

Women included in the current study were participants in the Pathways Study and were diagnosed with stage I-IV breast cancer between 2003 and 2015. During follow-up, 524 recurrences and 834 deaths occurred, including 369 breast cancer-specific deaths, 314 cardiovascular disease-specific deaths, and 151 deaths from other health problems.

Alcohol consumption was assessed for the 6 months prior to cohort entry, which occurred at an average of about 2 months after diagnosis, as well as 6 months later – at an average of about 8 months after diagnosis – using a food-frequency questionnaire.

Compared with nondrinkers (36.9%), drinkers were more likely younger, more educated, and current or past smokers, the investigators noted.

“This profile appears counterintuitive yet might reflect a healthier lifestyle contributing to better overall survival. Furthermore, higher levels of alcohol consumption could lead to improvement in insulin sensitivity and reduction in insulin-like growth factor-1,” they speculated, noting that reduced fasting insulin concentrations and lower insulin-like growth factor-1 levels are linked with a decreased risk of type 2 diabetes, cardiovascular disease, and cancer.

“Many women with a history of breast cancer are interested in how to improve their prognosis and survival by making lifestyle changes after diagnosis,” they wrote, explaining the rationale for the study. “Current cancer prevention guidelines recommend avoiding alcohol intake or limiting consumption to no more than one drink per day for women. However, no specific guideline exists for cancer survivors other than following the cancer prevention guidelines to reduce the risk of a second cancer.”

High-quality studies on the impact of alcohol consumption on breast cancer prognosis are lacking, they added.

“Given that consuming alcohol is a potentially modifiable lifestyle factor after breast cancer diagnosis, further confirmation is warranted in other large prospective studies of breast cancer survivors with detailed exposure assessment and focus on body size,” they concluded.

The group is the first to report this finding in obese women, and they “strongly believe more research is needed to see if the same association is seen in other studies,” Dr. Kwan told this news organization.

“After a cancer diagnosis, many patients are motivated to make lifestyle changes,” she said. “That often includes adding exercise to their daily routine and eating a healthier diet. Our study findings suggest that doctors can tell patients that having up to a glass of alcohol a day is not likely to increase their risk of a breast cancer recurrence.”

This study was funded by the National Cancer Institute. The authors reported having no disclosures.
 

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

 

 

Case 1: Myocarditis

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

 

 

Case 2: Uveitis

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

 

 

Case 1: Myocarditis

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

 

 

Case 2: Uveitis

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Immune checkpoint inhibitors (ICIs), often broadly referred to as immunotherapy, are being prescribed at increasing rates due to their effectiveness in treating a growing number of advanced solid tumors and hematologic malignancies.¹ It has been well established that T-cell signaling mechanisms designed to combat foreign pathogens have been involved in the mitigation of tumor proliferation.² This protective process can be supported or restricted by infection, medication, or mutations.

ICIs support T-cell–mediated destruction of tumor cells by inhibiting the mechanisms designed to limit autoimmunity, specifically the programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) pathways. The results have been impressive, leading to an expansive number of US Food and Drug Administration (FDA) approvals across a diverse set of malignancies. Consequently, the Nobel Prize in Physiology or Medicine was awarded for such work in 2018.³

BACKGROUND

While altering these pathways has been shown to hinder tumor growth, the lesser restrictions on the immune system can drive unwanted autoimmune inflammation to host tissue. These toxicities are collectively known as immune-mediated adverse reactions (IMARs). Clinically and histologically, IMARs frequently manifest similarly to other autoimmune conditions and may affect any organ, including skin, liver, lungs, heart, intestine (small and large), kidneys, eyes, endocrine glands, and neurologic tissue.^4,5 According to recent studies, as many as 20% to 30% of patients receiving a single ICI will experience at least 1 clinically significant IMAR, and about 13% are classified as severe; however, < 10% of patients will have their ICIs discontinued due to these reactions.⁶

Though infrequent, a thorough understanding of the severity of IMARs to ICIs is critical for the diagnosis and management of these organ-threatening and potentially life-threatening toxicities. With the growing use of these agents and more FDA approvals for dual checkpoint blockage (concurrent use of CTLA-4 and PD-1/PD-L1 inhibitors), the absolute number of IMARs is expected to rise, thereby leading to more exposure of such events to both oncology and nononcology clinicians. Prior literature has clearly described the treatments and outcomes for many common severe toxicities; however, information regarding presentations and outcomes for rare IMARs is lacking.⁷

A few fascinating cases of rare toxicities have been observed at the New Mexico Veterans Affairs Medical Center (NMVAMC) in Albuquerque despite its relatively small size compared with other US Department of Veterans Affairs medical centers. As such, herein, the diagnostic evaluation, treatments, and outcomes of rare IMARs are reported for each case, and the related literature is reviewed.

Patient Selection

Patients who were required to discontinue or postpone treatment with any ICI blocking the CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, cemiplimab), or PD-L1 (atezolizumab, avelumab, durvalumab) pathways between 2015 to 2021 due to toxicity at the NMVAMC were eligible for inclusion. The electronic health record was reviewed for each eligible case, and the patient demographics, disease characteristics, toxicities, and outcomes were documented for each patient. For the 57 patients who received ICIs within the chosen period, 11 required a treatment break or discontinuation. Of these, 3 cases were selected for reporting due to the rare IMARs observed. This study was approved by the NMVAMC Institutional Review Board.

 

 

Case 1: Myocarditis

An 84-year-old man receiving a chemoimmunotherapy regimen consisting of carboplatin, pemetrexed, and pembrolizumab for recurrent, stage IV lung adenocarcinoma developed grade 4 cardiomyopathy, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, during his treatment.⁸ He was treated for 2 cycles before he began experiencing an increase in liver enzymes.

The patient’s presentation was concerning for myocarditis, and he was quickly admitted to NMVAMC. Cardiac catheterization did not reveal any signs of coronary occlusive disease. Prednisone 1 mg/kg was administered immediately; however, given continued chest pain and volume overload, he was quickly transitioned to solumedrol 1000 mg IV daily. After the initiation of his treatment, the patient’s transaminitis began to resolve, and troponin levels began to decrease; however, his symptoms continued to worsen, and his troponin rose again. By the fourth day of hospitalization, the patient was treated with infliximab, a tumor necrosis factor-α inhibitor shown to reverse ICI-induced autoimmune inflammation, with only mild improvement of his symptoms. The patient’s condition continued to deteriorate, his troponin levels remained elevated, and his family decided to withhold additional treatment. The patient died shortly thereafter.

Discussion

Cardiotoxicity resulting from ICI therapy is far less common than the other potential severe toxicities associated with ICIs. Nevertheless, many cases of ICI-induced cardiac inflammation have been reported, and it has been widely established that patients treated with ICIs are generally at higher risk for acute coronary syndrome.^9-11 Acute cardiotoxicity secondary to autoimmune destruction of cardiac tissue includes myocarditis, pericarditis, and vasculitis, which may manifest with symptoms of heart failure and/or arrhythmia. Grading of ICI-induced cardiomyopathy has been defined by both CTCAE and the American Society of Clinical Oncology (ASCO), with grade 4 representing moderate to severe clinical decompensation requiring IV medications in the setting of life-threatening conditions.

Review articles have described the treatment options for severe cases.^7,12 As detailed in prior reports, once ICI-induced cardiomyopathy is suspected, urgent admission and immediate evaluation to rule out acute coronary syndrome should be undertaken. Given the potential for deterioration despite the occasional insidious onset, aggressive cardiac monitoring, and close follow-up to measure response to interventions should be undertaken.

 

 

Case 2: Uveitis

A 70-year-old man who received pembrolizumab as a bladder-sparing approach for his superficial bladder cancer refractory to intravesical treatments developed uveitis. Approximately 3 months following the initiation of treatment, the patient reported bilateral itchy eyes, erythema, and tearing. He had a known history of allergic conjunctivitis that predated the ICI therapy, and consequently, it was unclear whether his symptoms were reflective of a more concerning issue. The patient’s symptoms continued to wax and wane for a few months, prompting a referral to ophthalmology colleagues at NMVAMC.

Ophthalmology evaluation identified uveitic glaucoma in the setting of his underlying chronic glaucoma. Pembrolizumab was discontinued, and the patient was counseled on choosing either cystectomy or locoregional therapies if further tumors arose. However, within a few weeks of administering topical steroid drops, his symptoms markedly improved, and he wished to be restarted on pembrolizumab. His uveitis remained in remission, and he has been treated with pembrolizumab for more than 1 year since this episode. He has had no clear findings of superficial bladder cancer recurrence while receiving ICI therapy.

Discussion

Uveitis is a known complication of pembrolizumab, and it has been shown to occur in 1% of patients with this treatment.^13,14 It should be noted that most of the studies of this IMAR occurred in patients with metastatic melanoma; therefore the rate of this condition in other patients is less understood. Overall, ocular IMARs secondary to anti-PD-1 and anti-PD-L1 therapies are rare.

The most common IMAR is surface ocular disease, consisting of dry eye disease (DED), conjunctivitis, uveitis, and keratitis. Of these, the most common ocular surface disease is DED, which occurred in 1% to 4% of patients treated with ICI therapy; most of these reactions are mild and self-limiting.¹⁵ Atezolizumab has the highest association with ocular inflammation and ipilimumab has the highest association with uveitis, with reported odds ratios of 18.89 and 10.54, respectively.¹⁶ Treatment of ICI-induced uveitis generally includes topical steroids and treatment discontinuation or break.¹⁷ Oral or IV steroids, infliximab, and procedural involvement may be considered in refractory cases or those initially presenting with marked vision loss. Close communication with ophthalmology colleagues to monitor visual acuity and ocular pressure multiple times weekly during the acute phase is required for treatment titration.

Case 3: Organizing Pneumonia

A man aged 63 years was diagnosed with malignant mesothelioma after incidentally noting a pleural effusion and thickening on routine low-dose computed tomography surveillance of pulmonary nodules. A biopsy was performed and was consistent with mesothelioma, and the patient was started on nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor). The patient was initiated on dual ICIs, and after 6 months of therapy, he had a promising complete response. However, after 9 months of therapy, he developed a new left upper lobe (LUL) pleural-based lesion (Figure 2A).

A biopsy was performed, and the histopathologic appearance was consistent with organizing pneumonia (OP) (Figure 3).

Discussion

ICIs can uncommonly drive pneumonitis, with the frequency adjusted based on the number of ICIs prescribed and the primary cancer involved. Across all cancers, up to 5% of patients treated with single-agent ICI therapy may experience pneumonitis, though often the findings may simply be radiographic without symptoms. Moreover, up to 10% of patients undergoing treatment for pulmonary cancer or those with dual ICI treatment regimens experience radiographic and/or clinical pneumonitis.¹⁸ The clinical manifestations include a broad spectrum of respiratory symptoms. Given the convoluting concerns of cancer progression and infection, a biopsy is often obtained. Histopathologic findings of pneumonitis may include diffuse alveolar damage and/or interstitial lung disease, with OP being a rare variant of ILD.

Among pulmonologists, OP is felt to have polymorphous imaging findings, and biopsy is required to confirm histology; however, histopathology cannot define etiology, and consequently, OP is somewhat of an umbrella diagnosis. The condition can be cryptogenic (idiopathic) or secondary to a multitude of conditions (infection, drug toxicity, or systemic disease). It is classically described as polypoid aggregations of fibroblasts that obstruct the alveolar spaces.¹⁹ This histopathologic pattern was demonstrated in our patient’s lung biopsy. Given a prior case description of ICIs, mesothelioma, OP development, and the unremarkable infectious workup, we felt that the patient’s OP was driven by his dual ICI therapy, thereby leading to the ultimate discontinuation of his ICIs and initiation of steroids.²⁰ Thankfully, the patient had already obtained a complete response to his ICIs, and hopefully, he can attain a durable remission with the addition of maintenance chemotherapy.

CONCLUSIONS

ICIs have revolutionized the treatment of a myriad of solid tumors and hematologic malignancies, and their use internationally is expected to increase. With the alteration in immunology pathways, clinicians in all fields will need to be familiarized with IMARs secondary to these agents, including rare subtypes. In addition, the variability in presentations relative to the patients’ treatment course was significant (between 2-9 months), and this highlights that these IMARs can occur at any time point and clinicians should be ever vigilant to spot symptoms in their patients.

It was unexpected for the 3 aforementioned rare toxicities to arise at NMVAMC among only 57 treated patients, and we speculate that these findings may have been observed for 1 of 3 reasons. First, caring for 3 patients with this collection of rare toxicities may have been due to chance. Second, though there is sparse literature studying the topic, the regional environment, including sunlight exposure and air quality, may play a role in the development of one or all of these rare toxicities. Third, rates of these toxicities may be underreported in the literature or attributed to other conditions rather than due to ICIs at other sites, and the uncommon nature of these IMARs may be overstated. Investigations evaluating rates of toxicities, including those traditionally uncommonly seen, based on regional location should be conducted before any further conclusions are drawn.

Prostate cancer will be diagnosed in 12.5% of men during their lifetime. It is the most commonly diagnosed solid organ cancer in men.¹ However, prostate cancer screening for prostate-specific antigen (PSA) remains controversial due to concerns about overdiagnosis, as the overall risk of dying of prostate cancer is only 2.4%.¹

To address the risk and benefits of PSA testing, in 2012 the US Preventive Services Task Force (USPSTF) recommended against routine PSA testing.² Updated 2018 recommendations continued this recommendation in men aged > 70 years but acknowledged a small potential benefit in men aged 55 to 69 years and suggested individualized shared decision making between patient and clinician.³ In addition, American Urological Association (AUA) guidelines for the early detection of prostate cancer recommend against PSA screening in men aged < 40 years or those aged > 70 years, shared decision making for individuals aged 55 to 70 years or in high-risk men aged 40 to 55 years (ie, family history of prostate cancer or African American race).⁴ PSA screening is not recommended for men with a life expectancy shorter than 10 to 15 years aged > 70 years.⁴

The Veterans Health Administration (VHA) is the largest integrated health care system in the US.⁵ In addition, the US Department of Veterans Affairs (VA) Spinal Cord Injury and Disorders System of Care operates 25 centers throughout the US.⁶ Life expectancy following spinal cord injury (SCI) increased significantly through the 1980s but has since plateaued, with life expectancy being impacted by age at injury, completeness of injury, and neurologic level.^7,8 As part of a program of uniform care, all persons with SCI followed at the Spinal Cord Injury and Disorders System of Care centers are offered comprehensive annual evaluations, including screening laboratory tests, such as PSA level.⁹

Patients with SCI present a unique challenge when interpreting PSA levels, given potentially confounding factors, including neurogenic bladder management, high rates of bacteriuria, urinary tract infections (UTIs), testosterone deficiency, and pelvic innervation that differs from the noninjured population.^10,11 Unfortunately, the literature on prostate cancer prevalence and average PSA levels in patients with SCI is limited by the small scope of studies and inconsistent data.^10-16 Therefore, the purpose of the current investigation was to quantify and analyze the rates of annual PSA testing for all men with SCI in the VHA.

Methods

Approval was granted by the Richmond VA Medical Center (VAMC) Institutional Review Board in Virginia, and by the VA Informatics and Computing Infrastructure (VINCI) data access request tracker system for extraction of data from the VA Corporate Data Warehouse. Microsoft Structured Query Language was used for data programming and query design. Statistical analysis was conducted using Stata version 15.1 with assistance from professional biostatisticians.

Only male veterans with a nervous system disorder affecting the spinal cord or with myelopathy were included, based on International Classification of Diseases (ICD) version 9 and 10 codes, corresponding to traumatic and nontraumatic myelopathy. Veterans diagnosed with myelopathy based on ICD codes corresponding to progressive or degenerative myelopathies, such as multiple sclerosis or amyotrophic lateral sclerosis, were excluded.

For each veteran, extracted data included the unique identification number, date of birth, ICD code, date ICD code first appeared, race, gender, death status (yes/no), date of death (when applicable), date of each PSA test, PSA test values, and the VAMC where each test was performed. Only tests for total PSA were included. The date that the ICD code first appeared served as an approximation for the date of SCI. The time frame for the study included all PSA tests in the VINCI database for 2000 through 2017. However, only post-SCI PSA tests were included in the analysis. Duplicate tests (same date/time) were eliminated.

Race is considered a risk factor for prostate cancer only for African American patients, likely due to racial health disparities.¹⁷ Given this, we chose to categorize race as either African American or other, with a third category for missing/inconsistent reporting. Age at time of the PSA test was categorized into 4 groups (≤ 39, 40-54, 55-69, and ≥ 70 years) based on AUA guidelines.⁴ The annual PSA testing rate was calculated for each veteran with SCI as the number of PSA tests per year. A mean annual PSA test rate was then calculated as the weighted (by exposure time) mean value for all annual PSA testing rates from 2000 through 2017 for each age group and race. Annual exposure was calculated for each veteran and defined as the number of days a veteran was eligible to have a PSA test. This started with the date of SCI diagnosis and ended with either the date of death or the date of last PSA. If a veteran moved from one age group to another in 1 year, the first part of this year’s exposure was included in the calculation of the annual PSA testing rate for the younger group and the second part was included for the calculation of the older group. For deceased veterans, the death date was excluded from the exposure period, and their exposure period ended on the day before death.

Statistical Analysis

To compare PSA testing rates between African American race and other races, Poisson regression was used with exposure treated as an offset (exposures were summed across years for each veteran). An indicator (dummy) variable for African American race vs other races was coded, and statistical significance was set at P < .05. To check sensitivity for the Poisson assumption that the mean was equal to the variance, negative binomial regression was used. To assess for geographic PSA testing rate variability, the data were further analyzed based on the locations where PSA tests were performed. This subanalysis was limited to veterans who had all PSA tests in a single station. For each station, the average PSA testing rate was calculated for each veteran, and the mean for all annual PSA testing rates was used to determine station-specific PSA testing rates.

Results

A total of 45,274 veterans were initially identified of which 367 females were excluded (Figure 1).

The PSA testing rate rose for veterans in the age groups ≤ 39, 40 to 54, and 55 to 69 years (Figure 2A).

Discussion

The goal of this study was to establish testing rates and analyze PSA testing trends across races and age groups in veterans with SCI. This is the largest cohort of patients with SCI analyzed in the literature. The key findings of this study were that despite clear AUA guidelines recommending against PSA testing in patients aged ≤ 39 years and ≥ 70 years, there are high rates of testing in veterans with SCI in these age groups (0.46 tests per year in those aged ≤ 39 years and 0.91 tests per year in those aged ≥ 70 years). In terms of race, as expected based on increased risk, African American veterans with SCI had higher PSA test rates.¹⁸ However, the continued increase in PSA testing rate for African American veterans aged ≥ 70 years was unexpected and not seen in other racial groups. As racial disparities are known to affect prostate cancer outcomes in African American men, it is reassuring that PSA testing was actually higher among African American men with SCI in our population, suggesting this vulnerable population is not being left behind in terms of screening.¹⁷ In contrast to other studies that show a lower rate of PSA screening in patients with SCI, our study suggests general PSA overtesting in veterans with SCI and a need for improved education for both veterans and their health care practitioners.¹⁹

Prostate Cancer Incidence

Although the exact mechanism behind alterations in prostate function in the SCI population have yet to be fully elucidated, research suggests that the prostate behaves differently after SCI. Animal models of prostate gland denervation show decreased prostate volume and suggest that SCI may lead to a reduction in prostatic secretory function associated with autonomic dysfunction. Shim and colleagues hypothesized that impaired autonomic prostate innervation alters the prostatic volume and PSA in patients with SCI.¹⁰

Additional studies looking at actual PSA levels in men with SCI reveal conflicting data.^10-15,20 Toricelli and colleagues retrospectively studied 140 men with SCI, of whom 34 had PSA levels available and found that mean PSA was not significantly different for patients with SCI compared with controls, but patients using clean intermittent catheterization had 2-fold higher PSA levels.²¹ In contrast, Konety and colleagues found that mean PSA was not significantly different from uninjured controls in their cohort of 79 patients with SCI, though they did find a correlation between indwelling catheter use and a higher PSA.²²

Studies have shown an overall decreased risk of prostate cancer in patients with SCI, though the mechanism remains unclear. A large cohort study from Taiwan showed a lower risk of prostate cancer for 54,401 patients with SCI with an adjusted hazard ratio of 0.73.²³ Patel and colleagues found the overall rate of prostate cancer in the population of veterans with SCI was lower than the general uninjured VA population, though this study was limited by scope with only 350 patients with SCI.²⁴ A more recent systematic review and meta-analysis of 9 studies evaluating the prevalence of prostate cancer in men with SCI found a reduction of up to 65% in the risk of prostate cancer in men with SCI, and PSA was found to be a poor screening tool for prostate cancer due to large study heterogeneity.¹⁶

PSA Screening

This study identified widespread overscreening using the PSA test in veterans with SCI, which is likely attributable to many factors. Per VHA Directive 1176, all eligible veterans are offered yearly interdisciplinary comprehensive evaluations, including laboratory testing, and as such veterans with SCI have high rates of annual visit attendance due to the complexity of their care.⁹ PSA testing is included in the standard battery of laboratory tests ordered for all patients with SCI during their annual examinations. Additionally, many SCI specialists use the PSA level in patients with SCI for identifying cystitis or prostatitis in patients with colonization who may not experience typical symptoms. Everaert and colleagues demonstrated the clinical utility for localizing UTIs to the upper or lower tract, with elevated PSA indicating prostatitis. They found that serum PSA has a sensitivity of 68% and a specificity of 100% in the differential diagnosis of prostatitis and pyelonephritis.²⁵ As such, the high PSA screening rates may be reflective of diagnostic use for infection rather than for cancer screening.

Likely as a response to the USPSTF recommendations, there has been a national slow decline in overall PSA screening rates since 2012.^26-28 A study from Vetterlein and colleagues examining changes in the PSA screening trends related to USPSTF recommendations found an 8.5% decline in overall PSA screening from 2012 to 2014.²⁹ However, the increase in PSA testing across all ages and races in the VA population with SCI over the same period is not entirely understood and suggests the need for further research and education in this area. Additionally, as factors associated with SCI impact the life expectancy of these patients, further shared decision making is needed in deciding whether to pursue PSA screening in this population to minimize unnecessary screening in patients with a life expectancy of < 10 to 15 years.

Limitations

This study is limited by the use of data identified by ICD codes rather than by review of individual health records. This required the use of decision algorithms for data points, such as the date of SCI. In addition, analysis was not able to capture shared decision making that may have contributed to PSA screening outside the recommended age ranges based on additional risk factors, such as family history of lethal malignancy. Furthermore, a detailed attempt to define specific age-adjusted PSA levels was beyond the scope of this study but will be addressed in later publications. In addition, we did not exclude individuals with a diagnosis of prostate adenocarcinoma, prostatitis, or recurrent UTIs because the onset, duration, and severity of disease could not be definitively ascertained. Finally, veterans with SCI are unique and may not be reflective of individuals with SCI who do not receive care within the VA. However, despite these limitations, this is, to our knowledge, the largest and most comprehensive study evaluating PSA testing rates in individuals with SCI.

Conclusions

Currently, PSA screening is recommended following shared decision making for patients at average risk aged 55 to 70 years. Patients with SCI experience many conditions that may affect PSA values, but data regarding normal PSA ranges and rates of prostate cancer in this population remain sparse. The study demonstrated high rates of overtesting in veterans with SCI, higher than expected testing rates in African American veterans, a paradoxical increase in PSA testing rates after the 2012 publication of the USPSTF PSA guidelines, and wide variability in testing rates depending on VA location.

African American men were tested at higher rates across all age groups, including in patients aged > 70 years. To balance the benefits of detecting clinically significant prostate cancer vs the risks of invasive testing in high-risk populations with SCI, more work is needed to determine the clinical impact of screening practices. Future work is currently ongoing to define age-based PSA values in patients with SCI.

Acknowledgments

This research was supported in part through funding from the Center for Rehabilitation Science and Engineering, Virginia Commonwealth University Health System.

Prostate cancer will be diagnosed in 12.5% of men during their lifetime. It is the most commonly diagnosed solid organ cancer in men.¹ However, prostate cancer screening for prostate-specific antigen (PSA) remains controversial due to concerns about overdiagnosis, as the overall risk of dying of prostate cancer is only 2.4%.¹

To address the risk and benefits of PSA testing, in 2012 the US Preventive Services Task Force (USPSTF) recommended against routine PSA testing.² Updated 2018 recommendations continued this recommendation in men aged > 70 years but acknowledged a small potential benefit in men aged 55 to 69 years and suggested individualized shared decision making between patient and clinician.³ In addition, American Urological Association (AUA) guidelines for the early detection of prostate cancer recommend against PSA screening in men aged < 40 years or those aged > 70 years, shared decision making for individuals aged 55 to 70 years or in high-risk men aged 40 to 55 years (ie, family history of prostate cancer or African American race).⁴ PSA screening is not recommended for men with a life expectancy shorter than 10 to 15 years aged > 70 years.⁴

The Veterans Health Administration (VHA) is the largest integrated health care system in the US.⁵ In addition, the US Department of Veterans Affairs (VA) Spinal Cord Injury and Disorders System of Care operates 25 centers throughout the US.⁶ Life expectancy following spinal cord injury (SCI) increased significantly through the 1980s but has since plateaued, with life expectancy being impacted by age at injury, completeness of injury, and neurologic level.^7,8 As part of a program of uniform care, all persons with SCI followed at the Spinal Cord Injury and Disorders System of Care centers are offered comprehensive annual evaluations, including screening laboratory tests, such as PSA level.⁹

Patients with SCI present a unique challenge when interpreting PSA levels, given potentially confounding factors, including neurogenic bladder management, high rates of bacteriuria, urinary tract infections (UTIs), testosterone deficiency, and pelvic innervation that differs from the noninjured population.^10,11 Unfortunately, the literature on prostate cancer prevalence and average PSA levels in patients with SCI is limited by the small scope of studies and inconsistent data.^10-16 Therefore, the purpose of the current investigation was to quantify and analyze the rates of annual PSA testing for all men with SCI in the VHA.

Methods

Approval was granted by the Richmond VA Medical Center (VAMC) Institutional Review Board in Virginia, and by the VA Informatics and Computing Infrastructure (VINCI) data access request tracker system for extraction of data from the VA Corporate Data Warehouse. Microsoft Structured Query Language was used for data programming and query design. Statistical analysis was conducted using Stata version 15.1 with assistance from professional biostatisticians.

Only male veterans with a nervous system disorder affecting the spinal cord or with myelopathy were included, based on International Classification of Diseases (ICD) version 9 and 10 codes, corresponding to traumatic and nontraumatic myelopathy. Veterans diagnosed with myelopathy based on ICD codes corresponding to progressive or degenerative myelopathies, such as multiple sclerosis or amyotrophic lateral sclerosis, were excluded.

For each veteran, extracted data included the unique identification number, date of birth, ICD code, date ICD code first appeared, race, gender, death status (yes/no), date of death (when applicable), date of each PSA test, PSA test values, and the VAMC where each test was performed. Only tests for total PSA were included. The date that the ICD code first appeared served as an approximation for the date of SCI. The time frame for the study included all PSA tests in the VINCI database for 2000 through 2017. However, only post-SCI PSA tests were included in the analysis. Duplicate tests (same date/time) were eliminated.

Race is considered a risk factor for prostate cancer only for African American patients, likely due to racial health disparities.¹⁷ Given this, we chose to categorize race as either African American or other, with a third category for missing/inconsistent reporting. Age at time of the PSA test was categorized into 4 groups (≤ 39, 40-54, 55-69, and ≥ 70 years) based on AUA guidelines.⁴ The annual PSA testing rate was calculated for each veteran with SCI as the number of PSA tests per year. A mean annual PSA test rate was then calculated as the weighted (by exposure time) mean value for all annual PSA testing rates from 2000 through 2017 for each age group and race. Annual exposure was calculated for each veteran and defined as the number of days a veteran was eligible to have a PSA test. This started with the date of SCI diagnosis and ended with either the date of death or the date of last PSA. If a veteran moved from one age group to another in 1 year, the first part of this year’s exposure was included in the calculation of the annual PSA testing rate for the younger group and the second part was included for the calculation of the older group. For deceased veterans, the death date was excluded from the exposure period, and their exposure period ended on the day before death.

Statistical Analysis

To compare PSA testing rates between African American race and other races, Poisson regression was used with exposure treated as an offset (exposures were summed across years for each veteran). An indicator (dummy) variable for African American race vs other races was coded, and statistical significance was set at P < .05. To check sensitivity for the Poisson assumption that the mean was equal to the variance, negative binomial regression was used. To assess for geographic PSA testing rate variability, the data were further analyzed based on the locations where PSA tests were performed. This subanalysis was limited to veterans who had all PSA tests in a single station. For each station, the average PSA testing rate was calculated for each veteran, and the mean for all annual PSA testing rates was used to determine station-specific PSA testing rates.

Results

A total of 45,274 veterans were initially identified of which 367 females were excluded (Figure 1).

The PSA testing rate rose for veterans in the age groups ≤ 39, 40 to 54, and 55 to 69 years (Figure 2A).

Discussion

The goal of this study was to establish testing rates and analyze PSA testing trends across races and age groups in veterans with SCI. This is the largest cohort of patients with SCI analyzed in the literature. The key findings of this study were that despite clear AUA guidelines recommending against PSA testing in patients aged ≤ 39 years and ≥ 70 years, there are high rates of testing in veterans with SCI in these age groups (0.46 tests per year in those aged ≤ 39 years and 0.91 tests per year in those aged ≥ 70 years). In terms of race, as expected based on increased risk, African American veterans with SCI had higher PSA test rates.¹⁸ However, the continued increase in PSA testing rate for African American veterans aged ≥ 70 years was unexpected and not seen in other racial groups. As racial disparities are known to affect prostate cancer outcomes in African American men, it is reassuring that PSA testing was actually higher among African American men with SCI in our population, suggesting this vulnerable population is not being left behind in terms of screening.¹⁷ In contrast to other studies that show a lower rate of PSA screening in patients with SCI, our study suggests general PSA overtesting in veterans with SCI and a need for improved education for both veterans and their health care practitioners.¹⁹

Prostate Cancer Incidence

Although the exact mechanism behind alterations in prostate function in the SCI population have yet to be fully elucidated, research suggests that the prostate behaves differently after SCI. Animal models of prostate gland denervation show decreased prostate volume and suggest that SCI may lead to a reduction in prostatic secretory function associated with autonomic dysfunction. Shim and colleagues hypothesized that impaired autonomic prostate innervation alters the prostatic volume and PSA in patients with SCI.¹⁰

Additional studies looking at actual PSA levels in men with SCI reveal conflicting data.^10-15,20 Toricelli and colleagues retrospectively studied 140 men with SCI, of whom 34 had PSA levels available and found that mean PSA was not significantly different for patients with SCI compared with controls, but patients using clean intermittent catheterization had 2-fold higher PSA levels.²¹ In contrast, Konety and colleagues found that mean PSA was not significantly different from uninjured controls in their cohort of 79 patients with SCI, though they did find a correlation between indwelling catheter use and a higher PSA.²²

Studies have shown an overall decreased risk of prostate cancer in patients with SCI, though the mechanism remains unclear. A large cohort study from Taiwan showed a lower risk of prostate cancer for 54,401 patients with SCI with an adjusted hazard ratio of 0.73.²³ Patel and colleagues found the overall rate of prostate cancer in the population of veterans with SCI was lower than the general uninjured VA population, though this study was limited by scope with only 350 patients with SCI.²⁴ A more recent systematic review and meta-analysis of 9 studies evaluating the prevalence of prostate cancer in men with SCI found a reduction of up to 65% in the risk of prostate cancer in men with SCI, and PSA was found to be a poor screening tool for prostate cancer due to large study heterogeneity.¹⁶

PSA Screening

This study identified widespread overscreening using the PSA test in veterans with SCI, which is likely attributable to many factors. Per VHA Directive 1176, all eligible veterans are offered yearly interdisciplinary comprehensive evaluations, including laboratory testing, and as such veterans with SCI have high rates of annual visit attendance due to the complexity of their care.⁹ PSA testing is included in the standard battery of laboratory tests ordered for all patients with SCI during their annual examinations. Additionally, many SCI specialists use the PSA level in patients with SCI for identifying cystitis or prostatitis in patients with colonization who may not experience typical symptoms. Everaert and colleagues demonstrated the clinical utility for localizing UTIs to the upper or lower tract, with elevated PSA indicating prostatitis. They found that serum PSA has a sensitivity of 68% and a specificity of 100% in the differential diagnosis of prostatitis and pyelonephritis.²⁵ As such, the high PSA screening rates may be reflective of diagnostic use for infection rather than for cancer screening.

Likely as a response to the USPSTF recommendations, there has been a national slow decline in overall PSA screening rates since 2012.^26-28 A study from Vetterlein and colleagues examining changes in the PSA screening trends related to USPSTF recommendations found an 8.5% decline in overall PSA screening from 2012 to 2014.²⁹ However, the increase in PSA testing across all ages and races in the VA population with SCI over the same period is not entirely understood and suggests the need for further research and education in this area. Additionally, as factors associated with SCI impact the life expectancy of these patients, further shared decision making is needed in deciding whether to pursue PSA screening in this population to minimize unnecessary screening in patients with a life expectancy of < 10 to 15 years.

Limitations

This study is limited by the use of data identified by ICD codes rather than by review of individual health records. This required the use of decision algorithms for data points, such as the date of SCI. In addition, analysis was not able to capture shared decision making that may have contributed to PSA screening outside the recommended age ranges based on additional risk factors, such as family history of lethal malignancy. Furthermore, a detailed attempt to define specific age-adjusted PSA levels was beyond the scope of this study but will be addressed in later publications. In addition, we did not exclude individuals with a diagnosis of prostate adenocarcinoma, prostatitis, or recurrent UTIs because the onset, duration, and severity of disease could not be definitively ascertained. Finally, veterans with SCI are unique and may not be reflective of individuals with SCI who do not receive care within the VA. However, despite these limitations, this is, to our knowledge, the largest and most comprehensive study evaluating PSA testing rates in individuals with SCI.

Conclusions

Currently, PSA screening is recommended following shared decision making for patients at average risk aged 55 to 70 years. Patients with SCI experience many conditions that may affect PSA values, but data regarding normal PSA ranges and rates of prostate cancer in this population remain sparse. The study demonstrated high rates of overtesting in veterans with SCI, higher than expected testing rates in African American veterans, a paradoxical increase in PSA testing rates after the 2012 publication of the USPSTF PSA guidelines, and wide variability in testing rates depending on VA location.

African American men were tested at higher rates across all age groups, including in patients aged > 70 years. To balance the benefits of detecting clinically significant prostate cancer vs the risks of invasive testing in high-risk populations with SCI, more work is needed to determine the clinical impact of screening practices. Future work is currently ongoing to define age-based PSA values in patients with SCI.

Acknowledgments

This research was supported in part through funding from the Center for Rehabilitation Science and Engineering, Virginia Commonwealth University Health System.

Prostate cancer will be diagnosed in 12.5% of men during their lifetime. It is the most commonly diagnosed solid organ cancer in men.¹ However, prostate cancer screening for prostate-specific antigen (PSA) remains controversial due to concerns about overdiagnosis, as the overall risk of dying of prostate cancer is only 2.4%.¹

To address the risk and benefits of PSA testing, in 2012 the US Preventive Services Task Force (USPSTF) recommended against routine PSA testing.² Updated 2018 recommendations continued this recommendation in men aged > 70 years but acknowledged a small potential benefit in men aged 55 to 69 years and suggested individualized shared decision making between patient and clinician.³ In addition, American Urological Association (AUA) guidelines for the early detection of prostate cancer recommend against PSA screening in men aged < 40 years or those aged > 70 years, shared decision making for individuals aged 55 to 70 years or in high-risk men aged 40 to 55 years (ie, family history of prostate cancer or African American race).⁴ PSA screening is not recommended for men with a life expectancy shorter than 10 to 15 years aged > 70 years.⁴

The Veterans Health Administration (VHA) is the largest integrated health care system in the US.⁵ In addition, the US Department of Veterans Affairs (VA) Spinal Cord Injury and Disorders System of Care operates 25 centers throughout the US.⁶ Life expectancy following spinal cord injury (SCI) increased significantly through the 1980s but has since plateaued, with life expectancy being impacted by age at injury, completeness of injury, and neurologic level.^7,8 As part of a program of uniform care, all persons with SCI followed at the Spinal Cord Injury and Disorders System of Care centers are offered comprehensive annual evaluations, including screening laboratory tests, such as PSA level.⁹

Patients with SCI present a unique challenge when interpreting PSA levels, given potentially confounding factors, including neurogenic bladder management, high rates of bacteriuria, urinary tract infections (UTIs), testosterone deficiency, and pelvic innervation that differs from the noninjured population.^10,11 Unfortunately, the literature on prostate cancer prevalence and average PSA levels in patients with SCI is limited by the small scope of studies and inconsistent data.^10-16 Therefore, the purpose of the current investigation was to quantify and analyze the rates of annual PSA testing for all men with SCI in the VHA.

Methods

Approval was granted by the Richmond VA Medical Center (VAMC) Institutional Review Board in Virginia, and by the VA Informatics and Computing Infrastructure (VINCI) data access request tracker system for extraction of data from the VA Corporate Data Warehouse. Microsoft Structured Query Language was used for data programming and query design. Statistical analysis was conducted using Stata version 15.1 with assistance from professional biostatisticians.

Only male veterans with a nervous system disorder affecting the spinal cord or with myelopathy were included, based on International Classification of Diseases (ICD) version 9 and 10 codes, corresponding to traumatic and nontraumatic myelopathy. Veterans diagnosed with myelopathy based on ICD codes corresponding to progressive or degenerative myelopathies, such as multiple sclerosis or amyotrophic lateral sclerosis, were excluded.

For each veteran, extracted data included the unique identification number, date of birth, ICD code, date ICD code first appeared, race, gender, death status (yes/no), date of death (when applicable), date of each PSA test, PSA test values, and the VAMC where each test was performed. Only tests for total PSA were included. The date that the ICD code first appeared served as an approximation for the date of SCI. The time frame for the study included all PSA tests in the VINCI database for 2000 through 2017. However, only post-SCI PSA tests were included in the analysis. Duplicate tests (same date/time) were eliminated.

Race is considered a risk factor for prostate cancer only for African American patients, likely due to racial health disparities.¹⁷ Given this, we chose to categorize race as either African American or other, with a third category for missing/inconsistent reporting. Age at time of the PSA test was categorized into 4 groups (≤ 39, 40-54, 55-69, and ≥ 70 years) based on AUA guidelines.⁴ The annual PSA testing rate was calculated for each veteran with SCI as the number of PSA tests per year. A mean annual PSA test rate was then calculated as the weighted (by exposure time) mean value for all annual PSA testing rates from 2000 through 2017 for each age group and race. Annual exposure was calculated for each veteran and defined as the number of days a veteran was eligible to have a PSA test. This started with the date of SCI diagnosis and ended with either the date of death or the date of last PSA. If a veteran moved from one age group to another in 1 year, the first part of this year’s exposure was included in the calculation of the annual PSA testing rate for the younger group and the second part was included for the calculation of the older group. For deceased veterans, the death date was excluded from the exposure period, and their exposure period ended on the day before death.

Statistical Analysis

To compare PSA testing rates between African American race and other races, Poisson regression was used with exposure treated as an offset (exposures were summed across years for each veteran). An indicator (dummy) variable for African American race vs other races was coded, and statistical significance was set at P < .05. To check sensitivity for the Poisson assumption that the mean was equal to the variance, negative binomial regression was used. To assess for geographic PSA testing rate variability, the data were further analyzed based on the locations where PSA tests were performed. This subanalysis was limited to veterans who had all PSA tests in a single station. For each station, the average PSA testing rate was calculated for each veteran, and the mean for all annual PSA testing rates was used to determine station-specific PSA testing rates.

Results

A total of 45,274 veterans were initially identified of which 367 females were excluded (Figure 1).

The PSA testing rate rose for veterans in the age groups ≤ 39, 40 to 54, and 55 to 69 years (Figure 2A).

Discussion

The goal of this study was to establish testing rates and analyze PSA testing trends across races and age groups in veterans with SCI. This is the largest cohort of patients with SCI analyzed in the literature. The key findings of this study were that despite clear AUA guidelines recommending against PSA testing in patients aged ≤ 39 years and ≥ 70 years, there are high rates of testing in veterans with SCI in these age groups (0.46 tests per year in those aged ≤ 39 years and 0.91 tests per year in those aged ≥ 70 years). In terms of race, as expected based on increased risk, African American veterans with SCI had higher PSA test rates.¹⁸ However, the continued increase in PSA testing rate for African American veterans aged ≥ 70 years was unexpected and not seen in other racial groups. As racial disparities are known to affect prostate cancer outcomes in African American men, it is reassuring that PSA testing was actually higher among African American men with SCI in our population, suggesting this vulnerable population is not being left behind in terms of screening.¹⁷ In contrast to other studies that show a lower rate of PSA screening in patients with SCI, our study suggests general PSA overtesting in veterans with SCI and a need for improved education for both veterans and their health care practitioners.¹⁹

Prostate Cancer Incidence

Although the exact mechanism behind alterations in prostate function in the SCI population have yet to be fully elucidated, research suggests that the prostate behaves differently after SCI. Animal models of prostate gland denervation show decreased prostate volume and suggest that SCI may lead to a reduction in prostatic secretory function associated with autonomic dysfunction. Shim and colleagues hypothesized that impaired autonomic prostate innervation alters the prostatic volume and PSA in patients with SCI.¹⁰

Additional studies looking at actual PSA levels in men with SCI reveal conflicting data.^10-15,20 Toricelli and colleagues retrospectively studied 140 men with SCI, of whom 34 had PSA levels available and found that mean PSA was not significantly different for patients with SCI compared with controls, but patients using clean intermittent catheterization had 2-fold higher PSA levels.²¹ In contrast, Konety and colleagues found that mean PSA was not significantly different from uninjured controls in their cohort of 79 patients with SCI, though they did find a correlation between indwelling catheter use and a higher PSA.²²

Studies have shown an overall decreased risk of prostate cancer in patients with SCI, though the mechanism remains unclear. A large cohort study from Taiwan showed a lower risk of prostate cancer for 54,401 patients with SCI with an adjusted hazard ratio of 0.73.²³ Patel and colleagues found the overall rate of prostate cancer in the population of veterans with SCI was lower than the general uninjured VA population, though this study was limited by scope with only 350 patients with SCI.²⁴ A more recent systematic review and meta-analysis of 9 studies evaluating the prevalence of prostate cancer in men with SCI found a reduction of up to 65% in the risk of prostate cancer in men with SCI, and PSA was found to be a poor screening tool for prostate cancer due to large study heterogeneity.¹⁶

PSA Screening

This study identified widespread overscreening using the PSA test in veterans with SCI, which is likely attributable to many factors. Per VHA Directive 1176, all eligible veterans are offered yearly interdisciplinary comprehensive evaluations, including laboratory testing, and as such veterans with SCI have high rates of annual visit attendance due to the complexity of their care.⁹ PSA testing is included in the standard battery of laboratory tests ordered for all patients with SCI during their annual examinations. Additionally, many SCI specialists use the PSA level in patients with SCI for identifying cystitis or prostatitis in patients with colonization who may not experience typical symptoms. Everaert and colleagues demonstrated the clinical utility for localizing UTIs to the upper or lower tract, with elevated PSA indicating prostatitis. They found that serum PSA has a sensitivity of 68% and a specificity of 100% in the differential diagnosis of prostatitis and pyelonephritis.²⁵ As such, the high PSA screening rates may be reflective of diagnostic use for infection rather than for cancer screening.

Likely as a response to the USPSTF recommendations, there has been a national slow decline in overall PSA screening rates since 2012.^26-28 A study from Vetterlein and colleagues examining changes in the PSA screening trends related to USPSTF recommendations found an 8.5% decline in overall PSA screening from 2012 to 2014.²⁹ However, the increase in PSA testing across all ages and races in the VA population with SCI over the same period is not entirely understood and suggests the need for further research and education in this area. Additionally, as factors associated with SCI impact the life expectancy of these patients, further shared decision making is needed in deciding whether to pursue PSA screening in this population to minimize unnecessary screening in patients with a life expectancy of < 10 to 15 years.

Limitations

This study is limited by the use of data identified by ICD codes rather than by review of individual health records. This required the use of decision algorithms for data points, such as the date of SCI. In addition, analysis was not able to capture shared decision making that may have contributed to PSA screening outside the recommended age ranges based on additional risk factors, such as family history of lethal malignancy. Furthermore, a detailed attempt to define specific age-adjusted PSA levels was beyond the scope of this study but will be addressed in later publications. In addition, we did not exclude individuals with a diagnosis of prostate adenocarcinoma, prostatitis, or recurrent UTIs because the onset, duration, and severity of disease could not be definitively ascertained. Finally, veterans with SCI are unique and may not be reflective of individuals with SCI who do not receive care within the VA. However, despite these limitations, this is, to our knowledge, the largest and most comprehensive study evaluating PSA testing rates in individuals with SCI.

Conclusions

Currently, PSA screening is recommended following shared decision making for patients at average risk aged 55 to 70 years. Patients with SCI experience many conditions that may affect PSA values, but data regarding normal PSA ranges and rates of prostate cancer in this population remain sparse. The study demonstrated high rates of overtesting in veterans with SCI, higher than expected testing rates in African American veterans, a paradoxical increase in PSA testing rates after the 2012 publication of the USPSTF PSA guidelines, and wide variability in testing rates depending on VA location.

African American men were tested at higher rates across all age groups, including in patients aged > 70 years. To balance the benefits of detecting clinically significant prostate cancer vs the risks of invasive testing in high-risk populations with SCI, more work is needed to determine the clinical impact of screening practices. Future work is currently ongoing to define age-based PSA values in patients with SCI.

Acknowledgments

This research was supported in part through funding from the Center for Rehabilitation Science and Engineering, Virginia Commonwealth University Health System.