The Veterans Health Administration (VHA) is transitioning from its native electronic health record (EHR) Vista/Computerized Patient Record System to the commercial Cerner/Oracle Health EHR. Though this process was temporarily discontinued in April 2023 due to patient safety, usability, and reliability concerns, it resumed in April 2026. It was originally projected to cost $50 billion to implement. ^1-3 As of March 9, 2024, 6 sites had transitioned to the new EHR.² The transition is the largest of its kind in the US, offering an unparalleled opportunity to examine the effects of EHR transitions on an often overlooked part of the workforce: health professions trainees (HPTs).

HPTs serve a central role in VHA. About one-third of patients receive care directly from HPTs who make up about one-third of the VHA workforce. VHA trains > 60 clinical disciplines, comprising > 122,000 trainees annually.^4,5 A paucity of literature exists exploring the experiences of HPTs during EHR transitions, and many studies are often limited to single-site or small populations. HPTs face distinct challenges and needs during EHR transitions and are particularly vulnerable to their negative impacts on retention, clinical training, and efficiency and confidence in EHR use.^6-10 HPTs at VHA sites that have already transitioned to the Cerner/Oracle Health EHR identified many challenges, including significant delays in gaining EHR access, pervasive perceptions of poor training, concerns that EHR functionality issues limited patient care, and decreased ability to track clinical skill acquisition.⁶ These challenges may impact some HPTs more than others (eg, students on short rotations are affected more acutely by delayed EHR access and usage).

This quality improvement project evaluated HPT EHR transition experiences at the Captain James A. Lovell Federal Health Care Center (FHCC). This article contributes to the limited literature on HPT transition experiences, identifies opportunities to support HPTs, and informs broader efforts in teaching HPTs new technologies.

Methods

FHCC is jointly operated by the US Department of Defense and US Department of Veterans Affairs (VA). It treats 80,000 inpatient and outpatients annually. FHCC was the sixth VA facility to transition to the new EHR, which went live on March 9, 2024.^2,11 About 700 HPTs rotate through FHCC annually. HPTs were eligible for inclusion if they were present during the March 9 transition according to a VA Office of Academic Affiliations database. A total of 216 HPTs were identified for inclusion.

Preparations for the transition included scaling down operations (ie, blocking clinician schedules, not scheduling future appointments that may conflict with the transition, making decisions on new facility- and service-line workflows, required EHR training, and speaking with support staff, including VHA National EHR Modernization Supplemental Staffing Unit [NESSU]). This evaluation was designated nonresearch/quality improvement by the VA Bedford Healthcare System Institutional Review Board.

Surveys

Forty-seven interviews were conducted with HPTs, site leaders, and supervisors from January 2024 to June 2024 (Table 1). Participants were identified by service leads and recruited via email; snowball sampling identified additional participants.

The evaluation team developed semistructured interview guides using grounded probes based on a pilot evaluation and existing research on EHR transitions.¹² Questions focused on participant experiences preparing for the EHR transition, learning and using the site’s EHR, and the impact the transition had on clinical training experiences. Interviews were conducted at different times to capture the range of user experiences: 1 month prelaunch, 2 to 6 weeks postlaunch, and 2 months postlaunch. Interviewees were informed of participant rights and provided verbal consent.

HPTs present at FHCC at each survey’s release were emailed invitations and 2 reminders. The anonymous surveys took about 10 minutes to complete. Survey items queried HPTs about their experiences preparing to use the new EHR, perceptions of the current EHR (adapted from the System Usability Scale), satisfaction with VHA training, impact on clinical training, ability to work with preceptors and patients, and experiences with the VHA clinical learning environment (adapted from the VHA Learners Preceptor Survey).^13-15 Survey questions used a 5-point Likert response scale.

Analysis

Interviewers completed postinterview summaries for team debriefing and consensus building. Interviews were coded using a priori (from piloting evaluations and relevant literature) and emergent (refined and developed from data) codes. Deductive and inductive content analyses were conducted. ¹⁶ Deductive analysis used a priori categories (eg, care coordination, EHR training). Inductive content analysis consisted of open and unstructured coding, capturing data outside a priori categories. Emergent codes captured unidentified categories. Qualitative researchers met weekly to discuss data and reach consensus on interpretation.

Descriptive analysis was conducted using top-2 box scoring (proportion responding within the 2 most favorable responses [agree/ strongly agree]). Survey data were analyzed in SAS.¹⁷ The analysis used a merging approach on simultaneously collected qualitative and quantitative data to reach findings consensus.¹⁸

Researcher and research team decisions may shape the data collected due to prior assumptions and experience.¹⁹ This analysis attempted to integrate reflexivity practices to enhance awareness of the researchers’ assumptions and positionality, including by integrating intent collaborative conversing and memorandum writing into the processes.^20,21

Results

This analysis created a survey and fielded responses from HPTs present at FHCC across 3 time points (6 months prelaunch, 1 month prelaunch, and 2 months postlaunch), resulting in a total of 103 responses and an average response rate of 19.0% (Table 2). Six key findings were identified in analysis of responses: (1) critiques of transition management; (2) concerns with training; (3) hope about the EHR; (4) at-the-elbow support was essential; (5) HPTs adjusted to, and later preferred, the new EHR; and (6) transition impacted clinical training, but not overall career plans for HPTs. Findings are presented in this section, with illustrative quantitative data and qualitative data quotes available in the eAppendix.

Critiques of the Transition’s Management

While participants were aware of the transition to the new EHR, most felt they did not have enough information or time to prepare for it, indicating it was “too little, too late.” HPTs felt necessary workflow processes for Cerner/Oracle Health were not determined with enough time to learn them prior to transition. Supervisors shared that important workflow and onboarding decisions remained undecided mere weeks before the transition. Some service lines did not decrease patient loads until right before the transition, making it difficult to manage their schedules and resulting in insufficient time to learn the new EHR.

EHR Training Concerns

Overall, HPTs expressed low satisfaction with computer-based Training Management System (TMS) EHR training, believing it did not prepare them for the new EHR. The percentage of HPTs satisfied or very satisfied with the quality of TMS training was lower than that of instructor-based training pre- and posttransition, with 50% of 36 prelaunch respondents, and 43% of 29 postlaunch respondents expressing satisfaction with computer-based trainings (Figure 1). HPTs were dissatisfied with the training content. They felt it was too general and failed to teach basic tasks in the workflow for their service areas and roles, such as writing a note or order. Furthermore, poor content was exacerbated by poor and unengaging instruction, and HPTs were dissatisfied with the practice EHR used in training, which glitched frequently.

EHR Transition Optimism

Even though the transition was stressful, most HPTs hoped it would be a temporary disruption and that they would quickly adjust to the new EHR. Many participants expected that once they switched to the new EHR, they would pick it up quickly. In addition, many anticipated Cerner/Oracle Health would be better and easier to use in the long run.

At-The-Elbow Support Essential

VHA peer support with NESSU was highly valued among HPTs. NESSU staff were highly knowledgeable and could provide both broad and service-line-specific support. NESSU provided prompt answers to EHR questions. This was particularly critical as other forms of in-person support were often inaccessible or absent during the transition.

HPTs found facility support helpful: 85% of 36 respondents reported being satisfied/ very satisfied with support from supervisors and preceptors, and 84% of 36 respondents were satisfied/very satisfied with technical support from facility informatics staff pretransition (n = 36) (Figure 2). NESSU and supervisor support with daily workflows were particularly helpful, as pretransition training only provided a general introduction to the EHR.

HPTs Adjusted to and Later Preferred the New EHR

The EHR learning experience was intense but short, with many HPTs feeling able to use it only 2 to 4 weeks posttransition. Confidence grew as HPTs came to view Cerner/Oracle Health as a more integrated and intuitive system than the previous EHR. Most participants preferred the new EHR, even if they criticized some features (eg, no group documentation capabilities). Survey participants frequently rated Cerner/Oracle Health usability higher than the original. A total of 32% of 29 posttransition respondents agreed or strongly agreed that Cerner/Oracle Health helps prevent situations that can lead to patient safety risks—higher than pretransition rates. Additionally, fewer respondents found the new EHR unnecessarily complex or thought it contained too many alerts and flags compared to the original EHR (Figure 3).

Impact on Clinical Training, Not Career Plans

The extensive time and energy the transition demanded of HPTs caused stress and affected their clinical training. Many believed they would have learned more if their training had happened outside the transition.

Concerns that the transition affected learning were most acutely felt pretransition. HPTs reporting that EHR implementation positively affected their clinical education fell from 38% of 36 respondents 6 months pretransition to 19% of 29 respondents 1 month pretransition, but returned to 37% posttransition (Figure 4). However, some HPTs believed there was a silver lining: it provided a learning experience they otherwise would not have had.

HPTs who believed the transition positively impacted their likelihood of pursuing future career opportunities within the VHA rose to 33% of 29 respondents posttransition. Overall, Cerner/Oracle Health was characterized as a tool: something used in training, but not something that precluded wanting VHA careers or having meaningful experiences, such as caring for patients.

Discussion

This evaluation addressed an underexplored aspect of EHR transitions: their impact on HPTs. It identified HPT challenges, including dissatisfaction with poor transition preparation and EHR training experiences. Promising findings include positive experiences with transition support, EHR uptake, and overall positive educational experiences despite the transition’s disruption.

When EHR users, including HPTs, are dissatisfied with transition preparations, consequent stress can lead to undesired effects, including increased burnout, inappropriate EHR use, and low work satisfaction.^22-24 Negative EHR transition experiences shape HPTs’ subsequent EHR adoption, user satisfaction, as well as confidence and career intent.^3,25,26 Health systems have strong incentives to implement effective transition change management.

HPTs at previous VHA EHR transition sites reported significantly more disruption to their clinical training compared with HPTs at FHCC. Academic programs were shut down at the first transition site, and HPTs expressed decreased interest in VHA careers at another, even a year posttransition.^6,27 These findings are consistent with the limited literature on the adverse impacts that EHR transitions have on HPTs.^7,28

HPT retention is critical. VA is mandated to prepare the next generation of HPTs for its needs, and those of the nation. The VA relies heavily on HPT retention to recruit clinicians: > 65% of VHA physicians nationwide participated in VHA training programs prior to recruitment into staff positions.^5,29

VHA should invest in transition change management with demonstrated, positive impacts on HPTs, such as in-house support from clinicians. Previous research found that lack of support was a major source of stress and negative outcomes.^6,27 Consequently, supporting HPTs through EHR transitions directly contributes to the VHA’s ability to attract high-quality staff from its HPTs. The challenges and promising practices described in this analysis underscore the necessity of understanding how all EHR users are affected by transitions. What happens to them has direct implications for the VA mission to provide safe, efficient care, and its mandate to provide quality clinical training to HPTs.

These findings hold hopeful implications for supporting HPT EHR use, both during and outside EHR transitions. HPTs expressing that an EHR is only 1 part of their clinical training experience suggests that change management can improve EHR transitions. HPT learning can enhance known factors that are important for HPTs in clinical training, including the health care organization’s mission, caring for patients, and personal development.

Further investigations may engage HPTs at future VHA sites making the transition to the new EHR. One focus would involve applying a learning health systems framework to examine the nature of change management efforts—and their effects on HPT transition experiences—iteratively across transition sites to evaluate the effect of the efforts. Another focus may be longitudinal engagement with HPTs at health care systems and sites transitioning to new EHRs. Research has found that disruptions to EHR usability, satisfaction, and care provision can persist for 2 years and beyond following an EHR transition.³⁰ Evaluating the long-term effects of transitions on HPTs is of interest, given their distinct characteristics and differences from employees.

Limitations

Study data came from voluntary participants at 1 highly engaged site, raising the possibility of self-selection bias. HPT experiences at other VA and non-VA sites may differ. Employees and HPTs were engaged during a high-stress event; snowballing recruitment reach was limited by high workloads and limited time for engagement. Statistical data were descriptive and should not be interpreted as causal. Results may reflect, in part, temporal effects, and respondents include HPTs at different stages of training and with different levels of VA experience. Survey sample sizes may limit generalizability; however, merging data streams strengthened the reliability of findings.

Conclusions

The results of this analysis of FHCC HPTs were notably more positive than those of HPTs at previous VHA EHR transition sites. VHA is one of many health care systems that provide clinical training for HPTs and relies on this population to provide patient care. By highlighting challenges and positive experiences of HPTs during an EHR transition, this evaluation produces actionable insights that can inform the actions of health care systems seeking to support HPTs during disruptive EHR transitions.

The Veterans Health Administration (VHA) is transitioning from its native electronic health record (EHR) Vista/Computerized Patient Record System to the commercial Cerner/Oracle Health EHR. Though this process was temporarily discontinued in April 2023 due to patient safety, usability, and reliability concerns, it resumed in April 2026. It was originally projected to cost $50 billion to implement. ^1-3 As of March 9, 2024, 6 sites had transitioned to the new EHR.² The transition is the largest of its kind in the US, offering an unparalleled opportunity to examine the effects of EHR transitions on an often overlooked part of the workforce: health professions trainees (HPTs).

HPTs serve a central role in VHA. About one-third of patients receive care directly from HPTs who make up about one-third of the VHA workforce. VHA trains > 60 clinical disciplines, comprising > 122,000 trainees annually.^4,5 A paucity of literature exists exploring the experiences of HPTs during EHR transitions, and many studies are often limited to single-site or small populations. HPTs face distinct challenges and needs during EHR transitions and are particularly vulnerable to their negative impacts on retention, clinical training, and efficiency and confidence in EHR use.^6-10 HPTs at VHA sites that have already transitioned to the Cerner/Oracle Health EHR identified many challenges, including significant delays in gaining EHR access, pervasive perceptions of poor training, concerns that EHR functionality issues limited patient care, and decreased ability to track clinical skill acquisition.⁶ These challenges may impact some HPTs more than others (eg, students on short rotations are affected more acutely by delayed EHR access and usage).

This quality improvement project evaluated HPT EHR transition experiences at the Captain James A. Lovell Federal Health Care Center (FHCC). This article contributes to the limited literature on HPT transition experiences, identifies opportunities to support HPTs, and informs broader efforts in teaching HPTs new technologies.

Methods

FHCC is jointly operated by the US Department of Defense and US Department of Veterans Affairs (VA). It treats 80,000 inpatient and outpatients annually. FHCC was the sixth VA facility to transition to the new EHR, which went live on March 9, 2024.^2,11 About 700 HPTs rotate through FHCC annually. HPTs were eligible for inclusion if they were present during the March 9 transition according to a VA Office of Academic Affiliations database. A total of 216 HPTs were identified for inclusion.

Preparations for the transition included scaling down operations (ie, blocking clinician schedules, not scheduling future appointments that may conflict with the transition, making decisions on new facility- and service-line workflows, required EHR training, and speaking with support staff, including VHA National EHR Modernization Supplemental Staffing Unit [NESSU]). This evaluation was designated nonresearch/quality improvement by the VA Bedford Healthcare System Institutional Review Board.

Surveys

Forty-seven interviews were conducted with HPTs, site leaders, and supervisors from January 2024 to June 2024 (Table 1). Participants were identified by service leads and recruited via email; snowball sampling identified additional participants.

The evaluation team developed semistructured interview guides using grounded probes based on a pilot evaluation and existing research on EHR transitions.¹² Questions focused on participant experiences preparing for the EHR transition, learning and using the site’s EHR, and the impact the transition had on clinical training experiences. Interviews were conducted at different times to capture the range of user experiences: 1 month prelaunch, 2 to 6 weeks postlaunch, and 2 months postlaunch. Interviewees were informed of participant rights and provided verbal consent.

HPTs present at FHCC at each survey’s release were emailed invitations and 2 reminders. The anonymous surveys took about 10 minutes to complete. Survey items queried HPTs about their experiences preparing to use the new EHR, perceptions of the current EHR (adapted from the System Usability Scale), satisfaction with VHA training, impact on clinical training, ability to work with preceptors and patients, and experiences with the VHA clinical learning environment (adapted from the VHA Learners Preceptor Survey).^13-15 Survey questions used a 5-point Likert response scale.

Analysis

Interviewers completed postinterview summaries for team debriefing and consensus building. Interviews were coded using a priori (from piloting evaluations and relevant literature) and emergent (refined and developed from data) codes. Deductive and inductive content analyses were conducted. ¹⁶ Deductive analysis used a priori categories (eg, care coordination, EHR training). Inductive content analysis consisted of open and unstructured coding, capturing data outside a priori categories. Emergent codes captured unidentified categories. Qualitative researchers met weekly to discuss data and reach consensus on interpretation.

Descriptive analysis was conducted using top-2 box scoring (proportion responding within the 2 most favorable responses [agree/ strongly agree]). Survey data were analyzed in SAS.¹⁷ The analysis used a merging approach on simultaneously collected qualitative and quantitative data to reach findings consensus.¹⁸

Researcher and research team decisions may shape the data collected due to prior assumptions and experience.¹⁹ This analysis attempted to integrate reflexivity practices to enhance awareness of the researchers’ assumptions and positionality, including by integrating intent collaborative conversing and memorandum writing into the processes.^20,21

Results

This analysis created a survey and fielded responses from HPTs present at FHCC across 3 time points (6 months prelaunch, 1 month prelaunch, and 2 months postlaunch), resulting in a total of 103 responses and an average response rate of 19.0% (Table 2). Six key findings were identified in analysis of responses: (1) critiques of transition management; (2) concerns with training; (3) hope about the EHR; (4) at-the-elbow support was essential; (5) HPTs adjusted to, and later preferred, the new EHR; and (6) transition impacted clinical training, but not overall career plans for HPTs. Findings are presented in this section, with illustrative quantitative data and qualitative data quotes available in the eAppendix.

Critiques of the Transition’s Management

While participants were aware of the transition to the new EHR, most felt they did not have enough information or time to prepare for it, indicating it was “too little, too late.” HPTs felt necessary workflow processes for Cerner/Oracle Health were not determined with enough time to learn them prior to transition. Supervisors shared that important workflow and onboarding decisions remained undecided mere weeks before the transition. Some service lines did not decrease patient loads until right before the transition, making it difficult to manage their schedules and resulting in insufficient time to learn the new EHR.

EHR Training Concerns

Overall, HPTs expressed low satisfaction with computer-based Training Management System (TMS) EHR training, believing it did not prepare them for the new EHR. The percentage of HPTs satisfied or very satisfied with the quality of TMS training was lower than that of instructor-based training pre- and posttransition, with 50% of 36 prelaunch respondents, and 43% of 29 postlaunch respondents expressing satisfaction with computer-based trainings (Figure 1). HPTs were dissatisfied with the training content. They felt it was too general and failed to teach basic tasks in the workflow for their service areas and roles, such as writing a note or order. Furthermore, poor content was exacerbated by poor and unengaging instruction, and HPTs were dissatisfied with the practice EHR used in training, which glitched frequently.

EHR Transition Optimism

Even though the transition was stressful, most HPTs hoped it would be a temporary disruption and that they would quickly adjust to the new EHR. Many participants expected that once they switched to the new EHR, they would pick it up quickly. In addition, many anticipated Cerner/Oracle Health would be better and easier to use in the long run.

At-The-Elbow Support Essential

VHA peer support with NESSU was highly valued among HPTs. NESSU staff were highly knowledgeable and could provide both broad and service-line-specific support. NESSU provided prompt answers to EHR questions. This was particularly critical as other forms of in-person support were often inaccessible or absent during the transition.

HPTs found facility support helpful: 85% of 36 respondents reported being satisfied/ very satisfied with support from supervisors and preceptors, and 84% of 36 respondents were satisfied/very satisfied with technical support from facility informatics staff pretransition (n = 36) (Figure 2). NESSU and supervisor support with daily workflows were particularly helpful, as pretransition training only provided a general introduction to the EHR.

HPTs Adjusted to and Later Preferred the New EHR

The EHR learning experience was intense but short, with many HPTs feeling able to use it only 2 to 4 weeks posttransition. Confidence grew as HPTs came to view Cerner/Oracle Health as a more integrated and intuitive system than the previous EHR. Most participants preferred the new EHR, even if they criticized some features (eg, no group documentation capabilities). Survey participants frequently rated Cerner/Oracle Health usability higher than the original. A total of 32% of 29 posttransition respondents agreed or strongly agreed that Cerner/Oracle Health helps prevent situations that can lead to patient safety risks—higher than pretransition rates. Additionally, fewer respondents found the new EHR unnecessarily complex or thought it contained too many alerts and flags compared to the original EHR (Figure 3).

Impact on Clinical Training, Not Career Plans

The extensive time and energy the transition demanded of HPTs caused stress and affected their clinical training. Many believed they would have learned more if their training had happened outside the transition.

Concerns that the transition affected learning were most acutely felt pretransition. HPTs reporting that EHR implementation positively affected their clinical education fell from 38% of 36 respondents 6 months pretransition to 19% of 29 respondents 1 month pretransition, but returned to 37% posttransition (Figure 4). However, some HPTs believed there was a silver lining: it provided a learning experience they otherwise would not have had.

HPTs who believed the transition positively impacted their likelihood of pursuing future career opportunities within the VHA rose to 33% of 29 respondents posttransition. Overall, Cerner/Oracle Health was characterized as a tool: something used in training, but not something that precluded wanting VHA careers or having meaningful experiences, such as caring for patients.

Discussion

This evaluation addressed an underexplored aspect of EHR transitions: their impact on HPTs. It identified HPT challenges, including dissatisfaction with poor transition preparation and EHR training experiences. Promising findings include positive experiences with transition support, EHR uptake, and overall positive educational experiences despite the transition’s disruption.

When EHR users, including HPTs, are dissatisfied with transition preparations, consequent stress can lead to undesired effects, including increased burnout, inappropriate EHR use, and low work satisfaction.^22-24 Negative EHR transition experiences shape HPTs’ subsequent EHR adoption, user satisfaction, as well as confidence and career intent.^3,25,26 Health systems have strong incentives to implement effective transition change management.

HPTs at previous VHA EHR transition sites reported significantly more disruption to their clinical training compared with HPTs at FHCC. Academic programs were shut down at the first transition site, and HPTs expressed decreased interest in VHA careers at another, even a year posttransition.^6,27 These findings are consistent with the limited literature on the adverse impacts that EHR transitions have on HPTs.^7,28

HPT retention is critical. VA is mandated to prepare the next generation of HPTs for its needs, and those of the nation. The VA relies heavily on HPT retention to recruit clinicians: > 65% of VHA physicians nationwide participated in VHA training programs prior to recruitment into staff positions.^5,29

VHA should invest in transition change management with demonstrated, positive impacts on HPTs, such as in-house support from clinicians. Previous research found that lack of support was a major source of stress and negative outcomes.^6,27 Consequently, supporting HPTs through EHR transitions directly contributes to the VHA’s ability to attract high-quality staff from its HPTs. The challenges and promising practices described in this analysis underscore the necessity of understanding how all EHR users are affected by transitions. What happens to them has direct implications for the VA mission to provide safe, efficient care, and its mandate to provide quality clinical training to HPTs.

These findings hold hopeful implications for supporting HPT EHR use, both during and outside EHR transitions. HPTs expressing that an EHR is only 1 part of their clinical training experience suggests that change management can improve EHR transitions. HPT learning can enhance known factors that are important for HPTs in clinical training, including the health care organization’s mission, caring for patients, and personal development.

Further investigations may engage HPTs at future VHA sites making the transition to the new EHR. One focus would involve applying a learning health systems framework to examine the nature of change management efforts—and their effects on HPT transition experiences—iteratively across transition sites to evaluate the effect of the efforts. Another focus may be longitudinal engagement with HPTs at health care systems and sites transitioning to new EHRs. Research has found that disruptions to EHR usability, satisfaction, and care provision can persist for 2 years and beyond following an EHR transition.³⁰ Evaluating the long-term effects of transitions on HPTs is of interest, given their distinct characteristics and differences from employees.

Limitations

Study data came from voluntary participants at 1 highly engaged site, raising the possibility of self-selection bias. HPT experiences at other VA and non-VA sites may differ. Employees and HPTs were engaged during a high-stress event; snowballing recruitment reach was limited by high workloads and limited time for engagement. Statistical data were descriptive and should not be interpreted as causal. Results may reflect, in part, temporal effects, and respondents include HPTs at different stages of training and with different levels of VA experience. Survey sample sizes may limit generalizability; however, merging data streams strengthened the reliability of findings.

Conclusions

The results of this analysis of FHCC HPTs were notably more positive than those of HPTs at previous VHA EHR transition sites. VHA is one of many health care systems that provide clinical training for HPTs and relies on this population to provide patient care. By highlighting challenges and positive experiences of HPTs during an EHR transition, this evaluation produces actionable insights that can inform the actions of health care systems seeking to support HPTs during disruptive EHR transitions.

The Veterans Health Administration (VHA) is transitioning from its native electronic health record (EHR) Vista/Computerized Patient Record System to the commercial Cerner/Oracle Health EHR. Though this process was temporarily discontinued in April 2023 due to patient safety, usability, and reliability concerns, it resumed in April 2026. It was originally projected to cost $50 billion to implement. ^1-3 As of March 9, 2024, 6 sites had transitioned to the new EHR.² The transition is the largest of its kind in the US, offering an unparalleled opportunity to examine the effects of EHR transitions on an often overlooked part of the workforce: health professions trainees (HPTs).

HPTs serve a central role in VHA. About one-third of patients receive care directly from HPTs who make up about one-third of the VHA workforce. VHA trains > 60 clinical disciplines, comprising > 122,000 trainees annually.^4,5 A paucity of literature exists exploring the experiences of HPTs during EHR transitions, and many studies are often limited to single-site or small populations. HPTs face distinct challenges and needs during EHR transitions and are particularly vulnerable to their negative impacts on retention, clinical training, and efficiency and confidence in EHR use.^6-10 HPTs at VHA sites that have already transitioned to the Cerner/Oracle Health EHR identified many challenges, including significant delays in gaining EHR access, pervasive perceptions of poor training, concerns that EHR functionality issues limited patient care, and decreased ability to track clinical skill acquisition.⁶ These challenges may impact some HPTs more than others (eg, students on short rotations are affected more acutely by delayed EHR access and usage).

This quality improvement project evaluated HPT EHR transition experiences at the Captain James A. Lovell Federal Health Care Center (FHCC). This article contributes to the limited literature on HPT transition experiences, identifies opportunities to support HPTs, and informs broader efforts in teaching HPTs new technologies.

Methods

FHCC is jointly operated by the US Department of Defense and US Department of Veterans Affairs (VA). It treats 80,000 inpatient and outpatients annually. FHCC was the sixth VA facility to transition to the new EHR, which went live on March 9, 2024.^2,11 About 700 HPTs rotate through FHCC annually. HPTs were eligible for inclusion if they were present during the March 9 transition according to a VA Office of Academic Affiliations database. A total of 216 HPTs were identified for inclusion.

Preparations for the transition included scaling down operations (ie, blocking clinician schedules, not scheduling future appointments that may conflict with the transition, making decisions on new facility- and service-line workflows, required EHR training, and speaking with support staff, including VHA National EHR Modernization Supplemental Staffing Unit [NESSU]). This evaluation was designated nonresearch/quality improvement by the VA Bedford Healthcare System Institutional Review Board.

Surveys

Forty-seven interviews were conducted with HPTs, site leaders, and supervisors from January 2024 to June 2024 (Table 1). Participants were identified by service leads and recruited via email; snowball sampling identified additional participants.

The evaluation team developed semistructured interview guides using grounded probes based on a pilot evaluation and existing research on EHR transitions.¹² Questions focused on participant experiences preparing for the EHR transition, learning and using the site’s EHR, and the impact the transition had on clinical training experiences. Interviews were conducted at different times to capture the range of user experiences: 1 month prelaunch, 2 to 6 weeks postlaunch, and 2 months postlaunch. Interviewees were informed of participant rights and provided verbal consent.

HPTs present at FHCC at each survey’s release were emailed invitations and 2 reminders. The anonymous surveys took about 10 minutes to complete. Survey items queried HPTs about their experiences preparing to use the new EHR, perceptions of the current EHR (adapted from the System Usability Scale), satisfaction with VHA training, impact on clinical training, ability to work with preceptors and patients, and experiences with the VHA clinical learning environment (adapted from the VHA Learners Preceptor Survey).^13-15 Survey questions used a 5-point Likert response scale.

Analysis

Interviewers completed postinterview summaries for team debriefing and consensus building. Interviews were coded using a priori (from piloting evaluations and relevant literature) and emergent (refined and developed from data) codes. Deductive and inductive content analyses were conducted. ¹⁶ Deductive analysis used a priori categories (eg, care coordination, EHR training). Inductive content analysis consisted of open and unstructured coding, capturing data outside a priori categories. Emergent codes captured unidentified categories. Qualitative researchers met weekly to discuss data and reach consensus on interpretation.

Descriptive analysis was conducted using top-2 box scoring (proportion responding within the 2 most favorable responses [agree/ strongly agree]). Survey data were analyzed in SAS.¹⁷ The analysis used a merging approach on simultaneously collected qualitative and quantitative data to reach findings consensus.¹⁸

Researcher and research team decisions may shape the data collected due to prior assumptions and experience.¹⁹ This analysis attempted to integrate reflexivity practices to enhance awareness of the researchers’ assumptions and positionality, including by integrating intent collaborative conversing and memorandum writing into the processes.^20,21

Results

This analysis created a survey and fielded responses from HPTs present at FHCC across 3 time points (6 months prelaunch, 1 month prelaunch, and 2 months postlaunch), resulting in a total of 103 responses and an average response rate of 19.0% (Table 2). Six key findings were identified in analysis of responses: (1) critiques of transition management; (2) concerns with training; (3) hope about the EHR; (4) at-the-elbow support was essential; (5) HPTs adjusted to, and later preferred, the new EHR; and (6) transition impacted clinical training, but not overall career plans for HPTs. Findings are presented in this section, with illustrative quantitative data and qualitative data quotes available in the eAppendix.

Critiques of the Transition’s Management

While participants were aware of the transition to the new EHR, most felt they did not have enough information or time to prepare for it, indicating it was “too little, too late.” HPTs felt necessary workflow processes for Cerner/Oracle Health were not determined with enough time to learn them prior to transition. Supervisors shared that important workflow and onboarding decisions remained undecided mere weeks before the transition. Some service lines did not decrease patient loads until right before the transition, making it difficult to manage their schedules and resulting in insufficient time to learn the new EHR.

EHR Training Concerns

Overall, HPTs expressed low satisfaction with computer-based Training Management System (TMS) EHR training, believing it did not prepare them for the new EHR. The percentage of HPTs satisfied or very satisfied with the quality of TMS training was lower than that of instructor-based training pre- and posttransition, with 50% of 36 prelaunch respondents, and 43% of 29 postlaunch respondents expressing satisfaction with computer-based trainings (Figure 1). HPTs were dissatisfied with the training content. They felt it was too general and failed to teach basic tasks in the workflow for their service areas and roles, such as writing a note or order. Furthermore, poor content was exacerbated by poor and unengaging instruction, and HPTs were dissatisfied with the practice EHR used in training, which glitched frequently.

EHR Transition Optimism

Even though the transition was stressful, most HPTs hoped it would be a temporary disruption and that they would quickly adjust to the new EHR. Many participants expected that once they switched to the new EHR, they would pick it up quickly. In addition, many anticipated Cerner/Oracle Health would be better and easier to use in the long run.

At-The-Elbow Support Essential

VHA peer support with NESSU was highly valued among HPTs. NESSU staff were highly knowledgeable and could provide both broad and service-line-specific support. NESSU provided prompt answers to EHR questions. This was particularly critical as other forms of in-person support were often inaccessible or absent during the transition.

HPTs found facility support helpful: 85% of 36 respondents reported being satisfied/ very satisfied with support from supervisors and preceptors, and 84% of 36 respondents were satisfied/very satisfied with technical support from facility informatics staff pretransition (n = 36) (Figure 2). NESSU and supervisor support with daily workflows were particularly helpful, as pretransition training only provided a general introduction to the EHR.

HPTs Adjusted to and Later Preferred the New EHR

The EHR learning experience was intense but short, with many HPTs feeling able to use it only 2 to 4 weeks posttransition. Confidence grew as HPTs came to view Cerner/Oracle Health as a more integrated and intuitive system than the previous EHR. Most participants preferred the new EHR, even if they criticized some features (eg, no group documentation capabilities). Survey participants frequently rated Cerner/Oracle Health usability higher than the original. A total of 32% of 29 posttransition respondents agreed or strongly agreed that Cerner/Oracle Health helps prevent situations that can lead to patient safety risks—higher than pretransition rates. Additionally, fewer respondents found the new EHR unnecessarily complex or thought it contained too many alerts and flags compared to the original EHR (Figure 3).

Impact on Clinical Training, Not Career Plans

The extensive time and energy the transition demanded of HPTs caused stress and affected their clinical training. Many believed they would have learned more if their training had happened outside the transition.

Concerns that the transition affected learning were most acutely felt pretransition. HPTs reporting that EHR implementation positively affected their clinical education fell from 38% of 36 respondents 6 months pretransition to 19% of 29 respondents 1 month pretransition, but returned to 37% posttransition (Figure 4). However, some HPTs believed there was a silver lining: it provided a learning experience they otherwise would not have had.

HPTs who believed the transition positively impacted their likelihood of pursuing future career opportunities within the VHA rose to 33% of 29 respondents posttransition. Overall, Cerner/Oracle Health was characterized as a tool: something used in training, but not something that precluded wanting VHA careers or having meaningful experiences, such as caring for patients.

Discussion

This evaluation addressed an underexplored aspect of EHR transitions: their impact on HPTs. It identified HPT challenges, including dissatisfaction with poor transition preparation and EHR training experiences. Promising findings include positive experiences with transition support, EHR uptake, and overall positive educational experiences despite the transition’s disruption.

When EHR users, including HPTs, are dissatisfied with transition preparations, consequent stress can lead to undesired effects, including increased burnout, inappropriate EHR use, and low work satisfaction.^22-24 Negative EHR transition experiences shape HPTs’ subsequent EHR adoption, user satisfaction, as well as confidence and career intent.^3,25,26 Health systems have strong incentives to implement effective transition change management.

HPTs at previous VHA EHR transition sites reported significantly more disruption to their clinical training compared with HPTs at FHCC. Academic programs were shut down at the first transition site, and HPTs expressed decreased interest in VHA careers at another, even a year posttransition.^6,27 These findings are consistent with the limited literature on the adverse impacts that EHR transitions have on HPTs.^7,28

HPT retention is critical. VA is mandated to prepare the next generation of HPTs for its needs, and those of the nation. The VA relies heavily on HPT retention to recruit clinicians: > 65% of VHA physicians nationwide participated in VHA training programs prior to recruitment into staff positions.^5,29

VHA should invest in transition change management with demonstrated, positive impacts on HPTs, such as in-house support from clinicians. Previous research found that lack of support was a major source of stress and negative outcomes.^6,27 Consequently, supporting HPTs through EHR transitions directly contributes to the VHA’s ability to attract high-quality staff from its HPTs. The challenges and promising practices described in this analysis underscore the necessity of understanding how all EHR users are affected by transitions. What happens to them has direct implications for the VA mission to provide safe, efficient care, and its mandate to provide quality clinical training to HPTs.

These findings hold hopeful implications for supporting HPT EHR use, both during and outside EHR transitions. HPTs expressing that an EHR is only 1 part of their clinical training experience suggests that change management can improve EHR transitions. HPT learning can enhance known factors that are important for HPTs in clinical training, including the health care organization’s mission, caring for patients, and personal development.

Further investigations may engage HPTs at future VHA sites making the transition to the new EHR. One focus would involve applying a learning health systems framework to examine the nature of change management efforts—and their effects on HPT transition experiences—iteratively across transition sites to evaluate the effect of the efforts. Another focus may be longitudinal engagement with HPTs at health care systems and sites transitioning to new EHRs. Research has found that disruptions to EHR usability, satisfaction, and care provision can persist for 2 years and beyond following an EHR transition.³⁰ Evaluating the long-term effects of transitions on HPTs is of interest, given their distinct characteristics and differences from employees.

Limitations

Study data came from voluntary participants at 1 highly engaged site, raising the possibility of self-selection bias. HPT experiences at other VA and non-VA sites may differ. Employees and HPTs were engaged during a high-stress event; snowballing recruitment reach was limited by high workloads and limited time for engagement. Statistical data were descriptive and should not be interpreted as causal. Results may reflect, in part, temporal effects, and respondents include HPTs at different stages of training and with different levels of VA experience. Survey sample sizes may limit generalizability; however, merging data streams strengthened the reliability of findings.

Conclusions

The results of this analysis of FHCC HPTs were notably more positive than those of HPTs at previous VHA EHR transition sites. VHA is one of many health care systems that provide clinical training for HPTs and relies on this population to provide patient care. By highlighting challenges and positive experiences of HPTs during an EHR transition, this evaluation produces actionable insights that can inform the actions of health care systems seeking to support HPTs during disruptive EHR transitions.

Exogenously, hypochlorous acid (HOCl) is a powerful oxidizing agent formed from chlorine dissolved in water. Within the body, it is part of the immune response, created by activated leukocytes, which form HOCl from hydrogen peroxide and chloride. HOCl has been used as a disinfectant in wound care due to its antimicrobial properties via inhibition of DNA synthesis, protein synthesis, and decreased adenosine triphosphate production. It specifically targets bacteria by blocking bacterial cell wall synthesis and decreasing DNA replication.¹ 

During the COVID-19 pandemic, HOCl was recommended by the US Environmental Protection Agency as a disinfectant.² HOCl can be purchased from a supplier, though its major limitation is its shelf life. The main environmental factors affecting its stability are sunlight exposure, temperatures > 25 °C, and air exposure. HOCl is stable and most potent when the pH falls between 3.5 and 5.5.³ It is best stored in a cool, dark environment to maintain efficacy for 2 weeks. Rossi-Fedele et al found that when exposed to sunlight, chlorine reduction starts on day 4, whereas solutions kept in dark storage remained more stable, with this process starting after day 14.⁴ 

HOCl can also be made on-site via a machine, which ranges in price from a portable version costing < $200 to a large commercial option that can cost $7000 to $25,000. HOCl is produced by mixing noniodinated salt and water, and using electrolysis, which generally takes less than 10 minutes before it is ready for use.² Given the cost and nonreusable nature of disinfecting wipes, HOCl may be more worthwhile for economic and disposal purposes in the long term. 

Different concentrations of HOCl are readily available commercially. Because topical application of 1% HOCl may cause skin irritation, solutions with lower concentrations have been developed including Vashe (0.03% HOCl; SteadMed), PhaseOne (0.025% HOCl solution; IHT), OCuSOFT (0.02% HOCl; OCuSOFT), Bruder (0.02% HOCl; Bruder Healthcare), Acuicyn (0.01% HOCl solution in dilute saline; Sonoma Pharmaceuticals), and Avenova (0.01% HOCl solution; NovaBay Pharmaceuticals).⁵ 

Aside from its surface utility, HOCl has been researched for its beneficial effects on skin. HOCl has been shown to be helpful intraoperatively and postoperatively in improving adverse effects (AEs) after hair restoration, including erythema and pruritus, and in optimizing healing by reducing inflammation, likely due to its antimicrobial properties and ability to promote oxygenation.⁶ Bucko et al demonstrated that Microcyn scar gel (with HOCl) was a superior nonirritating, nontoxic method of not only improving scar appearance (vascularity, scar height, and pliability) but also reducing scar symptoms of pain and pruritus in comparison to 100% silicone scar gel (traditional application used to improve scarring).⁷ Zhang et al demonstrated that HOCl consistently improved symptom relief of blepharitis, including meibomian gland, eyelash, and eyelid redness, irritation, and appearance in comparison as well as were better tolerated in comparison to traditional recommendations of eyelid compresses and wash (tea tree oil, diluted baby shampoo, and topical antibiotics).⁸ In children with moderate to severe atopic dermatitis, Majewski et al compared a traditional bleach bath with a body wash containing hypochlorite (NaOCl; hypochlorous acid in alkaline aqueous solution). The body wash proved to be more convenient (showering vs 10-minute bath) and significantly improved symptoms while reducing the need for topical corticosteroids (common treatment modality for atopic dermatitis).⁹ 

The skin is the body’s primary defense against both dermatologic and respiratory infections. The face is especially vulnerable to microbes via airborne or environmental transmission, mechanical irritation, and touch. In the military environment, personal protective equipment (PPE) or uniform items may increase the risk of dermatologic conditions such as allergic or irritant dermatitis, infection, and friction blisters. 

In a literature review of 312 dermatologic articles published between 2002 and 2022, Singal and Lipner found that among deployed soldiers serving in hot and dry climates, dermatitis and eczematous conditions were the most common, whereas bacterial and fungal conditions were most common in hot and humid settings. In the nondeployed setting, dermatitis and eczematous, acne, and fungal infections were the most common skin conditions. This is reflected by the unique circumstances that service members face at home and while deployed, when they may be more vulnerable to developing new or worsening chronic skin conditions depending on the environment (access to shelter, humid vs dry environments), and decreased access or time for hygiene (shared quarters at home in barracks or on deployment). Occupation-related conditions also play a large role in military dermatologic conditions.¹⁰ 

Dever et al noted the unique risks and exposures in the environment itself (plants, arthropods) as well as uniform items (protective gear) that carry an increased risk of friction irritation and dermatitis. Occupational exposures commonly associated with irritant contact dermatitis include alcohols, oils, fuel, disinfectants, and solvents. Chemicals in military uniforms themselves (eg, formaldehyde resins, disperse dyes, and chromate-containing dyes) also have the potential to cause allergic contact dermatitis, which can be challenging to address given the emphasis on uniformity and standards.¹¹ PPE also may exacerbate rosacea and acne. 

Some pathologies are associated specifically with bacteria, such as Cutibacterium acnes, as seen in acne vulgaris. Colonization of bacteria on the face may create biofilms that are difficult to detect, may be resistant to antibiotic therapy, and are implicated in other dermatologic conditions, such as persistent wounds, atopic dermatitis, and candidiasis.¹² 

Biofilm and antibiotic resistance already pose a risk to patient care, but the unique environmental conditions and exposures of military settings can amplify this risk in the military population.¹³ Using HOCl in austere environments or the field for wound care may help reduce microbial load and the subsequent need for systemic antibiotics which carry the risk of gastrointestinal AEs and resistance.¹ 

An optimized healing rate would support operational objectives by enabling service members to remain on full duty and avoid medications, which may prevent them from special duty, such as aviation. Sakarya et al found that HOCl solution enhanced wound healing in contrast with povidone-iodine (PI), while a study by Dharap et al discussed how HOCl provided major improvement in ulcer wound size (and infection), as well as significant reduction of inflammation.¹³ 

Anagnostopoulos et al studied the efficacy of 0.01% HOCl vs other disinfectants (5% PI, 4% chlorhexidine gluconate [CHG] and 70% isopropyl alcohol [IPA]) against common skin organisms, including methicillin-susceptible Staphylococcus aureus and methicillin-susceptible Staphylococcus epidermidis. The study found that HOCl had at least equal if not greater efficacy to PI, CHG, and IPA depending on the bacterial strain, demonstrating immediate bactericidal effects.¹⁴ 

Furthermore, HOCl has been shown to be useful in suturing and wound closure by reducing microbial load when soaked gauze is placed in wound beds prior to closure, while not harming surrounding tissue.¹⁵ This would be especially advantageous for military health care when specialist follow-up would be delayed or to prevent infection risk while en route to higher care. Aside from its disinfectant strength, it’s also well tolerated. HOCl studies on human tissue demonstrate its efficacy to prevent irritation and AEs while also preventing infection and promoting wound healing. 

Gozukucuk and Cakiroglu studied the use of HOCl as a skin disinfectant before neonatal circumcision and demonstrated fewer adverse effects compared with the more commonly used PI. Neonates treated with PI prior to circumcision resulted in greater postoperative edema and increased duration of wound healing compared with infants treated with HOCl.¹⁶ Furthermore, studies have shown that PI can lead to irritant dermatitis or chemical burns if not properly dried or if it becomes pooled because of occlusion dressings.¹⁷ 

Aside from its indicated use for infection or wound care, anti-inflammatory properties of HOCl also may be beneficial for off-label use in preventing flareups of chronic conditions as well as for treating symptoms while awaiting specialist evaluation. This might be the case during US-based training exercises, in remote locations without nearby dermatologists, or during virtual care because of internet constraints. For chronic conditions such as rosacea or atopic dermatitis, which research has shown are related to mast cell activation and degranulation and cytokine release, HOCl has been shown to reduce histamine, neutrophil-generated leukotrienes, in addition to interleukin-6 and interleukin-2 to improve symptoms by reducing inflammation.¹⁸ 

Limitations of HOCl to explore would be extending its shelf life, exploring its various forms (eg, spray, topical) and storage limitations, and training of the machine and materials needed to be made in-house if not purchased. There are also no official guidelines for clinicians to recommend HOCl to patients, and research should be expanded on its use in humans, though it generally is well tolerated without AEs. HOCl has the potential to be a potent, nontoxic, inexpensive tool in med bags or at austere clinics to help maintain a sterile space for procedures, prevent infection while rendering care, and help with exacerbations or prevent flare-ups of chronic conditions such as psoriasis, acne, and atopic dermatitis while specialist care is pending. 

Exogenously, hypochlorous acid (HOCl) is a powerful oxidizing agent formed from chlorine dissolved in water. Within the body, it is part of the immune response, created by activated leukocytes, which form HOCl from hydrogen peroxide and chloride. HOCl has been used as a disinfectant in wound care due to its antimicrobial properties via inhibition of DNA synthesis, protein synthesis, and decreased adenosine triphosphate production. It specifically targets bacteria by blocking bacterial cell wall synthesis and decreasing DNA replication.¹ 

During the COVID-19 pandemic, HOCl was recommended by the US Environmental Protection Agency as a disinfectant.² HOCl can be purchased from a supplier, though its major limitation is its shelf life. The main environmental factors affecting its stability are sunlight exposure, temperatures > 25 °C, and air exposure. HOCl is stable and most potent when the pH falls between 3.5 and 5.5.³ It is best stored in a cool, dark environment to maintain efficacy for 2 weeks. Rossi-Fedele et al found that when exposed to sunlight, chlorine reduction starts on day 4, whereas solutions kept in dark storage remained more stable, with this process starting after day 14.⁴ 

HOCl can also be made on-site via a machine, which ranges in price from a portable version costing < $200 to a large commercial option that can cost $7000 to $25,000. HOCl is produced by mixing noniodinated salt and water, and using electrolysis, which generally takes less than 10 minutes before it is ready for use.² Given the cost and nonreusable nature of disinfecting wipes, HOCl may be more worthwhile for economic and disposal purposes in the long term. 

Different concentrations of HOCl are readily available commercially. Because topical application of 1% HOCl may cause skin irritation, solutions with lower concentrations have been developed including Vashe (0.03% HOCl; SteadMed), PhaseOne (0.025% HOCl solution; IHT), OCuSOFT (0.02% HOCl; OCuSOFT), Bruder (0.02% HOCl; Bruder Healthcare), Acuicyn (0.01% HOCl solution in dilute saline; Sonoma Pharmaceuticals), and Avenova (0.01% HOCl solution; NovaBay Pharmaceuticals).⁵ 

Aside from its surface utility, HOCl has been researched for its beneficial effects on skin. HOCl has been shown to be helpful intraoperatively and postoperatively in improving adverse effects (AEs) after hair restoration, including erythema and pruritus, and in optimizing healing by reducing inflammation, likely due to its antimicrobial properties and ability to promote oxygenation.⁶ Bucko et al demonstrated that Microcyn scar gel (with HOCl) was a superior nonirritating, nontoxic method of not only improving scar appearance (vascularity, scar height, and pliability) but also reducing scar symptoms of pain and pruritus in comparison to 100% silicone scar gel (traditional application used to improve scarring).⁷ Zhang et al demonstrated that HOCl consistently improved symptom relief of blepharitis, including meibomian gland, eyelash, and eyelid redness, irritation, and appearance in comparison as well as were better tolerated in comparison to traditional recommendations of eyelid compresses and wash (tea tree oil, diluted baby shampoo, and topical antibiotics).⁸ In children with moderate to severe atopic dermatitis, Majewski et al compared a traditional bleach bath with a body wash containing hypochlorite (NaOCl; hypochlorous acid in alkaline aqueous solution). The body wash proved to be more convenient (showering vs 10-minute bath) and significantly improved symptoms while reducing the need for topical corticosteroids (common treatment modality for atopic dermatitis).⁹ 

The skin is the body’s primary defense against both dermatologic and respiratory infections. The face is especially vulnerable to microbes via airborne or environmental transmission, mechanical irritation, and touch. In the military environment, personal protective equipment (PPE) or uniform items may increase the risk of dermatologic conditions such as allergic or irritant dermatitis, infection, and friction blisters. 

In a literature review of 312 dermatologic articles published between 2002 and 2022, Singal and Lipner found that among deployed soldiers serving in hot and dry climates, dermatitis and eczematous conditions were the most common, whereas bacterial and fungal conditions were most common in hot and humid settings. In the nondeployed setting, dermatitis and eczematous, acne, and fungal infections were the most common skin conditions. This is reflected by the unique circumstances that service members face at home and while deployed, when they may be more vulnerable to developing new or worsening chronic skin conditions depending on the environment (access to shelter, humid vs dry environments), and decreased access or time for hygiene (shared quarters at home in barracks or on deployment). Occupation-related conditions also play a large role in military dermatologic conditions.¹⁰ 

Dever et al noted the unique risks and exposures in the environment itself (plants, arthropods) as well as uniform items (protective gear) that carry an increased risk of friction irritation and dermatitis. Occupational exposures commonly associated with irritant contact dermatitis include alcohols, oils, fuel, disinfectants, and solvents. Chemicals in military uniforms themselves (eg, formaldehyde resins, disperse dyes, and chromate-containing dyes) also have the potential to cause allergic contact dermatitis, which can be challenging to address given the emphasis on uniformity and standards.¹¹ PPE also may exacerbate rosacea and acne. 

Some pathologies are associated specifically with bacteria, such as Cutibacterium acnes, as seen in acne vulgaris. Colonization of bacteria on the face may create biofilms that are difficult to detect, may be resistant to antibiotic therapy, and are implicated in other dermatologic conditions, such as persistent wounds, atopic dermatitis, and candidiasis.¹² 

Biofilm and antibiotic resistance already pose a risk to patient care, but the unique environmental conditions and exposures of military settings can amplify this risk in the military population.¹³ Using HOCl in austere environments or the field for wound care may help reduce microbial load and the subsequent need for systemic antibiotics which carry the risk of gastrointestinal AEs and resistance.¹ 

An optimized healing rate would support operational objectives by enabling service members to remain on full duty and avoid medications, which may prevent them from special duty, such as aviation. Sakarya et al found that HOCl solution enhanced wound healing in contrast with povidone-iodine (PI), while a study by Dharap et al discussed how HOCl provided major improvement in ulcer wound size (and infection), as well as significant reduction of inflammation.¹³ 

Anagnostopoulos et al studied the efficacy of 0.01% HOCl vs other disinfectants (5% PI, 4% chlorhexidine gluconate [CHG] and 70% isopropyl alcohol [IPA]) against common skin organisms, including methicillin-susceptible Staphylococcus aureus and methicillin-susceptible Staphylococcus epidermidis. The study found that HOCl had at least equal if not greater efficacy to PI, CHG, and IPA depending on the bacterial strain, demonstrating immediate bactericidal effects.¹⁴ 

Furthermore, HOCl has been shown to be useful in suturing and wound closure by reducing microbial load when soaked gauze is placed in wound beds prior to closure, while not harming surrounding tissue.¹⁵ This would be especially advantageous for military health care when specialist follow-up would be delayed or to prevent infection risk while en route to higher care. Aside from its disinfectant strength, it’s also well tolerated. HOCl studies on human tissue demonstrate its efficacy to prevent irritation and AEs while also preventing infection and promoting wound healing. 

Gozukucuk and Cakiroglu studied the use of HOCl as a skin disinfectant before neonatal circumcision and demonstrated fewer adverse effects compared with the more commonly used PI. Neonates treated with PI prior to circumcision resulted in greater postoperative edema and increased duration of wound healing compared with infants treated with HOCl.¹⁶ Furthermore, studies have shown that PI can lead to irritant dermatitis or chemical burns if not properly dried or if it becomes pooled because of occlusion dressings.¹⁷ 

Aside from its indicated use for infection or wound care, anti-inflammatory properties of HOCl also may be beneficial for off-label use in preventing flareups of chronic conditions as well as for treating symptoms while awaiting specialist evaluation. This might be the case during US-based training exercises, in remote locations without nearby dermatologists, or during virtual care because of internet constraints. For chronic conditions such as rosacea or atopic dermatitis, which research has shown are related to mast cell activation and degranulation and cytokine release, HOCl has been shown to reduce histamine, neutrophil-generated leukotrienes, in addition to interleukin-6 and interleukin-2 to improve symptoms by reducing inflammation.¹⁸ 

Limitations of HOCl to explore would be extending its shelf life, exploring its various forms (eg, spray, topical) and storage limitations, and training of the machine and materials needed to be made in-house if not purchased. There are also no official guidelines for clinicians to recommend HOCl to patients, and research should be expanded on its use in humans, though it generally is well tolerated without AEs. HOCl has the potential to be a potent, nontoxic, inexpensive tool in med bags or at austere clinics to help maintain a sterile space for procedures, prevent infection while rendering care, and help with exacerbations or prevent flare-ups of chronic conditions such as psoriasis, acne, and atopic dermatitis while specialist care is pending. 

Exogenously, hypochlorous acid (HOCl) is a powerful oxidizing agent formed from chlorine dissolved in water. Within the body, it is part of the immune response, created by activated leukocytes, which form HOCl from hydrogen peroxide and chloride. HOCl has been used as a disinfectant in wound care due to its antimicrobial properties via inhibition of DNA synthesis, protein synthesis, and decreased adenosine triphosphate production. It specifically targets bacteria by blocking bacterial cell wall synthesis and decreasing DNA replication.¹ 

During the COVID-19 pandemic, HOCl was recommended by the US Environmental Protection Agency as a disinfectant.² HOCl can be purchased from a supplier, though its major limitation is its shelf life. The main environmental factors affecting its stability are sunlight exposure, temperatures > 25 °C, and air exposure. HOCl is stable and most potent when the pH falls between 3.5 and 5.5.³ It is best stored in a cool, dark environment to maintain efficacy for 2 weeks. Rossi-Fedele et al found that when exposed to sunlight, chlorine reduction starts on day 4, whereas solutions kept in dark storage remained more stable, with this process starting after day 14.⁴ 

HOCl can also be made on-site via a machine, which ranges in price from a portable version costing < $200 to a large commercial option that can cost $7000 to $25,000. HOCl is produced by mixing noniodinated salt and water, and using electrolysis, which generally takes less than 10 minutes before it is ready for use.² Given the cost and nonreusable nature of disinfecting wipes, HOCl may be more worthwhile for economic and disposal purposes in the long term. 

Different concentrations of HOCl are readily available commercially. Because topical application of 1% HOCl may cause skin irritation, solutions with lower concentrations have been developed including Vashe (0.03% HOCl; SteadMed), PhaseOne (0.025% HOCl solution; IHT), OCuSOFT (0.02% HOCl; OCuSOFT), Bruder (0.02% HOCl; Bruder Healthcare), Acuicyn (0.01% HOCl solution in dilute saline; Sonoma Pharmaceuticals), and Avenova (0.01% HOCl solution; NovaBay Pharmaceuticals).⁵ 

Aside from its surface utility, HOCl has been researched for its beneficial effects on skin. HOCl has been shown to be helpful intraoperatively and postoperatively in improving adverse effects (AEs) after hair restoration, including erythema and pruritus, and in optimizing healing by reducing inflammation, likely due to its antimicrobial properties and ability to promote oxygenation.⁶ Bucko et al demonstrated that Microcyn scar gel (with HOCl) was a superior nonirritating, nontoxic method of not only improving scar appearance (vascularity, scar height, and pliability) but also reducing scar symptoms of pain and pruritus in comparison to 100% silicone scar gel (traditional application used to improve scarring).⁷ Zhang et al demonstrated that HOCl consistently improved symptom relief of blepharitis, including meibomian gland, eyelash, and eyelid redness, irritation, and appearance in comparison as well as were better tolerated in comparison to traditional recommendations of eyelid compresses and wash (tea tree oil, diluted baby shampoo, and topical antibiotics).⁸ In children with moderate to severe atopic dermatitis, Majewski et al compared a traditional bleach bath with a body wash containing hypochlorite (NaOCl; hypochlorous acid in alkaline aqueous solution). The body wash proved to be more convenient (showering vs 10-minute bath) and significantly improved symptoms while reducing the need for topical corticosteroids (common treatment modality for atopic dermatitis).⁹ 

The skin is the body’s primary defense against both dermatologic and respiratory infections. The face is especially vulnerable to microbes via airborne or environmental transmission, mechanical irritation, and touch. In the military environment, personal protective equipment (PPE) or uniform items may increase the risk of dermatologic conditions such as allergic or irritant dermatitis, infection, and friction blisters. 

In a literature review of 312 dermatologic articles published between 2002 and 2022, Singal and Lipner found that among deployed soldiers serving in hot and dry climates, dermatitis and eczematous conditions were the most common, whereas bacterial and fungal conditions were most common in hot and humid settings. In the nondeployed setting, dermatitis and eczematous, acne, and fungal infections were the most common skin conditions. This is reflected by the unique circumstances that service members face at home and while deployed, when they may be more vulnerable to developing new or worsening chronic skin conditions depending on the environment (access to shelter, humid vs dry environments), and decreased access or time for hygiene (shared quarters at home in barracks or on deployment). Occupation-related conditions also play a large role in military dermatologic conditions.¹⁰ 

Dever et al noted the unique risks and exposures in the environment itself (plants, arthropods) as well as uniform items (protective gear) that carry an increased risk of friction irritation and dermatitis. Occupational exposures commonly associated with irritant contact dermatitis include alcohols, oils, fuel, disinfectants, and solvents. Chemicals in military uniforms themselves (eg, formaldehyde resins, disperse dyes, and chromate-containing dyes) also have the potential to cause allergic contact dermatitis, which can be challenging to address given the emphasis on uniformity and standards.¹¹ PPE also may exacerbate rosacea and acne. 

Some pathologies are associated specifically with bacteria, such as Cutibacterium acnes, as seen in acne vulgaris. Colonization of bacteria on the face may create biofilms that are difficult to detect, may be resistant to antibiotic therapy, and are implicated in other dermatologic conditions, such as persistent wounds, atopic dermatitis, and candidiasis.¹² 

Biofilm and antibiotic resistance already pose a risk to patient care, but the unique environmental conditions and exposures of military settings can amplify this risk in the military population.¹³ Using HOCl in austere environments or the field for wound care may help reduce microbial load and the subsequent need for systemic antibiotics which carry the risk of gastrointestinal AEs and resistance.¹ 

An optimized healing rate would support operational objectives by enabling service members to remain on full duty and avoid medications, which may prevent them from special duty, such as aviation. Sakarya et al found that HOCl solution enhanced wound healing in contrast with povidone-iodine (PI), while a study by Dharap et al discussed how HOCl provided major improvement in ulcer wound size (and infection), as well as significant reduction of inflammation.¹³ 

Anagnostopoulos et al studied the efficacy of 0.01% HOCl vs other disinfectants (5% PI, 4% chlorhexidine gluconate [CHG] and 70% isopropyl alcohol [IPA]) against common skin organisms, including methicillin-susceptible Staphylococcus aureus and methicillin-susceptible Staphylococcus epidermidis. The study found that HOCl had at least equal if not greater efficacy to PI, CHG, and IPA depending on the bacterial strain, demonstrating immediate bactericidal effects.¹⁴ 

Furthermore, HOCl has been shown to be useful in suturing and wound closure by reducing microbial load when soaked gauze is placed in wound beds prior to closure, while not harming surrounding tissue.¹⁵ This would be especially advantageous for military health care when specialist follow-up would be delayed or to prevent infection risk while en route to higher care. Aside from its disinfectant strength, it’s also well tolerated. HOCl studies on human tissue demonstrate its efficacy to prevent irritation and AEs while also preventing infection and promoting wound healing. 

Gozukucuk and Cakiroglu studied the use of HOCl as a skin disinfectant before neonatal circumcision and demonstrated fewer adverse effects compared with the more commonly used PI. Neonates treated with PI prior to circumcision resulted in greater postoperative edema and increased duration of wound healing compared with infants treated with HOCl.¹⁶ Furthermore, studies have shown that PI can lead to irritant dermatitis or chemical burns if not properly dried or if it becomes pooled because of occlusion dressings.¹⁷ 

Aside from its indicated use for infection or wound care, anti-inflammatory properties of HOCl also may be beneficial for off-label use in preventing flareups of chronic conditions as well as for treating symptoms while awaiting specialist evaluation. This might be the case during US-based training exercises, in remote locations without nearby dermatologists, or during virtual care because of internet constraints. For chronic conditions such as rosacea or atopic dermatitis, which research has shown are related to mast cell activation and degranulation and cytokine release, HOCl has been shown to reduce histamine, neutrophil-generated leukotrienes, in addition to interleukin-6 and interleukin-2 to improve symptoms by reducing inflammation.¹⁸ 

Limitations of HOCl to explore would be extending its shelf life, exploring its various forms (eg, spray, topical) and storage limitations, and training of the machine and materials needed to be made in-house if not purchased. There are also no official guidelines for clinicians to recommend HOCl to patients, and research should be expanded on its use in humans, though it generally is well tolerated without AEs. HOCl has the potential to be a potent, nontoxic, inexpensive tool in med bags or at austere clinics to help maintain a sterile space for procedures, prevent infection while rendering care, and help with exacerbations or prevent flare-ups of chronic conditions such as psoriasis, acne, and atopic dermatitis while specialist care is pending. 

Render unto Caesar the things that are Caesar’s, and to God the things that are God’s.
Matthew 22:21

While in my 20s, I taught religious education at a church on the Army base where I was born and had the honor of working with military chaplains. During my US Department of Veterans Affairs career, I closely collaborated with chaplains—many of whom were veterans—on patient care and ethics consultations. Some were quite proud of their rank and interested in climbing the ladder of promotion. A few made sure you knew what they wore or had worn on their uniform, while most were incredibly humble and sheepish when soldiers saluted them. Those visible responses to rank may be hidden if chaplains will no longer be permitted to wear insignia indicating their grade. 

Department of War Secretary Peter Hegseth, a combat veteran who has championed a “combative” form of Christianity, announced in April 2026 that chaplains would no longer wear their rank on their uniform.¹ Details of how this shift will be translated into regulation, policy, and actions were not provided. Secretary Hegseth did not remove the actual rank of members of the chaplain corps and they would retain their rank, attendant pay, benefits, responsibilities, and privileges. However, instead of bearing the insignia of their military station, under this new policy only the symbol of their religious profession would identify them. Currently, both a military officer’s rank and religious symbol are displayed.² 

Useful insight can be gained from an historical perspective, which demonstrates that the concerns and contention about the issue of chaplain’s wearing rank are not new. There have been chaplains in the US Army since 1775.³ Army chaplains initially wore only a religious symbol on their clothing. In April 1914, chaplain leaders successful argued that chaplains deserved the privileges, respect, and prospect for promotion that rank symbolized and where authorized to display their position. Four years later, General Jack Pershing cabled the then Secretary of War opposing the new policy: “Believe the work of chaplains would be facilitated if they were not given military rank ... Many of our principal ministers believe that their relations would be closer if they did not have military titles and did not wear insignia.”4 Interestingly, Secretary Hegseth articulated the same concern: “A chaplain is first and foremost a chaplain and an officer second. This change is a visual representation of that fact.”⁵ 

Hegseth has stated that in recent years the military chaplain corps had drifted too far in the direction of providing spiritual counseling and psychological support. This contravenes the current competencies especially for company-grade military chaplains who primarily minister to the moral distress and spiritual needs of service members.⁴ The removal of rank is thus best understood as part of Secretary Hegseth’s broader plan to remake the chaplain corps into his vision of religious ministry in the military.⁵ 

Secretary Hegseth proffered several arguments for the necessity of removing rank in part to reorient the chaplain corps to what he calls a more fundamental mission. The first was theological: chaplains need to prioritize their “divine calling” rather than any human distinction. Chaplain theologians and ethicists have expressed similar concerns that in wearing rank, military chaplains become servants of the state and not of God. Adam Tietje articulates the corruptive influence this shift in the source of legitimacy has on the military chaplain’s spiritual mission: 

This undermines the ability of chaplains to provide care and counsel to both soldiers and leaders that is not muddied with the interests of the military. Chaplains without rank are better positioned to hear and advocate for their soldier’s matters of conscience as well as bear witness to the moral claims of their respective religious communities especially about war itself.³ 

The second argument is pastoral. Hegseth contends that service members of lower rank would feel more comfortable and secure approaching chaplains with no outward sign of their higher position. Chaplain interactions with military personnel carry a degree of confidentiality higher than that of either doctors or lawyers. Chaplains, as they were in the past, remain divided on this important consideration.^4,5 

The third argument is ethical in nature. Secretary Hegseth contends that excluding any manifestation of military rank, “speaks to the difficult balance of the duality” of the role.⁶ It seems he is proposing that chaplains displaying only the image of their faith commitment symbolically resolves the inherent moral conflict between serving human masters as a military officer, and the divine as a minister.⁷ Military chaplains and health care professionals are all too familiar with the dilemma of having 2 masters and the challenge of negotiating legally and ethically overlapping roles.^8-10 

This may seem to some like a minor change in chaplain etiquette to some, but to others it signals a significant ethical and political change with potential import beyond chaplaincy. One military commentator has suggested the move sets a dangerous precedent that could eventually be applied to both health care professionals and the judge advocate corps.¹¹ At this point this is only speculation and its slippery slope arguments are logically suspect without evidence. Yet at least 1 study suggests that the influence of military physician’s rank on patient care may lead to inequities in the care delivered to patients with lower grade.¹² 

It is commanders who are the decision-makers in the military. Chaplains who are field grade officers serve as trusted staff advisors in moral, ethical, and spiritual matters.⁴ Some chaplains fear that without rank leaders at all levels will not have adequate trust and sufficient respect to heed their crucial counsel especially regarding high-stakes strategic decisions in wartime.⁸ The more serious concern is with a major shift in the locus of authority to determine the professional identity of chaplains, that could in theory be expanded to impact military health care practitioners, and attorneys. The independent expert judgment of these professionals regarding what is necessary to fulfil their respective roles in providing spiritual ministry, medical care, and legal is critical to uphold the highest values of the US military.¹¹ Chaplains have long struggled with what they owe to the Caesar and to God: how the Secretary’s recent decision will shape that rendering is uncertain. What is certain is that military chaplains of all faiths and in every branch of the armed services will continue to minister to their brothers and sisters in arms with courage and compassion. 

Render unto Caesar the things that are Caesar’s, and to God the things that are God’s.
Matthew 22:21

While in my 20s, I taught religious education at a church on the Army base where I was born and had the honor of working with military chaplains. During my US Department of Veterans Affairs career, I closely collaborated with chaplains—many of whom were veterans—on patient care and ethics consultations. Some were quite proud of their rank and interested in climbing the ladder of promotion. A few made sure you knew what they wore or had worn on their uniform, while most were incredibly humble and sheepish when soldiers saluted them. Those visible responses to rank may be hidden if chaplains will no longer be permitted to wear insignia indicating their grade. 

Department of War Secretary Peter Hegseth, a combat veteran who has championed a “combative” form of Christianity, announced in April 2026 that chaplains would no longer wear their rank on their uniform.¹ Details of how this shift will be translated into regulation, policy, and actions were not provided. Secretary Hegseth did not remove the actual rank of members of the chaplain corps and they would retain their rank, attendant pay, benefits, responsibilities, and privileges. However, instead of bearing the insignia of their military station, under this new policy only the symbol of their religious profession would identify them. Currently, both a military officer’s rank and religious symbol are displayed.² 

Useful insight can be gained from an historical perspective, which demonstrates that the concerns and contention about the issue of chaplain’s wearing rank are not new. There have been chaplains in the US Army since 1775.³ Army chaplains initially wore only a religious symbol on their clothing. In April 1914, chaplain leaders successful argued that chaplains deserved the privileges, respect, and prospect for promotion that rank symbolized and where authorized to display their position. Four years later, General Jack Pershing cabled the then Secretary of War opposing the new policy: “Believe the work of chaplains would be facilitated if they were not given military rank ... Many of our principal ministers believe that their relations would be closer if they did not have military titles and did not wear insignia.”4 Interestingly, Secretary Hegseth articulated the same concern: “A chaplain is first and foremost a chaplain and an officer second. This change is a visual representation of that fact.”⁵ 

Hegseth has stated that in recent years the military chaplain corps had drifted too far in the direction of providing spiritual counseling and psychological support. This contravenes the current competencies especially for company-grade military chaplains who primarily minister to the moral distress and spiritual needs of service members.⁴ The removal of rank is thus best understood as part of Secretary Hegseth’s broader plan to remake the chaplain corps into his vision of religious ministry in the military.⁵ 

Secretary Hegseth proffered several arguments for the necessity of removing rank in part to reorient the chaplain corps to what he calls a more fundamental mission. The first was theological: chaplains need to prioritize their “divine calling” rather than any human distinction. Chaplain theologians and ethicists have expressed similar concerns that in wearing rank, military chaplains become servants of the state and not of God. Adam Tietje articulates the corruptive influence this shift in the source of legitimacy has on the military chaplain’s spiritual mission: 

This undermines the ability of chaplains to provide care and counsel to both soldiers and leaders that is not muddied with the interests of the military. Chaplains without rank are better positioned to hear and advocate for their soldier’s matters of conscience as well as bear witness to the moral claims of their respective religious communities especially about war itself.³ 

The second argument is pastoral. Hegseth contends that service members of lower rank would feel more comfortable and secure approaching chaplains with no outward sign of their higher position. Chaplain interactions with military personnel carry a degree of confidentiality higher than that of either doctors or lawyers. Chaplains, as they were in the past, remain divided on this important consideration.^4,5 

The third argument is ethical in nature. Secretary Hegseth contends that excluding any manifestation of military rank, “speaks to the difficult balance of the duality” of the role.⁶ It seems he is proposing that chaplains displaying only the image of their faith commitment symbolically resolves the inherent moral conflict between serving human masters as a military officer, and the divine as a minister.⁷ Military chaplains and health care professionals are all too familiar with the dilemma of having 2 masters and the challenge of negotiating legally and ethically overlapping roles.^8-10 

This may seem to some like a minor change in chaplain etiquette to some, but to others it signals a significant ethical and political change with potential import beyond chaplaincy. One military commentator has suggested the move sets a dangerous precedent that could eventually be applied to both health care professionals and the judge advocate corps.¹¹ At this point this is only speculation and its slippery slope arguments are logically suspect without evidence. Yet at least 1 study suggests that the influence of military physician’s rank on patient care may lead to inequities in the care delivered to patients with lower grade.¹² 

It is commanders who are the decision-makers in the military. Chaplains who are field grade officers serve as trusted staff advisors in moral, ethical, and spiritual matters.⁴ Some chaplains fear that without rank leaders at all levels will not have adequate trust and sufficient respect to heed their crucial counsel especially regarding high-stakes strategic decisions in wartime.⁸ The more serious concern is with a major shift in the locus of authority to determine the professional identity of chaplains, that could in theory be expanded to impact military health care practitioners, and attorneys. The independent expert judgment of these professionals regarding what is necessary to fulfil their respective roles in providing spiritual ministry, medical care, and legal is critical to uphold the highest values of the US military.¹¹ Chaplains have long struggled with what they owe to the Caesar and to God: how the Secretary’s recent decision will shape that rendering is uncertain. What is certain is that military chaplains of all faiths and in every branch of the armed services will continue to minister to their brothers and sisters in arms with courage and compassion. 

Render unto Caesar the things that are Caesar’s, and to God the things that are God’s.
Matthew 22:21

While in my 20s, I taught religious education at a church on the Army base where I was born and had the honor of working with military chaplains. During my US Department of Veterans Affairs career, I closely collaborated with chaplains—many of whom were veterans—on patient care and ethics consultations. Some were quite proud of their rank and interested in climbing the ladder of promotion. A few made sure you knew what they wore or had worn on their uniform, while most were incredibly humble and sheepish when soldiers saluted them. Those visible responses to rank may be hidden if chaplains will no longer be permitted to wear insignia indicating their grade. 

Department of War Secretary Peter Hegseth, a combat veteran who has championed a “combative” form of Christianity, announced in April 2026 that chaplains would no longer wear their rank on their uniform.¹ Details of how this shift will be translated into regulation, policy, and actions were not provided. Secretary Hegseth did not remove the actual rank of members of the chaplain corps and they would retain their rank, attendant pay, benefits, responsibilities, and privileges. However, instead of bearing the insignia of their military station, under this new policy only the symbol of their religious profession would identify them. Currently, both a military officer’s rank and religious symbol are displayed.² 

Useful insight can be gained from an historical perspective, which demonstrates that the concerns and contention about the issue of chaplain’s wearing rank are not new. There have been chaplains in the US Army since 1775.³ Army chaplains initially wore only a religious symbol on their clothing. In April 1914, chaplain leaders successful argued that chaplains deserved the privileges, respect, and prospect for promotion that rank symbolized and where authorized to display their position. Four years later, General Jack Pershing cabled the then Secretary of War opposing the new policy: “Believe the work of chaplains would be facilitated if they were not given military rank ... Many of our principal ministers believe that their relations would be closer if they did not have military titles and did not wear insignia.”4 Interestingly, Secretary Hegseth articulated the same concern: “A chaplain is first and foremost a chaplain and an officer second. This change is a visual representation of that fact.”⁵ 

Hegseth has stated that in recent years the military chaplain corps had drifted too far in the direction of providing spiritual counseling and psychological support. This contravenes the current competencies especially for company-grade military chaplains who primarily minister to the moral distress and spiritual needs of service members.⁴ The removal of rank is thus best understood as part of Secretary Hegseth’s broader plan to remake the chaplain corps into his vision of religious ministry in the military.⁵ 

Secretary Hegseth proffered several arguments for the necessity of removing rank in part to reorient the chaplain corps to what he calls a more fundamental mission. The first was theological: chaplains need to prioritize their “divine calling” rather than any human distinction. Chaplain theologians and ethicists have expressed similar concerns that in wearing rank, military chaplains become servants of the state and not of God. Adam Tietje articulates the corruptive influence this shift in the source of legitimacy has on the military chaplain’s spiritual mission: 

This undermines the ability of chaplains to provide care and counsel to both soldiers and leaders that is not muddied with the interests of the military. Chaplains without rank are better positioned to hear and advocate for their soldier’s matters of conscience as well as bear witness to the moral claims of their respective religious communities especially about war itself.³ 

The second argument is pastoral. Hegseth contends that service members of lower rank would feel more comfortable and secure approaching chaplains with no outward sign of their higher position. Chaplain interactions with military personnel carry a degree of confidentiality higher than that of either doctors or lawyers. Chaplains, as they were in the past, remain divided on this important consideration.^4,5 

The third argument is ethical in nature. Secretary Hegseth contends that excluding any manifestation of military rank, “speaks to the difficult balance of the duality” of the role.⁶ It seems he is proposing that chaplains displaying only the image of their faith commitment symbolically resolves the inherent moral conflict between serving human masters as a military officer, and the divine as a minister.⁷ Military chaplains and health care professionals are all too familiar with the dilemma of having 2 masters and the challenge of negotiating legally and ethically overlapping roles.^8-10 

This may seem to some like a minor change in chaplain etiquette to some, but to others it signals a significant ethical and political change with potential import beyond chaplaincy. One military commentator has suggested the move sets a dangerous precedent that could eventually be applied to both health care professionals and the judge advocate corps.¹¹ At this point this is only speculation and its slippery slope arguments are logically suspect without evidence. Yet at least 1 study suggests that the influence of military physician’s rank on patient care may lead to inequities in the care delivered to patients with lower grade.¹² 

It is commanders who are the decision-makers in the military. Chaplains who are field grade officers serve as trusted staff advisors in moral, ethical, and spiritual matters.⁴ Some chaplains fear that without rank leaders at all levels will not have adequate trust and sufficient respect to heed their crucial counsel especially regarding high-stakes strategic decisions in wartime.⁸ The more serious concern is with a major shift in the locus of authority to determine the professional identity of chaplains, that could in theory be expanded to impact military health care practitioners, and attorneys. The independent expert judgment of these professionals regarding what is necessary to fulfil their respective roles in providing spiritual ministry, medical care, and legal is critical to uphold the highest values of the US military.¹¹ Chaplains have long struggled with what they owe to the Caesar and to God: how the Secretary’s recent decision will shape that rendering is uncertain. What is certain is that military chaplains of all faiths and in every branch of the armed services will continue to minister to their brothers and sisters in arms with courage and compassion. 

Cannabis has a long history of use for medicinal and recreational purposes. Research illustrates the potential benefits and increased prevalence of cannabis use in patients with cancer.¹ Cannabis products have been shown to possess antineoplastic and palliative activity, improving nociceptive and neuropathic pain in addition to chemotherapy-related nausea and vomiting.^2-5 Despite these developments and changing social attitudes toward cannabis, there remains a lack of comprehensive data on patient perspectives regarding its use, especially in regions where cannabis remains illegal. This knowledge gap is notable among veterans undergoing cancer treatment in states where cannabis is prohibited. Up to 57% of veterans report lifetime marijuana use, making it crucial to understand this population’s cannabis use patterns and potential interactions with cancer treatments.⁶

This observational study sought to determine the prevalence of cannabis use among patients undergoing cancer treatment at the US Department of Veterans Affairs (VA) Memphis Healthcare System and evaluate the potential risks associated with combining cannabis products with anticancer therapies.

METHODS

This prospective observational study identified cannabis use among veterans receiving antineoplastic therapy at the Lt. Col. Luke Weathers Jr. VA Medical Center (WJVAMC) and analyzed potential interactions between cannabis products and their cancer treatments. Participants included adults aged > 18 years undergoing antineoplastic therapy at WJVAMC who consented to the study. Data collection involved a written survey approved by the WJVAMC Institutional Review Board and verbal consent from participants. The survey asked participants about their cannabis use in the previous 90 days, including details on quantity, frequency, and method of consumption (eg, inhalation, oral, topical). No incentives were offered for participation.

Surveys from 50 patients who used cannabis were analyzed and their electronic health records were reviewed for sex, age, diagnosis, and antineoplastic regimen. This information was securely stored. A literature review was conducted using PubMed and the Cochrane Library to explore potential interactions between cannabis and the antineoplastic agents that were prescribed to patients in the study, focusing on toxicity, efficacy, or synergistic effects.

Patients were categorized into 4 groups based on treatment: cytotoxic chemotherapy, immunotherapy, endocrine therapy, and targeted therapy. Patients undergoing multiple types of therapies were included in each applicable category.

RESULTS

A total of 132 patients agreed to participate. Fifty patients (38%) acknowledged using cannabis products within 90 days. The patients that used cannabis products within 90 days of the survey reported the following malignancies: 8 patients (16%) had prostate cancer, 3 patients (6%) had hepatocellular carcinoma, 7 patients (14%) had pancreatic carcinoma, 5 patients (10%) had multiple myeloma, 3 patients (6%) had chronic lymphocytic leukemia, 9 patients (18%) had non-small cell lung cancer, 3 patients (6%) had breast cancer, 3 (6%) patients had bladder cancer, 2 patients (4%) had renal cell carcinoma, 1 (2%) patient had chronic myeloid leukemia, 1 (2%) patient had renal amyloid, 1 patient (2%) had supraglottic squamous cell carcinoma, 1 patient (2%) had esophageal carcinoma, 1 (2%) patient had small cell lung cancer, 1 (2%) patient had gastric cancer, and 1 patient (2%) had follicular lymphoma.

Five (10%) of the cannabis users were female, and 45 (90%) were male. Twenty-nine patients (58%) were aged 66 to 75 years, 16 (32%) were aged 56 to 65 years, 3 (6%) were aged 46 to 55 years, and 2 (4%) were aged 76 to 85 years.

Thirty-five patients (70%) inhaled cannabis as opposed to using it via other formulations or a combination (eg, inhalation and topical). Thirty-eight percent of patients used cannabis once daily, 24% used < 1 daily, and 28% used it ≥ 2 times daily. Five patients (10%) did not report the frequency of their cannabis use. Among the patients who reported cannabis use, 21 (42%) were undergoing cytotoxic chemotherapy, 19 (38%) were undergoing immunotherapy, 12 (24%) were undergoing targeted therapy, and 10 (20%) were undergoing endocrine therapy. Some patients were treated with multiple types of antineoplastic agents and were counted in multiple categories (Table 1).

Following a literature review of cannabis and antineoplastic agents, patients were evaluated for the potential effects of cannabis on their treatment. The literature review revealed that 31% of cytotoxic chemotherapy agents received by patients in this study might have increased toxicity, and 19% could have reduced efficacy when combined with cannabis. Among immunotherapy agents received by patients in this study, 70% might have decreased efficacy when combined with cannabis use. For targeted therapies, 35% could have increased toxicity, and 70% of endocrine agents could potentially have decreased efficacy (Table 2).

DISCUSSION

This prospective study corroborates previous research by demonstrating that more than one-third of patients receiving oncology care at WJVAMC use cannabis, most often inhaled. Cannabis use was observed among patients undergoing various cancer therapies, including cytotoxic chemotherapy, immunotherapy, targeted therapy, and endocrine therapy. The most common malignancies among cannabis users at WJVAMC include patients with lung cancer, prostate cancer, pancreatic cancer, and multiple myeloma. Cannabis use in patients with pancreatic cancer and multiple myeloma was significantly out of proportion to their prevalence at WJVAMC. This could potentially be due to their drastic effect on quality of life.

Cannabis use increased the risk of toxicity in patients treated with cytotoxic chemotherapy and targeted therapy. Cannabis use potentially decreased efficacy for patients treated with cytotoxic chemotherapy and/or immunotherapy. Cannabis use did not increase the risk of toxicity or efficacy in patients treated with endocrine therapy.

Antineoplastics/Cannabis Interactions

The potential interactions between cannabis and antineoplastic therapies administered at WJVAMC are worth exploring. While this review aims to shed light on possible interactions, it is important to acknowledge that much of the data is preliminary and derived from in vitro studies. The interactions should be interpreted as potential risks rather than established facts. Additional research is needed to confirm these interactions and effectively guide clinical practices. Understanding these dynamics is essential to optimize patient care and manage the complex interplay between cannabis use and cancer treatment.

Originating from Central Asia, the cannabis plant contains > 400 medicinally relevant compounds, of which about 100 are cannabinoids (CBs). Key CBs are cannabidiol (CBD), a nonpsychoactive compound, and ?-9-tetrahydrocannabinol (THC), a psychoactive compound. THC can make up 20% to 30% of the dry weight of female cannabis flowers.⁷

CBs act through the endocannabinoid system, involving CB1 and CB2 receptors, endogenous CBs like anandamide (AEA) and 2-arachidonoylglycerol, and various enzymes. These endogenous CBs, derived from arachidonic acid, play roles in cell growth and proliferation.⁸ In some studies, AEA has induced apoptosis in neuroblastoma cells and inhibited proliferation in breast cancer cells. However, other research suggests AEA may block apoptosis under certain conditions.⁹

CB receptors are transmembrane proteins that interact with CBs differently depending on tissue type and CB structure. Synthetic CBs are designed to target specific receptors, while natural CBs may act as both agonists and antagonists.¹⁰

Cytochrome P450 Metabolism

The human cytochrome P450 (CYP) 3A subfamily affects the metabolism of many therapeutic drugs, including cancer therapeutics.¹¹ The various compositions of cannabis are primarily metabolized by the CYP450 pathway, the same as many cancer-directed pharmacologic treatments. CBs act as both CYP inducers and inhibitors. THC, for example, is a CYP inducer whereas CBD is a CYP inhibitor; both are found in the various compounds available for consumption.^12,13 Pharmacology research has suggested potential interactions and effects on established adverse symptoms, but clinical data are lacking, and current research revealing interactions are only recognized in vitro.¹⁴

The Antineoplastic Activity of Cannabis

CBs can affect various cancer-related pathways such as PKB, AMPK, CAMKK-ß, mTOR, PDHK, HIF-1 a, and PPAR-γ. Δ-9-THC can selectively induce apoptosis in tumor cells without harming normal cells, though the exact mechanism remains unclear. Promising results from early mouse studies led to a 2006 human study where intracranial Δ-9-THC in patients with recurrent glioma yielded a median survival of 24 weeks, with 2 patients surviving > 1 year.¹⁵

In a 2022 review article, Cherkasova et al highlighted potential clinical benefits of cannabis across various cancers. They found that upregulated CB1 receptors in colon cancer might enhance the effect of 5-fluorouracil. However, many studies are preliminary and therefore not definitive.¹⁰

Additional research is needed to refine these findings. Challenges include variability in cannabis formulations, the complex tumor microenvironment, and the legal and psychoactive issues surrounding cannabis use. These factors complicate the design of multicenter randomized studies and may deter patients from disclosing cannabis use, thereby hindering efforts to fully understand its therapeutic potential.

Cannabis/Cytotoxic Chemotherapy Interactions

The chemotherapy agents used in this study included carboplatin, paclitaxel, 5-fluorouracil, etoposide, irinotecan, oxaliplatin, pemetrexed, docetaxel, cabazitaxel, T-DM1, gemcitabine, and cyclophosphamide. There is a paucity of research regarding the interactions between cytotoxic chemotherapy and cannabis. Most studies focused on CBD due to its inhibition of the CYP450 pathway, which is used for metabolizing cytotoxic chemotherapies. Through this mechanism, CBD could potentially increase the concentrations of chemotherapeutic agents, enhancing their toxicity.

When combined with irinotecan, cannabis can pose risks. Δ-9-THC undergoes first-pass metabolism in the liver, mediated by the CYP450 system and CYP3A4. The glucuronidation of irinotecan is mediated by uridine diphosphate glycosyltransferase, leading to its recirculation within the hepatic system and potentially increased toxicity due to prolonged drug presence. Cannabis may also compete with drug binding to albumin, altering the plasma concentrations of irinotecan and its conversion to the metabolite SN38.¹⁶

Cannabis products can affect chemotherapy levels by interacting with cellular transporters. The MRP1 transporter family, encoded by the ABCC gene family, is expressed mainly in the lung, kidney, skeletal muscle, and hematopoietic stem cells. A 2018 study investigating the effects of THC, CBD, and CBN on MRP1 transporters found that the presence of a cannabis component increased the concentration of vincristine 3-fold. Additional studies suggest the interaction with the CB1 receptor may lead to changes in the expression of MRP1 transporters.¹⁷

CBD inhibits the BCRP transporter, which functions as an efflux pump for methotrexate. Consequently, CBD can increase methotrexate levels, potentially enhancing efficacy but also worsening adverse effects.¹⁸

In pancreatic cancer, CBD specifically interacts with gemcitabine. CB1 and CB2 receptors are upregulated, and CBD inhibits the GPR55 receptor. These interactions may enhance the antineoplastic effect of gemcitabine, reducing cell cycle progression and growth.¹⁹

CBD also interacts with temozolomide (TMZ) by affecting extracellular vesicles used by cells for pro-oncogenic signaling and immune system evasion. Experiments on patient-derived glioblastoma cells, both chemotherapy-resistant and chemotherapy-sensitive, found that CBD increases the formation of extracellular vesicles with reduced levels of miR21 (pro-oncogenic) and elevated levels of miR126 (antioncogenic).²⁰ CBD has also been found to decrease prohibitin levels, a protein associated with TMZ resistance.

In patients with glioblastoma, CBD combined with chemotherapeutic agents like TMZ, carmustine, doxorubicin, and cisplatin has shown increased sensitivity and improved tumor response. CBD is also known to inhibit NF-kB, a pathway that sustains tumor viability despite chemotherapy.²¹ Additionally, CBD inhibits the P-glycoprotein system, affecting chemotherapy efflux from neoplastic cells.¹⁴ In vitro studies have found that CBD is synergistic with bortezomib in inhibiting cancer cell viability. In another glioblastoma model, CBD enhanced the antiproliferative effects of both TMZ and carmustine.¹⁴

Different cannabis formulations may vary in how they interact with various cytotoxic chemotherapeutic agents. Some may potentiate the effects of chemotherapy and act synergistically to inhibit tumor growth, while others may lead to increased toxicity.¹⁰ More research is needed to determine which formulations, in combination with specific agents and doses, may have significant interactions that warrant adjustments in chemotherapy dosing.

Cannabis/Immunotherapy Interactions

Cannabis is an immunosuppressant. Data suggest the use of cannabis during immunotherapy worsens treatment outcomes in patients with cancer.²² Exogenous (THC) and endogenous (AEA) CBs negatively affect antitumor immunity by impairing the function of tumor-specific T cells via CB2 and by inhibiting the Jak1-STATs signaling in T cells through CNR2. Xiong et al found that THC reduces the therapeutic effect of anti-PD-1 therapy.²²

In a prospective observational clinical study, Bar-Sela et al analyzed 102 patients with advanced cancer—of which 68 were cannabis users—that were started on immune checkpoint inhibitor therapy. The study found that cannabis users on anti-PD-1 (nivolumab, pembrolizumab), anti-CTLA-4 (ipilimumab), and anti-PD-L1 (durvalumab, atezolizumab) had a significant decrease in time to treatment progression and overall survival vs cannabis non-users.²³ However, a 2023 study by Waissengrin et al found that concomitant use of medical cannabis with pembrolizumab had no harmful effect in advanced non-small cell lung cancer.²⁴ Time to treatment progression of cannabis users did not differ from cannabis nonusers.²⁵

Cannabis/Endocrine Therapy Interactions

In addition to having direct antineoplastic activity on tumor cells, data exist that show how cannabis affects the endocrine system. In animal models, cannabis has been found to suppress the whole hypothalamic-pituitary-adrenal axis as well as other hormones like thyroid, prolactin, and growth hormone. In breast cancer, cannabis competes with estrogen for the estrogen receptor and suppresses growth.²⁶

The endocrine agents used by patients with cancer in this study were antiandrogens like abiraterone, enzalutamide, tamoxifen and anastrozole. Abiraterone is metabolized by CYP450 isoenzymes and uridine diphosphate glycosyltransferases. Cannabis inhibits both processes and therefore may lead to increased toxicities.²⁷ Conversely, enzalutamide is a strong CYP3A inducer, and cannabis use during enzalutamide therapy may significantly increase the toxic effects of cannabis.

There is evidence that molecular pathways involving CB receptors and estrogens overlap, which may lead to interactions when antiestrogens are used in cannabis users with hormone receptor-positive breast cancer.²⁶ In preclinical studies, tamoxifen has been shown to act as an inverse agonist on CB1 and CB2 receptors, though the significance of this finding is unclear. There is no research evaluating the effects of CBs on tamoxifen treatment. However, CBD has been found to potentiate the effectiveness of anastrozole or exemestane in breast cancer cell lines.²⁸ Dobovišek et al demonstrated no inhibitory effect of CBD on the activity of tamoxifen, fulvestrant, or palbociclib in breast cancer cell lines.²⁹ The interactions between hormone receptor-positive breast cancer and cannabinoids are complex, and the clinical significance of these interactions remains difficult to identify.

Cannabis/Targeted Therapy Interactions

The targeted therapies used by patients in this study included zanubrutinib, ibrutinib, sorafenib, acalabrutinib, dabrafenib, trametinib, trastuzumab, bevacizumab, daratumumab, and imatinib. Compared to other classes of cancer treatments, most studies have not demonstrated decreased efficacy or increased toxicity of targeted anticancer drugs when used concomitantly with CBD.²⁹

Trastuzumab is a recombinant humanized monoclonal antibody that targets the proto-oncogene HER2/neu. It is used to treat select patients with metastatic breast cancer. Studies have shown that cannabis use does not attenuate the effectiveness of trastuzumab in HER2-positive and triple-negative breast cancer subtypes.²⁹ One study found that CBD, in combination with chemotherapeutics and Bruton tyrosine kinase inhibitors, such as ibrutinib and zanubrutinib, has synergistic potential for treating diffuse large B-cell lymphoma and mantle cell lymphoma cell lines. This synergy is attributed to the CB1 antagonist activity of cannabis against diffuse large B-cell lymphoma and mantle cell lymphoma cell lines.^30,31

Moreover, combining cannabinoids with bevacizumab (a monoclonal anti-VEGF antibody) has been shown to decrease tumor growth and intratumoral hypoxia in clinically relevant human glioblastoma models. This effect is mediated through the downregulation of HIF-1α.³² Long-term studies evaluating the potential harmful or synergistic potential of CBD on targeted anticancer therapy are needed.

CONCLUSIONS

This exploratory study of patients receiving cancer therapy at WJVAMC found a significant prevalence of concurrent cannabis use among patients undergoing antineoplastic treatments. Given that many antineoplastic agents are metabolized by the CYP450 enzyme system, the findings of this study suggest that concurrent cannabis use may pose risks of suboptimal therapeutic outcomes due to potential interactions affecting drug metabolism. These interactions could impact the efficacy and toxicity of the antineoplastic therapies, potentially leading to diminished therapeutic effects or exacerbated adverse reactions.

Patients should be informed regarding the potential decreased efficacy of immunotherapy with concurrent use of cannabis products. They should also be aware of the possibility of increased toxicity with other treatment modalities, though the exact impact on efficacy remains unclear. This highlights the necessity of caution when combining cannabis with prescribed cancer treatments.

While this study identified possible interactions, its data are preliminary and highlight the need for more rigorous research. Future studies should include larger, well-designed cohorts to compare outcomes between cannabis users and nonusers. Such research is essential to fully elucidate the clinical implications of cannabis use during cancer treatment, address the high prevalence of cannabis use among patients with cancer, and mitigate potential risks associated with combining cannabis products with antineoplastic therapies. This will ensure that treatment strategies are optimized for safety and efficacy in this complex patient population.

Cannabis has a long history of use for medicinal and recreational purposes. Research illustrates the potential benefits and increased prevalence of cannabis use in patients with cancer.¹ Cannabis products have been shown to possess antineoplastic and palliative activity, improving nociceptive and neuropathic pain in addition to chemotherapy-related nausea and vomiting.^2-5 Despite these developments and changing social attitudes toward cannabis, there remains a lack of comprehensive data on patient perspectives regarding its use, especially in regions where cannabis remains illegal. This knowledge gap is notable among veterans undergoing cancer treatment in states where cannabis is prohibited. Up to 57% of veterans report lifetime marijuana use, making it crucial to understand this population’s cannabis use patterns and potential interactions with cancer treatments.⁶

This observational study sought to determine the prevalence of cannabis use among patients undergoing cancer treatment at the US Department of Veterans Affairs (VA) Memphis Healthcare System and evaluate the potential risks associated with combining cannabis products with anticancer therapies.

METHODS

This prospective observational study identified cannabis use among veterans receiving antineoplastic therapy at the Lt. Col. Luke Weathers Jr. VA Medical Center (WJVAMC) and analyzed potential interactions between cannabis products and their cancer treatments. Participants included adults aged > 18 years undergoing antineoplastic therapy at WJVAMC who consented to the study. Data collection involved a written survey approved by the WJVAMC Institutional Review Board and verbal consent from participants. The survey asked participants about their cannabis use in the previous 90 days, including details on quantity, frequency, and method of consumption (eg, inhalation, oral, topical). No incentives were offered for participation.

Surveys from 50 patients who used cannabis were analyzed and their electronic health records were reviewed for sex, age, diagnosis, and antineoplastic regimen. This information was securely stored. A literature review was conducted using PubMed and the Cochrane Library to explore potential interactions between cannabis and the antineoplastic agents that were prescribed to patients in the study, focusing on toxicity, efficacy, or synergistic effects.

Patients were categorized into 4 groups based on treatment: cytotoxic chemotherapy, immunotherapy, endocrine therapy, and targeted therapy. Patients undergoing multiple types of therapies were included in each applicable category.

RESULTS

A total of 132 patients agreed to participate. Fifty patients (38%) acknowledged using cannabis products within 90 days. The patients that used cannabis products within 90 days of the survey reported the following malignancies: 8 patients (16%) had prostate cancer, 3 patients (6%) had hepatocellular carcinoma, 7 patients (14%) had pancreatic carcinoma, 5 patients (10%) had multiple myeloma, 3 patients (6%) had chronic lymphocytic leukemia, 9 patients (18%) had non-small cell lung cancer, 3 patients (6%) had breast cancer, 3 (6%) patients had bladder cancer, 2 patients (4%) had renal cell carcinoma, 1 (2%) patient had chronic myeloid leukemia, 1 (2%) patient had renal amyloid, 1 patient (2%) had supraglottic squamous cell carcinoma, 1 patient (2%) had esophageal carcinoma, 1 (2%) patient had small cell lung cancer, 1 (2%) patient had gastric cancer, and 1 patient (2%) had follicular lymphoma.

Five (10%) of the cannabis users were female, and 45 (90%) were male. Twenty-nine patients (58%) were aged 66 to 75 years, 16 (32%) were aged 56 to 65 years, 3 (6%) were aged 46 to 55 years, and 2 (4%) were aged 76 to 85 years.

Thirty-five patients (70%) inhaled cannabis as opposed to using it via other formulations or a combination (eg, inhalation and topical). Thirty-eight percent of patients used cannabis once daily, 24% used < 1 daily, and 28% used it ≥ 2 times daily. Five patients (10%) did not report the frequency of their cannabis use. Among the patients who reported cannabis use, 21 (42%) were undergoing cytotoxic chemotherapy, 19 (38%) were undergoing immunotherapy, 12 (24%) were undergoing targeted therapy, and 10 (20%) were undergoing endocrine therapy. Some patients were treated with multiple types of antineoplastic agents and were counted in multiple categories (Table 1).

Following a literature review of cannabis and antineoplastic agents, patients were evaluated for the potential effects of cannabis on their treatment. The literature review revealed that 31% of cytotoxic chemotherapy agents received by patients in this study might have increased toxicity, and 19% could have reduced efficacy when combined with cannabis. Among immunotherapy agents received by patients in this study, 70% might have decreased efficacy when combined with cannabis use. For targeted therapies, 35% could have increased toxicity, and 70% of endocrine agents could potentially have decreased efficacy (Table 2).

DISCUSSION

This prospective study corroborates previous research by demonstrating that more than one-third of patients receiving oncology care at WJVAMC use cannabis, most often inhaled. Cannabis use was observed among patients undergoing various cancer therapies, including cytotoxic chemotherapy, immunotherapy, targeted therapy, and endocrine therapy. The most common malignancies among cannabis users at WJVAMC include patients with lung cancer, prostate cancer, pancreatic cancer, and multiple myeloma. Cannabis use in patients with pancreatic cancer and multiple myeloma was significantly out of proportion to their prevalence at WJVAMC. This could potentially be due to their drastic effect on quality of life.

Cannabis use increased the risk of toxicity in patients treated with cytotoxic chemotherapy and targeted therapy. Cannabis use potentially decreased efficacy for patients treated with cytotoxic chemotherapy and/or immunotherapy. Cannabis use did not increase the risk of toxicity or efficacy in patients treated with endocrine therapy.

Antineoplastics/Cannabis Interactions

The potential interactions between cannabis and antineoplastic therapies administered at WJVAMC are worth exploring. While this review aims to shed light on possible interactions, it is important to acknowledge that much of the data is preliminary and derived from in vitro studies. The interactions should be interpreted as potential risks rather than established facts. Additional research is needed to confirm these interactions and effectively guide clinical practices. Understanding these dynamics is essential to optimize patient care and manage the complex interplay between cannabis use and cancer treatment.

Originating from Central Asia, the cannabis plant contains > 400 medicinally relevant compounds, of which about 100 are cannabinoids (CBs). Key CBs are cannabidiol (CBD), a nonpsychoactive compound, and ?-9-tetrahydrocannabinol (THC), a psychoactive compound. THC can make up 20% to 30% of the dry weight of female cannabis flowers.⁷

CBs act through the endocannabinoid system, involving CB1 and CB2 receptors, endogenous CBs like anandamide (AEA) and 2-arachidonoylglycerol, and various enzymes. These endogenous CBs, derived from arachidonic acid, play roles in cell growth and proliferation.⁸ In some studies, AEA has induced apoptosis in neuroblastoma cells and inhibited proliferation in breast cancer cells. However, other research suggests AEA may block apoptosis under certain conditions.⁹

CB receptors are transmembrane proteins that interact with CBs differently depending on tissue type and CB structure. Synthetic CBs are designed to target specific receptors, while natural CBs may act as both agonists and antagonists.¹⁰

Cytochrome P450 Metabolism

The human cytochrome P450 (CYP) 3A subfamily affects the metabolism of many therapeutic drugs, including cancer therapeutics.¹¹ The various compositions of cannabis are primarily metabolized by the CYP450 pathway, the same as many cancer-directed pharmacologic treatments. CBs act as both CYP inducers and inhibitors. THC, for example, is a CYP inducer whereas CBD is a CYP inhibitor; both are found in the various compounds available for consumption.^12,13 Pharmacology research has suggested potential interactions and effects on established adverse symptoms, but clinical data are lacking, and current research revealing interactions are only recognized in vitro.¹⁴

The Antineoplastic Activity of Cannabis

CBs can affect various cancer-related pathways such as PKB, AMPK, CAMKK-ß, mTOR, PDHK, HIF-1 a, and PPAR-γ. Δ-9-THC can selectively induce apoptosis in tumor cells without harming normal cells, though the exact mechanism remains unclear. Promising results from early mouse studies led to a 2006 human study where intracranial Δ-9-THC in patients with recurrent glioma yielded a median survival of 24 weeks, with 2 patients surviving > 1 year.¹⁵

In a 2022 review article, Cherkasova et al highlighted potential clinical benefits of cannabis across various cancers. They found that upregulated CB1 receptors in colon cancer might enhance the effect of 5-fluorouracil. However, many studies are preliminary and therefore not definitive.¹⁰

Additional research is needed to refine these findings. Challenges include variability in cannabis formulations, the complex tumor microenvironment, and the legal and psychoactive issues surrounding cannabis use. These factors complicate the design of multicenter randomized studies and may deter patients from disclosing cannabis use, thereby hindering efforts to fully understand its therapeutic potential.

Cannabis/Cytotoxic Chemotherapy Interactions

The chemotherapy agents used in this study included carboplatin, paclitaxel, 5-fluorouracil, etoposide, irinotecan, oxaliplatin, pemetrexed, docetaxel, cabazitaxel, T-DM1, gemcitabine, and cyclophosphamide. There is a paucity of research regarding the interactions between cytotoxic chemotherapy and cannabis. Most studies focused on CBD due to its inhibition of the CYP450 pathway, which is used for metabolizing cytotoxic chemotherapies. Through this mechanism, CBD could potentially increase the concentrations of chemotherapeutic agents, enhancing their toxicity.

When combined with irinotecan, cannabis can pose risks. Δ-9-THC undergoes first-pass metabolism in the liver, mediated by the CYP450 system and CYP3A4. The glucuronidation of irinotecan is mediated by uridine diphosphate glycosyltransferase, leading to its recirculation within the hepatic system and potentially increased toxicity due to prolonged drug presence. Cannabis may also compete with drug binding to albumin, altering the plasma concentrations of irinotecan and its conversion to the metabolite SN38.¹⁶

Cannabis products can affect chemotherapy levels by interacting with cellular transporters. The MRP1 transporter family, encoded by the ABCC gene family, is expressed mainly in the lung, kidney, skeletal muscle, and hematopoietic stem cells. A 2018 study investigating the effects of THC, CBD, and CBN on MRP1 transporters found that the presence of a cannabis component increased the concentration of vincristine 3-fold. Additional studies suggest the interaction with the CB1 receptor may lead to changes in the expression of MRP1 transporters.¹⁷

CBD inhibits the BCRP transporter, which functions as an efflux pump for methotrexate. Consequently, CBD can increase methotrexate levels, potentially enhancing efficacy but also worsening adverse effects.¹⁸

In pancreatic cancer, CBD specifically interacts with gemcitabine. CB1 and CB2 receptors are upregulated, and CBD inhibits the GPR55 receptor. These interactions may enhance the antineoplastic effect of gemcitabine, reducing cell cycle progression and growth.¹⁹

CBD also interacts with temozolomide (TMZ) by affecting extracellular vesicles used by cells for pro-oncogenic signaling and immune system evasion. Experiments on patient-derived glioblastoma cells, both chemotherapy-resistant and chemotherapy-sensitive, found that CBD increases the formation of extracellular vesicles with reduced levels of miR21 (pro-oncogenic) and elevated levels of miR126 (antioncogenic).²⁰ CBD has also been found to decrease prohibitin levels, a protein associated with TMZ resistance.

In patients with glioblastoma, CBD combined with chemotherapeutic agents like TMZ, carmustine, doxorubicin, and cisplatin has shown increased sensitivity and improved tumor response. CBD is also known to inhibit NF-kB, a pathway that sustains tumor viability despite chemotherapy.²¹ Additionally, CBD inhibits the P-glycoprotein system, affecting chemotherapy efflux from neoplastic cells.¹⁴ In vitro studies have found that CBD is synergistic with bortezomib in inhibiting cancer cell viability. In another glioblastoma model, CBD enhanced the antiproliferative effects of both TMZ and carmustine.¹⁴

Different cannabis formulations may vary in how they interact with various cytotoxic chemotherapeutic agents. Some may potentiate the effects of chemotherapy and act synergistically to inhibit tumor growth, while others may lead to increased toxicity.¹⁰ More research is needed to determine which formulations, in combination with specific agents and doses, may have significant interactions that warrant adjustments in chemotherapy dosing.

Cannabis/Immunotherapy Interactions

Cannabis is an immunosuppressant. Data suggest the use of cannabis during immunotherapy worsens treatment outcomes in patients with cancer.²² Exogenous (THC) and endogenous (AEA) CBs negatively affect antitumor immunity by impairing the function of tumor-specific T cells via CB2 and by inhibiting the Jak1-STATs signaling in T cells through CNR2. Xiong et al found that THC reduces the therapeutic effect of anti-PD-1 therapy.²²

In a prospective observational clinical study, Bar-Sela et al analyzed 102 patients with advanced cancer—of which 68 were cannabis users—that were started on immune checkpoint inhibitor therapy. The study found that cannabis users on anti-PD-1 (nivolumab, pembrolizumab), anti-CTLA-4 (ipilimumab), and anti-PD-L1 (durvalumab, atezolizumab) had a significant decrease in time to treatment progression and overall survival vs cannabis non-users.²³ However, a 2023 study by Waissengrin et al found that concomitant use of medical cannabis with pembrolizumab had no harmful effect in advanced non-small cell lung cancer.²⁴ Time to treatment progression of cannabis users did not differ from cannabis nonusers.²⁵

Cannabis/Endocrine Therapy Interactions

In addition to having direct antineoplastic activity on tumor cells, data exist that show how cannabis affects the endocrine system. In animal models, cannabis has been found to suppress the whole hypothalamic-pituitary-adrenal axis as well as other hormones like thyroid, prolactin, and growth hormone. In breast cancer, cannabis competes with estrogen for the estrogen receptor and suppresses growth.²⁶

The endocrine agents used by patients with cancer in this study were antiandrogens like abiraterone, enzalutamide, tamoxifen and anastrozole. Abiraterone is metabolized by CYP450 isoenzymes and uridine diphosphate glycosyltransferases. Cannabis inhibits both processes and therefore may lead to increased toxicities.²⁷ Conversely, enzalutamide is a strong CYP3A inducer, and cannabis use during enzalutamide therapy may significantly increase the toxic effects of cannabis.

There is evidence that molecular pathways involving CB receptors and estrogens overlap, which may lead to interactions when antiestrogens are used in cannabis users with hormone receptor-positive breast cancer.²⁶ In preclinical studies, tamoxifen has been shown to act as an inverse agonist on CB1 and CB2 receptors, though the significance of this finding is unclear. There is no research evaluating the effects of CBs on tamoxifen treatment. However, CBD has been found to potentiate the effectiveness of anastrozole or exemestane in breast cancer cell lines.²⁸ Dobovišek et al demonstrated no inhibitory effect of CBD on the activity of tamoxifen, fulvestrant, or palbociclib in breast cancer cell lines.²⁹ The interactions between hormone receptor-positive breast cancer and cannabinoids are complex, and the clinical significance of these interactions remains difficult to identify.

Cannabis/Targeted Therapy Interactions

The targeted therapies used by patients in this study included zanubrutinib, ibrutinib, sorafenib, acalabrutinib, dabrafenib, trametinib, trastuzumab, bevacizumab, daratumumab, and imatinib. Compared to other classes of cancer treatments, most studies have not demonstrated decreased efficacy or increased toxicity of targeted anticancer drugs when used concomitantly with CBD.²⁹

Trastuzumab is a recombinant humanized monoclonal antibody that targets the proto-oncogene HER2/neu. It is used to treat select patients with metastatic breast cancer. Studies have shown that cannabis use does not attenuate the effectiveness of trastuzumab in HER2-positive and triple-negative breast cancer subtypes.²⁹ One study found that CBD, in combination with chemotherapeutics and Bruton tyrosine kinase inhibitors, such as ibrutinib and zanubrutinib, has synergistic potential for treating diffuse large B-cell lymphoma and mantle cell lymphoma cell lines. This synergy is attributed to the CB1 antagonist activity of cannabis against diffuse large B-cell lymphoma and mantle cell lymphoma cell lines.^30,31

Moreover, combining cannabinoids with bevacizumab (a monoclonal anti-VEGF antibody) has been shown to decrease tumor growth and intratumoral hypoxia in clinically relevant human glioblastoma models. This effect is mediated through the downregulation of HIF-1α.³² Long-term studies evaluating the potential harmful or synergistic potential of CBD on targeted anticancer therapy are needed.

CONCLUSIONS

This exploratory study of patients receiving cancer therapy at WJVAMC found a significant prevalence of concurrent cannabis use among patients undergoing antineoplastic treatments. Given that many antineoplastic agents are metabolized by the CYP450 enzyme system, the findings of this study suggest that concurrent cannabis use may pose risks of suboptimal therapeutic outcomes due to potential interactions affecting drug metabolism. These interactions could impact the efficacy and toxicity of the antineoplastic therapies, potentially leading to diminished therapeutic effects or exacerbated adverse reactions.

Patients should be informed regarding the potential decreased efficacy of immunotherapy with concurrent use of cannabis products. They should also be aware of the possibility of increased toxicity with other treatment modalities, though the exact impact on efficacy remains unclear. This highlights the necessity of caution when combining cannabis with prescribed cancer treatments.

While this study identified possible interactions, its data are preliminary and highlight the need for more rigorous research. Future studies should include larger, well-designed cohorts to compare outcomes between cannabis users and nonusers. Such research is essential to fully elucidate the clinical implications of cannabis use during cancer treatment, address the high prevalence of cannabis use among patients with cancer, and mitigate potential risks associated with combining cannabis products with antineoplastic therapies. This will ensure that treatment strategies are optimized for safety and efficacy in this complex patient population.

Cannabis has a long history of use for medicinal and recreational purposes. Research illustrates the potential benefits and increased prevalence of cannabis use in patients with cancer.¹ Cannabis products have been shown to possess antineoplastic and palliative activity, improving nociceptive and neuropathic pain in addition to chemotherapy-related nausea and vomiting.^2-5 Despite these developments and changing social attitudes toward cannabis, there remains a lack of comprehensive data on patient perspectives regarding its use, especially in regions where cannabis remains illegal. This knowledge gap is notable among veterans undergoing cancer treatment in states where cannabis is prohibited. Up to 57% of veterans report lifetime marijuana use, making it crucial to understand this population’s cannabis use patterns and potential interactions with cancer treatments.⁶

This observational study sought to determine the prevalence of cannabis use among patients undergoing cancer treatment at the US Department of Veterans Affairs (VA) Memphis Healthcare System and evaluate the potential risks associated with combining cannabis products with anticancer therapies.

METHODS

This prospective observational study identified cannabis use among veterans receiving antineoplastic therapy at the Lt. Col. Luke Weathers Jr. VA Medical Center (WJVAMC) and analyzed potential interactions between cannabis products and their cancer treatments. Participants included adults aged > 18 years undergoing antineoplastic therapy at WJVAMC who consented to the study. Data collection involved a written survey approved by the WJVAMC Institutional Review Board and verbal consent from participants. The survey asked participants about their cannabis use in the previous 90 days, including details on quantity, frequency, and method of consumption (eg, inhalation, oral, topical). No incentives were offered for participation.

Surveys from 50 patients who used cannabis were analyzed and their electronic health records were reviewed for sex, age, diagnosis, and antineoplastic regimen. This information was securely stored. A literature review was conducted using PubMed and the Cochrane Library to explore potential interactions between cannabis and the antineoplastic agents that were prescribed to patients in the study, focusing on toxicity, efficacy, or synergistic effects.

Patients were categorized into 4 groups based on treatment: cytotoxic chemotherapy, immunotherapy, endocrine therapy, and targeted therapy. Patients undergoing multiple types of therapies were included in each applicable category.

RESULTS

A total of 132 patients agreed to participate. Fifty patients (38%) acknowledged using cannabis products within 90 days. The patients that used cannabis products within 90 days of the survey reported the following malignancies: 8 patients (16%) had prostate cancer, 3 patients (6%) had hepatocellular carcinoma, 7 patients (14%) had pancreatic carcinoma, 5 patients (10%) had multiple myeloma, 3 patients (6%) had chronic lymphocytic leukemia, 9 patients (18%) had non-small cell lung cancer, 3 patients (6%) had breast cancer, 3 (6%) patients had bladder cancer, 2 patients (4%) had renal cell carcinoma, 1 (2%) patient had chronic myeloid leukemia, 1 (2%) patient had renal amyloid, 1 patient (2%) had supraglottic squamous cell carcinoma, 1 patient (2%) had esophageal carcinoma, 1 (2%) patient had small cell lung cancer, 1 (2%) patient had gastric cancer, and 1 patient (2%) had follicular lymphoma.

Five (10%) of the cannabis users were female, and 45 (90%) were male. Twenty-nine patients (58%) were aged 66 to 75 years, 16 (32%) were aged 56 to 65 years, 3 (6%) were aged 46 to 55 years, and 2 (4%) were aged 76 to 85 years.

Thirty-five patients (70%) inhaled cannabis as opposed to using it via other formulations or a combination (eg, inhalation and topical). Thirty-eight percent of patients used cannabis once daily, 24% used < 1 daily, and 28% used it ≥ 2 times daily. Five patients (10%) did not report the frequency of their cannabis use. Among the patients who reported cannabis use, 21 (42%) were undergoing cytotoxic chemotherapy, 19 (38%) were undergoing immunotherapy, 12 (24%) were undergoing targeted therapy, and 10 (20%) were undergoing endocrine therapy. Some patients were treated with multiple types of antineoplastic agents and were counted in multiple categories (Table 1).

Following a literature review of cannabis and antineoplastic agents, patients were evaluated for the potential effects of cannabis on their treatment. The literature review revealed that 31% of cytotoxic chemotherapy agents received by patients in this study might have increased toxicity, and 19% could have reduced efficacy when combined with cannabis. Among immunotherapy agents received by patients in this study, 70% might have decreased efficacy when combined with cannabis use. For targeted therapies, 35% could have increased toxicity, and 70% of endocrine agents could potentially have decreased efficacy (Table 2).

DISCUSSION

This prospective study corroborates previous research by demonstrating that more than one-third of patients receiving oncology care at WJVAMC use cannabis, most often inhaled. Cannabis use was observed among patients undergoing various cancer therapies, including cytotoxic chemotherapy, immunotherapy, targeted therapy, and endocrine therapy. The most common malignancies among cannabis users at WJVAMC include patients with lung cancer, prostate cancer, pancreatic cancer, and multiple myeloma. Cannabis use in patients with pancreatic cancer and multiple myeloma was significantly out of proportion to their prevalence at WJVAMC. This could potentially be due to their drastic effect on quality of life.

Cannabis use increased the risk of toxicity in patients treated with cytotoxic chemotherapy and targeted therapy. Cannabis use potentially decreased efficacy for patients treated with cytotoxic chemotherapy and/or immunotherapy. Cannabis use did not increase the risk of toxicity or efficacy in patients treated with endocrine therapy.

Antineoplastics/Cannabis Interactions

The potential interactions between cannabis and antineoplastic therapies administered at WJVAMC are worth exploring. While this review aims to shed light on possible interactions, it is important to acknowledge that much of the data is preliminary and derived from in vitro studies. The interactions should be interpreted as potential risks rather than established facts. Additional research is needed to confirm these interactions and effectively guide clinical practices. Understanding these dynamics is essential to optimize patient care and manage the complex interplay between cannabis use and cancer treatment.

Originating from Central Asia, the cannabis plant contains > 400 medicinally relevant compounds, of which about 100 are cannabinoids (CBs). Key CBs are cannabidiol (CBD), a nonpsychoactive compound, and ?-9-tetrahydrocannabinol (THC), a psychoactive compound. THC can make up 20% to 30% of the dry weight of female cannabis flowers.⁷

CBs act through the endocannabinoid system, involving CB1 and CB2 receptors, endogenous CBs like anandamide (AEA) and 2-arachidonoylglycerol, and various enzymes. These endogenous CBs, derived from arachidonic acid, play roles in cell growth and proliferation.⁸ In some studies, AEA has induced apoptosis in neuroblastoma cells and inhibited proliferation in breast cancer cells. However, other research suggests AEA may block apoptosis under certain conditions.⁹

CB receptors are transmembrane proteins that interact with CBs differently depending on tissue type and CB structure. Synthetic CBs are designed to target specific receptors, while natural CBs may act as both agonists and antagonists.¹⁰

Cytochrome P450 Metabolism

The human cytochrome P450 (CYP) 3A subfamily affects the metabolism of many therapeutic drugs, including cancer therapeutics.¹¹ The various compositions of cannabis are primarily metabolized by the CYP450 pathway, the same as many cancer-directed pharmacologic treatments. CBs act as both CYP inducers and inhibitors. THC, for example, is a CYP inducer whereas CBD is a CYP inhibitor; both are found in the various compounds available for consumption.^12,13 Pharmacology research has suggested potential interactions and effects on established adverse symptoms, but clinical data are lacking, and current research revealing interactions are only recognized in vitro.¹⁴

The Antineoplastic Activity of Cannabis

CBs can affect various cancer-related pathways such as PKB, AMPK, CAMKK-ß, mTOR, PDHK, HIF-1 a, and PPAR-γ. Δ-9-THC can selectively induce apoptosis in tumor cells without harming normal cells, though the exact mechanism remains unclear. Promising results from early mouse studies led to a 2006 human study where intracranial Δ-9-THC in patients with recurrent glioma yielded a median survival of 24 weeks, with 2 patients surviving > 1 year.¹⁵

In a 2022 review article, Cherkasova et al highlighted potential clinical benefits of cannabis across various cancers. They found that upregulated CB1 receptors in colon cancer might enhance the effect of 5-fluorouracil. However, many studies are preliminary and therefore not definitive.¹⁰

Additional research is needed to refine these findings. Challenges include variability in cannabis formulations, the complex tumor microenvironment, and the legal and psychoactive issues surrounding cannabis use. These factors complicate the design of multicenter randomized studies and may deter patients from disclosing cannabis use, thereby hindering efforts to fully understand its therapeutic potential.

Cannabis/Cytotoxic Chemotherapy Interactions

The chemotherapy agents used in this study included carboplatin, paclitaxel, 5-fluorouracil, etoposide, irinotecan, oxaliplatin, pemetrexed, docetaxel, cabazitaxel, T-DM1, gemcitabine, and cyclophosphamide. There is a paucity of research regarding the interactions between cytotoxic chemotherapy and cannabis. Most studies focused on CBD due to its inhibition of the CYP450 pathway, which is used for metabolizing cytotoxic chemotherapies. Through this mechanism, CBD could potentially increase the concentrations of chemotherapeutic agents, enhancing their toxicity.

When combined with irinotecan, cannabis can pose risks. Δ-9-THC undergoes first-pass metabolism in the liver, mediated by the CYP450 system and CYP3A4. The glucuronidation of irinotecan is mediated by uridine diphosphate glycosyltransferase, leading to its recirculation within the hepatic system and potentially increased toxicity due to prolonged drug presence. Cannabis may also compete with drug binding to albumin, altering the plasma concentrations of irinotecan and its conversion to the metabolite SN38.¹⁶

Cannabis products can affect chemotherapy levels by interacting with cellular transporters. The MRP1 transporter family, encoded by the ABCC gene family, is expressed mainly in the lung, kidney, skeletal muscle, and hematopoietic stem cells. A 2018 study investigating the effects of THC, CBD, and CBN on MRP1 transporters found that the presence of a cannabis component increased the concentration of vincristine 3-fold. Additional studies suggest the interaction with the CB1 receptor may lead to changes in the expression of MRP1 transporters.¹⁷

CBD inhibits the BCRP transporter, which functions as an efflux pump for methotrexate. Consequently, CBD can increase methotrexate levels, potentially enhancing efficacy but also worsening adverse effects.¹⁸

In pancreatic cancer, CBD specifically interacts with gemcitabine. CB1 and CB2 receptors are upregulated, and CBD inhibits the GPR55 receptor. These interactions may enhance the antineoplastic effect of gemcitabine, reducing cell cycle progression and growth.¹⁹

CBD also interacts with temozolomide (TMZ) by affecting extracellular vesicles used by cells for pro-oncogenic signaling and immune system evasion. Experiments on patient-derived glioblastoma cells, both chemotherapy-resistant and chemotherapy-sensitive, found that CBD increases the formation of extracellular vesicles with reduced levels of miR21 (pro-oncogenic) and elevated levels of miR126 (antioncogenic).²⁰ CBD has also been found to decrease prohibitin levels, a protein associated with TMZ resistance.

In patients with glioblastoma, CBD combined with chemotherapeutic agents like TMZ, carmustine, doxorubicin, and cisplatin has shown increased sensitivity and improved tumor response. CBD is also known to inhibit NF-kB, a pathway that sustains tumor viability despite chemotherapy.²¹ Additionally, CBD inhibits the P-glycoprotein system, affecting chemotherapy efflux from neoplastic cells.¹⁴ In vitro studies have found that CBD is synergistic with bortezomib in inhibiting cancer cell viability. In another glioblastoma model, CBD enhanced the antiproliferative effects of both TMZ and carmustine.¹⁴

Different cannabis formulations may vary in how they interact with various cytotoxic chemotherapeutic agents. Some may potentiate the effects of chemotherapy and act synergistically to inhibit tumor growth, while others may lead to increased toxicity.¹⁰ More research is needed to determine which formulations, in combination with specific agents and doses, may have significant interactions that warrant adjustments in chemotherapy dosing.

Cannabis/Immunotherapy Interactions

Cannabis is an immunosuppressant. Data suggest the use of cannabis during immunotherapy worsens treatment outcomes in patients with cancer.²² Exogenous (THC) and endogenous (AEA) CBs negatively affect antitumor immunity by impairing the function of tumor-specific T cells via CB2 and by inhibiting the Jak1-STATs signaling in T cells through CNR2. Xiong et al found that THC reduces the therapeutic effect of anti-PD-1 therapy.²²

In a prospective observational clinical study, Bar-Sela et al analyzed 102 patients with advanced cancer—of which 68 were cannabis users—that were started on immune checkpoint inhibitor therapy. The study found that cannabis users on anti-PD-1 (nivolumab, pembrolizumab), anti-CTLA-4 (ipilimumab), and anti-PD-L1 (durvalumab, atezolizumab) had a significant decrease in time to treatment progression and overall survival vs cannabis non-users.²³ However, a 2023 study by Waissengrin et al found that concomitant use of medical cannabis with pembrolizumab had no harmful effect in advanced non-small cell lung cancer.²⁴ Time to treatment progression of cannabis users did not differ from cannabis nonusers.²⁵

Cannabis/Endocrine Therapy Interactions

In addition to having direct antineoplastic activity on tumor cells, data exist that show how cannabis affects the endocrine system. In animal models, cannabis has been found to suppress the whole hypothalamic-pituitary-adrenal axis as well as other hormones like thyroid, prolactin, and growth hormone. In breast cancer, cannabis competes with estrogen for the estrogen receptor and suppresses growth.²⁶

The endocrine agents used by patients with cancer in this study were antiandrogens like abiraterone, enzalutamide, tamoxifen and anastrozole. Abiraterone is metabolized by CYP450 isoenzymes and uridine diphosphate glycosyltransferases. Cannabis inhibits both processes and therefore may lead to increased toxicities.²⁷ Conversely, enzalutamide is a strong CYP3A inducer, and cannabis use during enzalutamide therapy may significantly increase the toxic effects of cannabis.

There is evidence that molecular pathways involving CB receptors and estrogens overlap, which may lead to interactions when antiestrogens are used in cannabis users with hormone receptor-positive breast cancer.²⁶ In preclinical studies, tamoxifen has been shown to act as an inverse agonist on CB1 and CB2 receptors, though the significance of this finding is unclear. There is no research evaluating the effects of CBs on tamoxifen treatment. However, CBD has been found to potentiate the effectiveness of anastrozole or exemestane in breast cancer cell lines.²⁸ Dobovišek et al demonstrated no inhibitory effect of CBD on the activity of tamoxifen, fulvestrant, or palbociclib in breast cancer cell lines.²⁹ The interactions between hormone receptor-positive breast cancer and cannabinoids are complex, and the clinical significance of these interactions remains difficult to identify.

Cannabis/Targeted Therapy Interactions

The targeted therapies used by patients in this study included zanubrutinib, ibrutinib, sorafenib, acalabrutinib, dabrafenib, trametinib, trastuzumab, bevacizumab, daratumumab, and imatinib. Compared to other classes of cancer treatments, most studies have not demonstrated decreased efficacy or increased toxicity of targeted anticancer drugs when used concomitantly with CBD.²⁹

Trastuzumab is a recombinant humanized monoclonal antibody that targets the proto-oncogene HER2/neu. It is used to treat select patients with metastatic breast cancer. Studies have shown that cannabis use does not attenuate the effectiveness of trastuzumab in HER2-positive and triple-negative breast cancer subtypes.²⁹ One study found that CBD, in combination with chemotherapeutics and Bruton tyrosine kinase inhibitors, such as ibrutinib and zanubrutinib, has synergistic potential for treating diffuse large B-cell lymphoma and mantle cell lymphoma cell lines. This synergy is attributed to the CB1 antagonist activity of cannabis against diffuse large B-cell lymphoma and mantle cell lymphoma cell lines.^30,31

Moreover, combining cannabinoids with bevacizumab (a monoclonal anti-VEGF antibody) has been shown to decrease tumor growth and intratumoral hypoxia in clinically relevant human glioblastoma models. This effect is mediated through the downregulation of HIF-1α.³² Long-term studies evaluating the potential harmful or synergistic potential of CBD on targeted anticancer therapy are needed.

CONCLUSIONS

This exploratory study of patients receiving cancer therapy at WJVAMC found a significant prevalence of concurrent cannabis use among patients undergoing antineoplastic treatments. Given that many antineoplastic agents are metabolized by the CYP450 enzyme system, the findings of this study suggest that concurrent cannabis use may pose risks of suboptimal therapeutic outcomes due to potential interactions affecting drug metabolism. These interactions could impact the efficacy and toxicity of the antineoplastic therapies, potentially leading to diminished therapeutic effects or exacerbated adverse reactions.

Patients should be informed regarding the potential decreased efficacy of immunotherapy with concurrent use of cannabis products. They should also be aware of the possibility of increased toxicity with other treatment modalities, though the exact impact on efficacy remains unclear. This highlights the necessity of caution when combining cannabis with prescribed cancer treatments.

While this study identified possible interactions, its data are preliminary and highlight the need for more rigorous research. Future studies should include larger, well-designed cohorts to compare outcomes between cannabis users and nonusers. Such research is essential to fully elucidate the clinical implications of cannabis use during cancer treatment, address the high prevalence of cannabis use among patients with cancer, and mitigate potential risks associated with combining cannabis products with antineoplastic therapies. This will ensure that treatment strategies are optimized for safety and efficacy in this complex patient population.

Prostate cancer is the most common cancer in US males, with an estimated 313,780 new cases and 35,770 deaths in 2025.¹ Several treatment options are available for localized prostate cancer that have similar outcomes, including active surveillance for low-risk cancers, surgery, or radiotherapy.^2,3 Conventional fractionation radiotherapy (CFRT) with 40 to 45 fractions over 8 to 9 weeks has been used for decades. Over the past 2 decades, moderate hypofractionation schedules with 2.4 to 3.4 Gy per fraction over 20 to 28 fractions have become standard, as many noninferiority randomized clinical trials (RCTs) such as CHHiP (UK),⁴ PROFIT (Canada and Europe),⁵ NRG Oncology RTOG 0415 (US),⁶ HYPRO (Netherlands),^7,8 and HYPO-RT-PC (Sweden and Denmark),⁹ have shown the noninferiority of moderately hypofractionated radiotherapy compared with CFRT. Notably, most of these noninferiority studies primarily included patients with low- or intermediate-risk prostate cancer, except for the HYPO-RT-PC trial,⁹ which also included patients with intermediate- and high-risk prostate cancer.

These noninferiority studies, along with technological advances in radiotherapy, such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and image-guided radiotherapy (IGRT), paved the path to ultrahypofractionated stereotactic body radiotherapy (SBRT) that is delivered in 5 fractions of ≥ 6 Gy. This high dose per fraction may have a radiobiologic advantage over conventional fractionation. The relatively low a/ß ratio of prostate cancer, estimated to be between 1 and 2, suggests that tumor cells may be particularly sensitive to the high doses per fraction delivered in SBRT.^10-13 Compared with CFRT, SBRT-induced tumor cell death may also be mediated through different pathways; this pathway appears to be generated in a dose-dependent manner, particularly with doses > 8 Gy per fraction.^14,15 Additionally, the higher a/ß ratio for the surrounding organs at risk, such as the bladder and rectum, theoretically allows for an improved therapeutic ratio window that maximizes tumor control while minimizing damage to healthy tissues.

A substantial body of evidence from prospective studies and meta-analyses supports the use of SBRT for localized prostate cancer. HYPO-RT-PC, a significant phase 3 noninferiority study, enrolled 1200 patients with intermediate (89%) and high-risk (11%) prostate cancer randomized between 2 arms, including CFRT to 78 Gy in 39 fractions and SBRT to 42.7 Gy in 7 fractions, treated 3 days weekly. After a median follow-up of 60 months, the estimated 5-year biochemical relapse-free survival rate was 84% in both groups.⁹ This trial was notable because it was the first randomized study to demonstrate that SBRT was noninferior to CFRT in intermediate- and high-risk prostate cancer patients. Another pivotal phase 3 trial, the PACE-B study, enrolled 874 patients to compare SBRT (36.25 Gy to the prostate gland, with a secondary dose of 40 Gy to the gross tumor volume where applicable, in 5 fractions) with CFRT (78 Gy in 39 fractions) and moderately hypofractionated radiotherapy (HFRT) (62 Gy in 20 fractions) in patients with low- or intermediate-risk prostate cancer. With a 74-month median follow-up, the study reported 5-year biochemical free rates of 94.6% for CFRT and 95.8% for SBRT, confirming the noninferiority of SBRT to CFRT.¹⁵

SBRT offers short, effective, and convenient treatment to many patients with localized prostate cancer. While previous guidelines were more restrictive, the March 2026 National Comprehensive Cancer Network (NCCN) guidelines now list SBRT as a preferred treatment modality for high-risk prostate cancer.¹⁶

Given the growing body of evidence supporting the efficacy and safety of SBRT, we implemented an SBRT program in 2014 at a tertiary care center for veterans. This retrospective study was undertaken to evaluate the early efficacy and toxicity of SBRT in patients with localized prostate cancer treated at our institution, including patients across all risk stratifications.

METHODS

We identified 242 patients diagnosed with prostate cancer who underwent SBRT treatment between November 2014 and October 2024 at Overland Park Veterans Affairs Radiation Oncology Clinic. For the final analysis, 46 patients with < 2 years of follow-up and 22 patients who died from causes other than prostate cancer were excluded, resulting in a cohort of 174 patients with ≥ 24-month follow-up.

Treatment

Patients eligible for staging underwent imaging according to NCCN guidelines, including computed tomography (CT) of the abdomen and pelvis, bone scintigraphy, or, in recent years, prostate-specific membrane antigen positron emission tomography, primarily used for unfavorable intermediate-risk (UIR) and high-risk (HR) cancers. Patients with a negative staging work-up for nodal or skeletal disease were included. Prior to planning the CT simulation, patients were given bowel preparation instructions, including a low-fiber and low-gas-producing diet, simethicone, and enemas, the night before and morning of the simulation. Patients were instructed to arrive with a comfortably full bladder, having not voided for 2 to 3 hours prior to the procedure. At Kansas City Veterans Affairs Medical Center (KCVAMC), SBRT treatment was generally restricted to patients with a baseline American Urological Association symptom score of 15 to 20 out of 35 and a prostate gland size < 80 mL to minimize the risk of acute urinary toxicity. We did not use intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast agents for planning CT simulation.

Patients were placed in a supine position, and a vacuum bag was used for immobilization. Following the CT simulation, the images were transferred to the Eclipse treatment planning system. The clinical target volume (CTV) encompassed the prostate and the proximal 1.0 cm of the seminal vesicles for Gleason score (GS) 1 to 2, and the entire seminal vesicle was included for GS 3 to 5, which is consistent with KCVAMC practice and established safety protocols. The planning target volume (PTV) was created by uniformly expanding the CTV by 5 to 7 mm, except for the posterior margin, which was limited to 3 to 5 mm. When elective nodal radiotherapy was planned for HR prostate cancer, the pelvic field for CT simulation started at the L-2 upper border, with the lower border extending to the lesser trochanter. The pelvic nodes were delineated per Radiation Therapy Oncology Group (RTOG) guidelines.¹⁷ The CTV nodes (CTVn), including common iliac, external and internal iliac nodes, obturator, and presacral nodes, were created by uniformly expanding the CTVn by 2 to 3 mm. Slice-by-slice corrections were made to avoid bowel overlap in these patients.

The use of androgen deprivation therapy (ADT) for a duration of 6 to 24 months was prescribed for patients with UIR or HR prostate cancer per NCCN guidelines.¹⁶ The prescribed dose to the PTV was 36.25 to 40 Gy (40 Gy was mostly used as a boost to the dominant lesion) in 5 fractions, with each fraction ranging from 7.25 to 8 Gy. For elective nodal radiotherapy in patients at HR, the prescribed dose was 25 Gy in 5 fractions. All patients were planned for VMAT, which aims to deliver ≥ 95% of the prescription dose to 95% of the PTV. Once the physician approved the treatment plan and physics quality assessment was completed, treatments commenced on an every-other-day schedule. Patients received the same bowel preparation instructions for each treatment as for the planning CT simulation. Daily treatment accuracy was confirmed via daily 3-dimensional cone-beam CT (CBCT) for IGRT. No fiducials or hydrogel rectal spacers were used.

Follow-up Schedule and Toxicity Assessment

Follow-up assessments were conducted 4 to 6 weeks after radiation therapy and then repeated every 6 months for 2 to 5 years, and annually thereafter. At each follow-up visit, patients were evaluated for genitourinary (GU) and gastrointestinal (GI) toxicity, according to RTOG toxicity criteria. Prostate-specific antigen (PSA) levels were monitored; in patients receiving ADT, testosterone levels were also checked.

Statistical Analysis

Biochemical failure was defined using the Phoenix definition (nadir PSA + 2 ng/mL). Differences between dose cohorts were assessed using the log-rank test for survival outcomes and X² testing for categorical variables. GU and GI toxicities were summarized as cumulative incidences of RTOG grade ≥ II events. Statistical significance was set at P < .05.

RESULTS

One hundred seventy-four patients were included in the retrospective review. Patients had a median follow-up of 45 months (range, 24-111) (Figure). The median age at treatment was 74 years (range, 51-88), and the median pretreatment PSA level was 11.9 ng/mL (range, 0.6-69.5). Twenty-six patients (14.9%) had a GS 1, 77 (44.3%) had GS 2, 41 (23.6%) had GS 3, 18 (10.3%) had GS 4, and 12 (6.9%) had GS 5. Fifty-one patients (29.3%) received elective pelvic nodal radiotherapy, and 93 patients (53.4%) received ADT (Table 1).

At 24 months follow-up, 6 patients (3.4%) had biochemical failures. One patient died from metastatic prostate cancer, and 5 patients are living with biochemical failure (Table 2). The actuarial 5-year overall survival (OS) rate was 99.4%, and the 5-year disease-free survival (DFS) rate was 96.6%. We performed a subanalysis comparing outcomes of the 36.25 Gy vs 40 Gy SBRT cohorts. There was no statistically significant difference in DFS, OS, or the cumulative incidence of grade II/III toxicity between patients treated with 40 Gy vs 36.25 Gy. Outcomes stratified by NCCN risk groups (low, intermediate, high/very high) are detailed in Table 3. As expected, DFS was slightly lower in the high-risk group, but overall disease control remained high across all stratifications.

The cumulative incidence of RTOG grade II and higher GU toxicity was 28.2% (Table 4). This included 46 patients (26.4%) with grade II GU toxicity and 2 patients (1.2%) who developed grade III GU complications (1 requiring self-catheterization and another a suprapubic catheter for urinary retention). One patient (0.6%) treated with a 40 Gy dose regimen experienced a grade IV GU complication in the form of a rectovesical fistula necessitating surgical intervention.

The cumulative incidence of RTOG grade II or higher GI toxicity was 3.4%, and no grade III or IV gastrointestinal toxicities were observed during the follow-up period. Importantly, intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast were not routinely used in this cohort of patients.

The high rates of actuarial 5-year DFS and OS observed suggest a favorable initial response to the SBRT regimen employed at KCVAMC. However, given the potential for late recurrence in patients with prostate cancer, longer follow-up is essential to determine the durability of these outcomes. The observed GU toxicity rate of 28.2% for grade II and higher events warrants careful consideration and compares with other published data on SBRT for prostate cancer.¹⁵ The occurrence of a grade IV rectovesical fistula, although rare, is a notable adverse event that warrants discussion in the context of the treatment approach. The low incidence of grade II or higher GI toxicity is an encouraging finding, particularly given that hydrogel rectal spacers are not routinely used to minimize rectal exposure.

DISCUSSION

The primary objective of this retrospective study was to evaluate the outcomes of SBRT for patients with localized prostate cancer treated at KCVAMC and to compare these results with those reported in the literature. Our findings demonstrate promising intermediate-term efficacy, with an estimated 5-year DFS of 96.6% and OS of 99.4% at a median follow-up of 45 months. Furthermore, the observed toxicity profile appears acceptable, with a cumulative grade II and higher GU toxicity rate of 28.2% and a grade II or higher GI toxicity rate of 3.4%. Notably, these outcomes were achieved without the routine use of intraprostatic fiducials or hydrogel rectal spacers.

Two pivotal randomized phase 3 trials have established the noninferiority of ultrahypofractionated radiotherapy (UHRT) with SBRT over conventional fractionation. The HYPO-RT-PC trial compared SBRT (42.7 Gy in 7 fractions) with conventional fractionation (78 Gy in 39 fractions) in intermediate- and high-risk patients with prostate cancer and reported a 5-year biochemical relapse-free survival of 84% in both arms.⁹ The PACE-B trial, which included patients at low- and intermediate-risk, compared SBRT (36.25 Gy in 5 fractions) with conventional or moderate HFRT and reported a 5-year biochemical control rate of 95.8% in the SBRT arm and 94.6% in the control arm.¹⁵

A comprehensive review and meta-analysis of 7 phase 3 studies involving 6795 patients compared different radiotherapy regimens, namely, UHRT, HFRT, and CFRT, and reported that after 5 years, the DFS rates were 85.1% for CFRT, 86% for HFRT, and 85% for UHRT, with no significant difference in toxicity among the 3 different treatment approaches.¹⁸ This suggests that shorter, more intense radiotherapy schedules (UHRT and HFRT) may be as effective and safe as traditional, longer courses of radiation.

There are multiple published nonrandomized prospective trials in which thousands of patients with extreme hypofractionation have been treated with different doses, fractions, and techniques. While heterogeneity and limited long-term follow-up in the existing evidence are acknowledged, these data suggest that prostate SBRT provides appropriate biochemical control with few high-grade toxicities, supporting its ongoing global use and justifying further prospective investigations. Comparative data are shown in Table 5. Several ongoing studies are evaluating noninferiority, superiority, and cost-effectiveness using different methodologies (Table 6).^9,15,19-24

This study’s efficacy outcomes, particularly the high DFS rate, are consistent with the findings from these landmark trials, suggesting that the SBRT regimen used at KCVAMC is effective in achieving early disease control despite 17.2% of patients having high-risk disease. The GU toxicity observed in this study, with a 28.2% rate of grade II or higher events, is also comparable with the 26.9% reported in the 5-fraction SBRT arm of the PACE-B trial, which had a longer median follow-up of 74 months.¹⁵ It is important to note that a portion of these grade II events occurred in patients who were already on a blockers for pre-existing lower urinary tract symptoms before starting radiotherapy, which may inflate the observed cumulative acute toxicity score.

A critical comparison is how SBRT toxicity aligns with moderate hypofractionation (eg, 60 Gy in 20 fractions or 70 Gy in 28 fractions as reported by others).^4,6 Our observed grade III and higher GU toxicity rate (1.7%) and grade III and higher GI toxicity rate (0%) are highly favorable when compared with historical moderate hypofractionation data, which typically report grade III GU toxicity in the range of 2% to 3% and grade III GI toxicity around 1% to 2%. This suggests that despite the higher dose per fraction, SBRT does not necessarily lead to increased severe acute toxicity, potentially offering a superior therapeutic ratio for GI and GU sparing.

However, the occurrence of a grade IV rectovesical fistula in 1 patient (0.6%)—who received the 40 Gy dose—was a serious complication that warrants careful consideration. This rare, but severe, complication in the higher dose cohort underscores the potential for increased organ-at-risk toxicity, particularly in the absence of a hydrogel rectal spacer, which is designed to mitigate high-dose rectal exposure. While the overall rate of significant GU toxicity remains low, this event highlights the potential risks associated with SBRT. Hydrogel rectal spacers are designed to increase the distance between the prostate and the rectum, which can reduce the rectal radiation dose and potentially mitigate the risk of such fistulas. The low rate of grade II or worse GI toxicity (3.4%) in our study is noteworthy, especially considering that hydrogel spacers were not routinely used. This finding aligns with the 2.5% GI toxicity rate reported in the SBRT arm of the PACE-B trial, suggesting that careful treatment planning and delivery techniques, such as VMAT-IMRT and daily CBCT for IGRT, may contribute to minimizing GI toxicity even without the use of rectal spacers.¹⁵ The exclusive use of 3-dimensional CBCT for IGRT in our study, without the use of fiducial markers, suggests that accurate target localization can be achieved with this approach, contributing to the observed efficacy and reduced toxicity.

Strengths and Limitations

This study’s retrospective, single-center design may have introduced selection bias. The median follow-up of 45 months, while substantial, is still relatively short for assessing very late toxicities and long-term oncologic outcomes in prostate cancer, which is known for late recurrences. Additionally, the lack of a direct comparison group within KCVAMC limits the ability to definitively attribute the observed outcomes solely to SBRT treatment. However, the strengths of this study include the inclusion of a consecutive series of veteran patients with localized prostate cancer across all risk categories, providing a real-world perspective on SBRT outcomes in a diverse patient population. Furthermore, the detailed assessment of efficacy and toxicity via standardized RTOG criteria enhances the comparability of our findings with those of other published prospective studies, despite the retrospective nature of the data.

CONCLUSIONS

This single-institution retrospective analysis revealed that short-term SBRT (36.25 to 40 Gy in 5 fractions), with a minimum follow-up of 24 months and a median follow-up of 45 months, for localized prostate cancer, including patients at HR, is associated with promising early efficacy and acceptable toxicity, even in the absence of routine fiducial or hydrogel spacer use. The favorable actuarial 5-year DFS and OS rates, coupled with a manageable toxicity profile, suggest that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer. However, a longer follow-up is necessary to confirm these findings and fully characterize the long-term efficacy and toxicity of this SBRT regimen. Nevertheless, the results contribute to the growing body of evidence suggesting that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer.

Prostate cancer is the most common cancer in US males, with an estimated 313,780 new cases and 35,770 deaths in 2025.¹ Several treatment options are available for localized prostate cancer that have similar outcomes, including active surveillance for low-risk cancers, surgery, or radiotherapy.^2,3 Conventional fractionation radiotherapy (CFRT) with 40 to 45 fractions over 8 to 9 weeks has been used for decades. Over the past 2 decades, moderate hypofractionation schedules with 2.4 to 3.4 Gy per fraction over 20 to 28 fractions have become standard, as many noninferiority randomized clinical trials (RCTs) such as CHHiP (UK),⁴ PROFIT (Canada and Europe),⁵ NRG Oncology RTOG 0415 (US),⁶ HYPRO (Netherlands),^7,8 and HYPO-RT-PC (Sweden and Denmark),⁹ have shown the noninferiority of moderately hypofractionated radiotherapy compared with CFRT. Notably, most of these noninferiority studies primarily included patients with low- or intermediate-risk prostate cancer, except for the HYPO-RT-PC trial,⁹ which also included patients with intermediate- and high-risk prostate cancer.

These noninferiority studies, along with technological advances in radiotherapy, such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and image-guided radiotherapy (IGRT), paved the path to ultrahypofractionated stereotactic body radiotherapy (SBRT) that is delivered in 5 fractions of ≥ 6 Gy. This high dose per fraction may have a radiobiologic advantage over conventional fractionation. The relatively low a/ß ratio of prostate cancer, estimated to be between 1 and 2, suggests that tumor cells may be particularly sensitive to the high doses per fraction delivered in SBRT.^10-13 Compared with CFRT, SBRT-induced tumor cell death may also be mediated through different pathways; this pathway appears to be generated in a dose-dependent manner, particularly with doses > 8 Gy per fraction.^14,15 Additionally, the higher a/ß ratio for the surrounding organs at risk, such as the bladder and rectum, theoretically allows for an improved therapeutic ratio window that maximizes tumor control while minimizing damage to healthy tissues.

A substantial body of evidence from prospective studies and meta-analyses supports the use of SBRT for localized prostate cancer. HYPO-RT-PC, a significant phase 3 noninferiority study, enrolled 1200 patients with intermediate (89%) and high-risk (11%) prostate cancer randomized between 2 arms, including CFRT to 78 Gy in 39 fractions and SBRT to 42.7 Gy in 7 fractions, treated 3 days weekly. After a median follow-up of 60 months, the estimated 5-year biochemical relapse-free survival rate was 84% in both groups.⁹ This trial was notable because it was the first randomized study to demonstrate that SBRT was noninferior to CFRT in intermediate- and high-risk prostate cancer patients. Another pivotal phase 3 trial, the PACE-B study, enrolled 874 patients to compare SBRT (36.25 Gy to the prostate gland, with a secondary dose of 40 Gy to the gross tumor volume where applicable, in 5 fractions) with CFRT (78 Gy in 39 fractions) and moderately hypofractionated radiotherapy (HFRT) (62 Gy in 20 fractions) in patients with low- or intermediate-risk prostate cancer. With a 74-month median follow-up, the study reported 5-year biochemical free rates of 94.6% for CFRT and 95.8% for SBRT, confirming the noninferiority of SBRT to CFRT.¹⁵

SBRT offers short, effective, and convenient treatment to many patients with localized prostate cancer. While previous guidelines were more restrictive, the March 2026 National Comprehensive Cancer Network (NCCN) guidelines now list SBRT as a preferred treatment modality for high-risk prostate cancer.¹⁶

Given the growing body of evidence supporting the efficacy and safety of SBRT, we implemented an SBRT program in 2014 at a tertiary care center for veterans. This retrospective study was undertaken to evaluate the early efficacy and toxicity of SBRT in patients with localized prostate cancer treated at our institution, including patients across all risk stratifications.

METHODS

We identified 242 patients diagnosed with prostate cancer who underwent SBRT treatment between November 2014 and October 2024 at Overland Park Veterans Affairs Radiation Oncology Clinic. For the final analysis, 46 patients with < 2 years of follow-up and 22 patients who died from causes other than prostate cancer were excluded, resulting in a cohort of 174 patients with ≥ 24-month follow-up.

Treatment

Patients eligible for staging underwent imaging according to NCCN guidelines, including computed tomography (CT) of the abdomen and pelvis, bone scintigraphy, or, in recent years, prostate-specific membrane antigen positron emission tomography, primarily used for unfavorable intermediate-risk (UIR) and high-risk (HR) cancers. Patients with a negative staging work-up for nodal or skeletal disease were included. Prior to planning the CT simulation, patients were given bowel preparation instructions, including a low-fiber and low-gas-producing diet, simethicone, and enemas, the night before and morning of the simulation. Patients were instructed to arrive with a comfortably full bladder, having not voided for 2 to 3 hours prior to the procedure. At Kansas City Veterans Affairs Medical Center (KCVAMC), SBRT treatment was generally restricted to patients with a baseline American Urological Association symptom score of 15 to 20 out of 35 and a prostate gland size < 80 mL to minimize the risk of acute urinary toxicity. We did not use intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast agents for planning CT simulation.

Patients were placed in a supine position, and a vacuum bag was used for immobilization. Following the CT simulation, the images were transferred to the Eclipse treatment planning system. The clinical target volume (CTV) encompassed the prostate and the proximal 1.0 cm of the seminal vesicles for Gleason score (GS) 1 to 2, and the entire seminal vesicle was included for GS 3 to 5, which is consistent with KCVAMC practice and established safety protocols. The planning target volume (PTV) was created by uniformly expanding the CTV by 5 to 7 mm, except for the posterior margin, which was limited to 3 to 5 mm. When elective nodal radiotherapy was planned for HR prostate cancer, the pelvic field for CT simulation started at the L-2 upper border, with the lower border extending to the lesser trochanter. The pelvic nodes were delineated per Radiation Therapy Oncology Group (RTOG) guidelines.¹⁷ The CTV nodes (CTVn), including common iliac, external and internal iliac nodes, obturator, and presacral nodes, were created by uniformly expanding the CTVn by 2 to 3 mm. Slice-by-slice corrections were made to avoid bowel overlap in these patients.

The use of androgen deprivation therapy (ADT) for a duration of 6 to 24 months was prescribed for patients with UIR or HR prostate cancer per NCCN guidelines.¹⁶ The prescribed dose to the PTV was 36.25 to 40 Gy (40 Gy was mostly used as a boost to the dominant lesion) in 5 fractions, with each fraction ranging from 7.25 to 8 Gy. For elective nodal radiotherapy in patients at HR, the prescribed dose was 25 Gy in 5 fractions. All patients were planned for VMAT, which aims to deliver ≥ 95% of the prescription dose to 95% of the PTV. Once the physician approved the treatment plan and physics quality assessment was completed, treatments commenced on an every-other-day schedule. Patients received the same bowel preparation instructions for each treatment as for the planning CT simulation. Daily treatment accuracy was confirmed via daily 3-dimensional cone-beam CT (CBCT) for IGRT. No fiducials or hydrogel rectal spacers were used.

Follow-up Schedule and Toxicity Assessment

Follow-up assessments were conducted 4 to 6 weeks after radiation therapy and then repeated every 6 months for 2 to 5 years, and annually thereafter. At each follow-up visit, patients were evaluated for genitourinary (GU) and gastrointestinal (GI) toxicity, according to RTOG toxicity criteria. Prostate-specific antigen (PSA) levels were monitored; in patients receiving ADT, testosterone levels were also checked.

Statistical Analysis

Biochemical failure was defined using the Phoenix definition (nadir PSA + 2 ng/mL). Differences between dose cohorts were assessed using the log-rank test for survival outcomes and X² testing for categorical variables. GU and GI toxicities were summarized as cumulative incidences of RTOG grade ≥ II events. Statistical significance was set at P < .05.

RESULTS

One hundred seventy-four patients were included in the retrospective review. Patients had a median follow-up of 45 months (range, 24-111) (Figure). The median age at treatment was 74 years (range, 51-88), and the median pretreatment PSA level was 11.9 ng/mL (range, 0.6-69.5). Twenty-six patients (14.9%) had a GS 1, 77 (44.3%) had GS 2, 41 (23.6%) had GS 3, 18 (10.3%) had GS 4, and 12 (6.9%) had GS 5. Fifty-one patients (29.3%) received elective pelvic nodal radiotherapy, and 93 patients (53.4%) received ADT (Table 1).

At 24 months follow-up, 6 patients (3.4%) had biochemical failures. One patient died from metastatic prostate cancer, and 5 patients are living with biochemical failure (Table 2). The actuarial 5-year overall survival (OS) rate was 99.4%, and the 5-year disease-free survival (DFS) rate was 96.6%. We performed a subanalysis comparing outcomes of the 36.25 Gy vs 40 Gy SBRT cohorts. There was no statistically significant difference in DFS, OS, or the cumulative incidence of grade II/III toxicity between patients treated with 40 Gy vs 36.25 Gy. Outcomes stratified by NCCN risk groups (low, intermediate, high/very high) are detailed in Table 3. As expected, DFS was slightly lower in the high-risk group, but overall disease control remained high across all stratifications.

The cumulative incidence of RTOG grade II and higher GU toxicity was 28.2% (Table 4). This included 46 patients (26.4%) with grade II GU toxicity and 2 patients (1.2%) who developed grade III GU complications (1 requiring self-catheterization and another a suprapubic catheter for urinary retention). One patient (0.6%) treated with a 40 Gy dose regimen experienced a grade IV GU complication in the form of a rectovesical fistula necessitating surgical intervention.

The cumulative incidence of RTOG grade II or higher GI toxicity was 3.4%, and no grade III or IV gastrointestinal toxicities were observed during the follow-up period. Importantly, intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast were not routinely used in this cohort of patients.

The high rates of actuarial 5-year DFS and OS observed suggest a favorable initial response to the SBRT regimen employed at KCVAMC. However, given the potential for late recurrence in patients with prostate cancer, longer follow-up is essential to determine the durability of these outcomes. The observed GU toxicity rate of 28.2% for grade II and higher events warrants careful consideration and compares with other published data on SBRT for prostate cancer.¹⁵ The occurrence of a grade IV rectovesical fistula, although rare, is a notable adverse event that warrants discussion in the context of the treatment approach. The low incidence of grade II or higher GI toxicity is an encouraging finding, particularly given that hydrogel rectal spacers are not routinely used to minimize rectal exposure.

DISCUSSION

The primary objective of this retrospective study was to evaluate the outcomes of SBRT for patients with localized prostate cancer treated at KCVAMC and to compare these results with those reported in the literature. Our findings demonstrate promising intermediate-term efficacy, with an estimated 5-year DFS of 96.6% and OS of 99.4% at a median follow-up of 45 months. Furthermore, the observed toxicity profile appears acceptable, with a cumulative grade II and higher GU toxicity rate of 28.2% and a grade II or higher GI toxicity rate of 3.4%. Notably, these outcomes were achieved without the routine use of intraprostatic fiducials or hydrogel rectal spacers.

Two pivotal randomized phase 3 trials have established the noninferiority of ultrahypofractionated radiotherapy (UHRT) with SBRT over conventional fractionation. The HYPO-RT-PC trial compared SBRT (42.7 Gy in 7 fractions) with conventional fractionation (78 Gy in 39 fractions) in intermediate- and high-risk patients with prostate cancer and reported a 5-year biochemical relapse-free survival of 84% in both arms.⁹ The PACE-B trial, which included patients at low- and intermediate-risk, compared SBRT (36.25 Gy in 5 fractions) with conventional or moderate HFRT and reported a 5-year biochemical control rate of 95.8% in the SBRT arm and 94.6% in the control arm.¹⁵

A comprehensive review and meta-analysis of 7 phase 3 studies involving 6795 patients compared different radiotherapy regimens, namely, UHRT, HFRT, and CFRT, and reported that after 5 years, the DFS rates were 85.1% for CFRT, 86% for HFRT, and 85% for UHRT, with no significant difference in toxicity among the 3 different treatment approaches.¹⁸ This suggests that shorter, more intense radiotherapy schedules (UHRT and HFRT) may be as effective and safe as traditional, longer courses of radiation.

There are multiple published nonrandomized prospective trials in which thousands of patients with extreme hypofractionation have been treated with different doses, fractions, and techniques. While heterogeneity and limited long-term follow-up in the existing evidence are acknowledged, these data suggest that prostate SBRT provides appropriate biochemical control with few high-grade toxicities, supporting its ongoing global use and justifying further prospective investigations. Comparative data are shown in Table 5. Several ongoing studies are evaluating noninferiority, superiority, and cost-effectiveness using different methodologies (Table 6).^9,15,19-24

This study’s efficacy outcomes, particularly the high DFS rate, are consistent with the findings from these landmark trials, suggesting that the SBRT regimen used at KCVAMC is effective in achieving early disease control despite 17.2% of patients having high-risk disease. The GU toxicity observed in this study, with a 28.2% rate of grade II or higher events, is also comparable with the 26.9% reported in the 5-fraction SBRT arm of the PACE-B trial, which had a longer median follow-up of 74 months.¹⁵ It is important to note that a portion of these grade II events occurred in patients who were already on a blockers for pre-existing lower urinary tract symptoms before starting radiotherapy, which may inflate the observed cumulative acute toxicity score.

A critical comparison is how SBRT toxicity aligns with moderate hypofractionation (eg, 60 Gy in 20 fractions or 70 Gy in 28 fractions as reported by others).^4,6 Our observed grade III and higher GU toxicity rate (1.7%) and grade III and higher GI toxicity rate (0%) are highly favorable when compared with historical moderate hypofractionation data, which typically report grade III GU toxicity in the range of 2% to 3% and grade III GI toxicity around 1% to 2%. This suggests that despite the higher dose per fraction, SBRT does not necessarily lead to increased severe acute toxicity, potentially offering a superior therapeutic ratio for GI and GU sparing.

However, the occurrence of a grade IV rectovesical fistula in 1 patient (0.6%)—who received the 40 Gy dose—was a serious complication that warrants careful consideration. This rare, but severe, complication in the higher dose cohort underscores the potential for increased organ-at-risk toxicity, particularly in the absence of a hydrogel rectal spacer, which is designed to mitigate high-dose rectal exposure. While the overall rate of significant GU toxicity remains low, this event highlights the potential risks associated with SBRT. Hydrogel rectal spacers are designed to increase the distance between the prostate and the rectum, which can reduce the rectal radiation dose and potentially mitigate the risk of such fistulas. The low rate of grade II or worse GI toxicity (3.4%) in our study is noteworthy, especially considering that hydrogel spacers were not routinely used. This finding aligns with the 2.5% GI toxicity rate reported in the SBRT arm of the PACE-B trial, suggesting that careful treatment planning and delivery techniques, such as VMAT-IMRT and daily CBCT for IGRT, may contribute to minimizing GI toxicity even without the use of rectal spacers.¹⁵ The exclusive use of 3-dimensional CBCT for IGRT in our study, without the use of fiducial markers, suggests that accurate target localization can be achieved with this approach, contributing to the observed efficacy and reduced toxicity.

Strengths and Limitations

This study’s retrospective, single-center design may have introduced selection bias. The median follow-up of 45 months, while substantial, is still relatively short for assessing very late toxicities and long-term oncologic outcomes in prostate cancer, which is known for late recurrences. Additionally, the lack of a direct comparison group within KCVAMC limits the ability to definitively attribute the observed outcomes solely to SBRT treatment. However, the strengths of this study include the inclusion of a consecutive series of veteran patients with localized prostate cancer across all risk categories, providing a real-world perspective on SBRT outcomes in a diverse patient population. Furthermore, the detailed assessment of efficacy and toxicity via standardized RTOG criteria enhances the comparability of our findings with those of other published prospective studies, despite the retrospective nature of the data.

CONCLUSIONS

This single-institution retrospective analysis revealed that short-term SBRT (36.25 to 40 Gy in 5 fractions), with a minimum follow-up of 24 months and a median follow-up of 45 months, for localized prostate cancer, including patients at HR, is associated with promising early efficacy and acceptable toxicity, even in the absence of routine fiducial or hydrogel spacer use. The favorable actuarial 5-year DFS and OS rates, coupled with a manageable toxicity profile, suggest that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer. However, a longer follow-up is necessary to confirm these findings and fully characterize the long-term efficacy and toxicity of this SBRT regimen. Nevertheless, the results contribute to the growing body of evidence suggesting that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer.

Prostate cancer is the most common cancer in US males, with an estimated 313,780 new cases and 35,770 deaths in 2025.¹ Several treatment options are available for localized prostate cancer that have similar outcomes, including active surveillance for low-risk cancers, surgery, or radiotherapy.^2,3 Conventional fractionation radiotherapy (CFRT) with 40 to 45 fractions over 8 to 9 weeks has been used for decades. Over the past 2 decades, moderate hypofractionation schedules with 2.4 to 3.4 Gy per fraction over 20 to 28 fractions have become standard, as many noninferiority randomized clinical trials (RCTs) such as CHHiP (UK),⁴ PROFIT (Canada and Europe),⁵ NRG Oncology RTOG 0415 (US),⁶ HYPRO (Netherlands),^7,8 and HYPO-RT-PC (Sweden and Denmark),⁹ have shown the noninferiority of moderately hypofractionated radiotherapy compared with CFRT. Notably, most of these noninferiority studies primarily included patients with low- or intermediate-risk prostate cancer, except for the HYPO-RT-PC trial,⁹ which also included patients with intermediate- and high-risk prostate cancer.

These noninferiority studies, along with technological advances in radiotherapy, such as intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and image-guided radiotherapy (IGRT), paved the path to ultrahypofractionated stereotactic body radiotherapy (SBRT) that is delivered in 5 fractions of ≥ 6 Gy. This high dose per fraction may have a radiobiologic advantage over conventional fractionation. The relatively low a/ß ratio of prostate cancer, estimated to be between 1 and 2, suggests that tumor cells may be particularly sensitive to the high doses per fraction delivered in SBRT.^10-13 Compared with CFRT, SBRT-induced tumor cell death may also be mediated through different pathways; this pathway appears to be generated in a dose-dependent manner, particularly with doses > 8 Gy per fraction.^14,15 Additionally, the higher a/ß ratio for the surrounding organs at risk, such as the bladder and rectum, theoretically allows for an improved therapeutic ratio window that maximizes tumor control while minimizing damage to healthy tissues.

A substantial body of evidence from prospective studies and meta-analyses supports the use of SBRT for localized prostate cancer. HYPO-RT-PC, a significant phase 3 noninferiority study, enrolled 1200 patients with intermediate (89%) and high-risk (11%) prostate cancer randomized between 2 arms, including CFRT to 78 Gy in 39 fractions and SBRT to 42.7 Gy in 7 fractions, treated 3 days weekly. After a median follow-up of 60 months, the estimated 5-year biochemical relapse-free survival rate was 84% in both groups.⁹ This trial was notable because it was the first randomized study to demonstrate that SBRT was noninferior to CFRT in intermediate- and high-risk prostate cancer patients. Another pivotal phase 3 trial, the PACE-B study, enrolled 874 patients to compare SBRT (36.25 Gy to the prostate gland, with a secondary dose of 40 Gy to the gross tumor volume where applicable, in 5 fractions) with CFRT (78 Gy in 39 fractions) and moderately hypofractionated radiotherapy (HFRT) (62 Gy in 20 fractions) in patients with low- or intermediate-risk prostate cancer. With a 74-month median follow-up, the study reported 5-year biochemical free rates of 94.6% for CFRT and 95.8% for SBRT, confirming the noninferiority of SBRT to CFRT.¹⁵

SBRT offers short, effective, and convenient treatment to many patients with localized prostate cancer. While previous guidelines were more restrictive, the March 2026 National Comprehensive Cancer Network (NCCN) guidelines now list SBRT as a preferred treatment modality for high-risk prostate cancer.¹⁶

Given the growing body of evidence supporting the efficacy and safety of SBRT, we implemented an SBRT program in 2014 at a tertiary care center for veterans. This retrospective study was undertaken to evaluate the early efficacy and toxicity of SBRT in patients with localized prostate cancer treated at our institution, including patients across all risk stratifications.

METHODS

We identified 242 patients diagnosed with prostate cancer who underwent SBRT treatment between November 2014 and October 2024 at Overland Park Veterans Affairs Radiation Oncology Clinic. For the final analysis, 46 patients with < 2 years of follow-up and 22 patients who died from causes other than prostate cancer were excluded, resulting in a cohort of 174 patients with ≥ 24-month follow-up.

Treatment

Patients eligible for staging underwent imaging according to NCCN guidelines, including computed tomography (CT) of the abdomen and pelvis, bone scintigraphy, or, in recent years, prostate-specific membrane antigen positron emission tomography, primarily used for unfavorable intermediate-risk (UIR) and high-risk (HR) cancers. Patients with a negative staging work-up for nodal or skeletal disease were included. Prior to planning the CT simulation, patients were given bowel preparation instructions, including a low-fiber and low-gas-producing diet, simethicone, and enemas, the night before and morning of the simulation. Patients were instructed to arrive with a comfortably full bladder, having not voided for 2 to 3 hours prior to the procedure. At Kansas City Veterans Affairs Medical Center (KCVAMC), SBRT treatment was generally restricted to patients with a baseline American Urological Association symptom score of 15 to 20 out of 35 and a prostate gland size < 80 mL to minimize the risk of acute urinary toxicity. We did not use intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast agents for planning CT simulation.

Patients were placed in a supine position, and a vacuum bag was used for immobilization. Following the CT simulation, the images were transferred to the Eclipse treatment planning system. The clinical target volume (CTV) encompassed the prostate and the proximal 1.0 cm of the seminal vesicles for Gleason score (GS) 1 to 2, and the entire seminal vesicle was included for GS 3 to 5, which is consistent with KCVAMC practice and established safety protocols. The planning target volume (PTV) was created by uniformly expanding the CTV by 5 to 7 mm, except for the posterior margin, which was limited to 3 to 5 mm. When elective nodal radiotherapy was planned for HR prostate cancer, the pelvic field for CT simulation started at the L-2 upper border, with the lower border extending to the lesser trochanter. The pelvic nodes were delineated per Radiation Therapy Oncology Group (RTOG) guidelines.¹⁷ The CTV nodes (CTVn), including common iliac, external and internal iliac nodes, obturator, and presacral nodes, were created by uniformly expanding the CTVn by 2 to 3 mm. Slice-by-slice corrections were made to avoid bowel overlap in these patients.

The use of androgen deprivation therapy (ADT) for a duration of 6 to 24 months was prescribed for patients with UIR or HR prostate cancer per NCCN guidelines.¹⁶ The prescribed dose to the PTV was 36.25 to 40 Gy (40 Gy was mostly used as a boost to the dominant lesion) in 5 fractions, with each fraction ranging from 7.25 to 8 Gy. For elective nodal radiotherapy in patients at HR, the prescribed dose was 25 Gy in 5 fractions. All patients were planned for VMAT, which aims to deliver ≥ 95% of the prescription dose to 95% of the PTV. Once the physician approved the treatment plan and physics quality assessment was completed, treatments commenced on an every-other-day schedule. Patients received the same bowel preparation instructions for each treatment as for the planning CT simulation. Daily treatment accuracy was confirmed via daily 3-dimensional cone-beam CT (CBCT) for IGRT. No fiducials or hydrogel rectal spacers were used.

Follow-up Schedule and Toxicity Assessment

Follow-up assessments were conducted 4 to 6 weeks after radiation therapy and then repeated every 6 months for 2 to 5 years, and annually thereafter. At each follow-up visit, patients were evaluated for genitourinary (GU) and gastrointestinal (GI) toxicity, according to RTOG toxicity criteria. Prostate-specific antigen (PSA) levels were monitored; in patients receiving ADT, testosterone levels were also checked.

Statistical Analysis

Biochemical failure was defined using the Phoenix definition (nadir PSA + 2 ng/mL). Differences between dose cohorts were assessed using the log-rank test for survival outcomes and X² testing for categorical variables. GU and GI toxicities were summarized as cumulative incidences of RTOG grade ≥ II events. Statistical significance was set at P < .05.

RESULTS

One hundred seventy-four patients were included in the retrospective review. Patients had a median follow-up of 45 months (range, 24-111) (Figure). The median age at treatment was 74 years (range, 51-88), and the median pretreatment PSA level was 11.9 ng/mL (range, 0.6-69.5). Twenty-six patients (14.9%) had a GS 1, 77 (44.3%) had GS 2, 41 (23.6%) had GS 3, 18 (10.3%) had GS 4, and 12 (6.9%) had GS 5. Fifty-one patients (29.3%) received elective pelvic nodal radiotherapy, and 93 patients (53.4%) received ADT (Table 1).

At 24 months follow-up, 6 patients (3.4%) had biochemical failures. One patient died from metastatic prostate cancer, and 5 patients are living with biochemical failure (Table 2). The actuarial 5-year overall survival (OS) rate was 99.4%, and the 5-year disease-free survival (DFS) rate was 96.6%. We performed a subanalysis comparing outcomes of the 36.25 Gy vs 40 Gy SBRT cohorts. There was no statistically significant difference in DFS, OS, or the cumulative incidence of grade II/III toxicity between patients treated with 40 Gy vs 36.25 Gy. Outcomes stratified by NCCN risk groups (low, intermediate, high/very high) are detailed in Table 3. As expected, DFS was slightly lower in the high-risk group, but overall disease control remained high across all stratifications.

The cumulative incidence of RTOG grade II and higher GU toxicity was 28.2% (Table 4). This included 46 patients (26.4%) with grade II GU toxicity and 2 patients (1.2%) who developed grade III GU complications (1 requiring self-catheterization and another a suprapubic catheter for urinary retention). One patient (0.6%) treated with a 40 Gy dose regimen experienced a grade IV GU complication in the form of a rectovesical fistula necessitating surgical intervention.

The cumulative incidence of RTOG grade II or higher GI toxicity was 3.4%, and no grade III or IV gastrointestinal toxicities were observed during the follow-up period. Importantly, intraprostatic fiducials, hydrogel rectal spacers, or intravenous contrast were not routinely used in this cohort of patients.

The high rates of actuarial 5-year DFS and OS observed suggest a favorable initial response to the SBRT regimen employed at KCVAMC. However, given the potential for late recurrence in patients with prostate cancer, longer follow-up is essential to determine the durability of these outcomes. The observed GU toxicity rate of 28.2% for grade II and higher events warrants careful consideration and compares with other published data on SBRT for prostate cancer.¹⁵ The occurrence of a grade IV rectovesical fistula, although rare, is a notable adverse event that warrants discussion in the context of the treatment approach. The low incidence of grade II or higher GI toxicity is an encouraging finding, particularly given that hydrogel rectal spacers are not routinely used to minimize rectal exposure.

DISCUSSION

The primary objective of this retrospective study was to evaluate the outcomes of SBRT for patients with localized prostate cancer treated at KCVAMC and to compare these results with those reported in the literature. Our findings demonstrate promising intermediate-term efficacy, with an estimated 5-year DFS of 96.6% and OS of 99.4% at a median follow-up of 45 months. Furthermore, the observed toxicity profile appears acceptable, with a cumulative grade II and higher GU toxicity rate of 28.2% and a grade II or higher GI toxicity rate of 3.4%. Notably, these outcomes were achieved without the routine use of intraprostatic fiducials or hydrogel rectal spacers.

Two pivotal randomized phase 3 trials have established the noninferiority of ultrahypofractionated radiotherapy (UHRT) with SBRT over conventional fractionation. The HYPO-RT-PC trial compared SBRT (42.7 Gy in 7 fractions) with conventional fractionation (78 Gy in 39 fractions) in intermediate- and high-risk patients with prostate cancer and reported a 5-year biochemical relapse-free survival of 84% in both arms.⁹ The PACE-B trial, which included patients at low- and intermediate-risk, compared SBRT (36.25 Gy in 5 fractions) with conventional or moderate HFRT and reported a 5-year biochemical control rate of 95.8% in the SBRT arm and 94.6% in the control arm.¹⁵

A comprehensive review and meta-analysis of 7 phase 3 studies involving 6795 patients compared different radiotherapy regimens, namely, UHRT, HFRT, and CFRT, and reported that after 5 years, the DFS rates were 85.1% for CFRT, 86% for HFRT, and 85% for UHRT, with no significant difference in toxicity among the 3 different treatment approaches.¹⁸ This suggests that shorter, more intense radiotherapy schedules (UHRT and HFRT) may be as effective and safe as traditional, longer courses of radiation.

There are multiple published nonrandomized prospective trials in which thousands of patients with extreme hypofractionation have been treated with different doses, fractions, and techniques. While heterogeneity and limited long-term follow-up in the existing evidence are acknowledged, these data suggest that prostate SBRT provides appropriate biochemical control with few high-grade toxicities, supporting its ongoing global use and justifying further prospective investigations. Comparative data are shown in Table 5. Several ongoing studies are evaluating noninferiority, superiority, and cost-effectiveness using different methodologies (Table 6).^9,15,19-24

This study’s efficacy outcomes, particularly the high DFS rate, are consistent with the findings from these landmark trials, suggesting that the SBRT regimen used at KCVAMC is effective in achieving early disease control despite 17.2% of patients having high-risk disease. The GU toxicity observed in this study, with a 28.2% rate of grade II or higher events, is also comparable with the 26.9% reported in the 5-fraction SBRT arm of the PACE-B trial, which had a longer median follow-up of 74 months.¹⁵ It is important to note that a portion of these grade II events occurred in patients who were already on a blockers for pre-existing lower urinary tract symptoms before starting radiotherapy, which may inflate the observed cumulative acute toxicity score.

A critical comparison is how SBRT toxicity aligns with moderate hypofractionation (eg, 60 Gy in 20 fractions or 70 Gy in 28 fractions as reported by others).^4,6 Our observed grade III and higher GU toxicity rate (1.7%) and grade III and higher GI toxicity rate (0%) are highly favorable when compared with historical moderate hypofractionation data, which typically report grade III GU toxicity in the range of 2% to 3% and grade III GI toxicity around 1% to 2%. This suggests that despite the higher dose per fraction, SBRT does not necessarily lead to increased severe acute toxicity, potentially offering a superior therapeutic ratio for GI and GU sparing.

However, the occurrence of a grade IV rectovesical fistula in 1 patient (0.6%)—who received the 40 Gy dose—was a serious complication that warrants careful consideration. This rare, but severe, complication in the higher dose cohort underscores the potential for increased organ-at-risk toxicity, particularly in the absence of a hydrogel rectal spacer, which is designed to mitigate high-dose rectal exposure. While the overall rate of significant GU toxicity remains low, this event highlights the potential risks associated with SBRT. Hydrogel rectal spacers are designed to increase the distance between the prostate and the rectum, which can reduce the rectal radiation dose and potentially mitigate the risk of such fistulas. The low rate of grade II or worse GI toxicity (3.4%) in our study is noteworthy, especially considering that hydrogel spacers were not routinely used. This finding aligns with the 2.5% GI toxicity rate reported in the SBRT arm of the PACE-B trial, suggesting that careful treatment planning and delivery techniques, such as VMAT-IMRT and daily CBCT for IGRT, may contribute to minimizing GI toxicity even without the use of rectal spacers.¹⁵ The exclusive use of 3-dimensional CBCT for IGRT in our study, without the use of fiducial markers, suggests that accurate target localization can be achieved with this approach, contributing to the observed efficacy and reduced toxicity.

Strengths and Limitations

This study’s retrospective, single-center design may have introduced selection bias. The median follow-up of 45 months, while substantial, is still relatively short for assessing very late toxicities and long-term oncologic outcomes in prostate cancer, which is known for late recurrences. Additionally, the lack of a direct comparison group within KCVAMC limits the ability to definitively attribute the observed outcomes solely to SBRT treatment. However, the strengths of this study include the inclusion of a consecutive series of veteran patients with localized prostate cancer across all risk categories, providing a real-world perspective on SBRT outcomes in a diverse patient population. Furthermore, the detailed assessment of efficacy and toxicity via standardized RTOG criteria enhances the comparability of our findings with those of other published prospective studies, despite the retrospective nature of the data.

CONCLUSIONS

This single-institution retrospective analysis revealed that short-term SBRT (36.25 to 40 Gy in 5 fractions), with a minimum follow-up of 24 months and a median follow-up of 45 months, for localized prostate cancer, including patients at HR, is associated with promising early efficacy and acceptable toxicity, even in the absence of routine fiducial or hydrogel spacer use. The favorable actuarial 5-year DFS and OS rates, coupled with a manageable toxicity profile, suggest that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer. However, a longer follow-up is necessary to confirm these findings and fully characterize the long-term efficacy and toxicity of this SBRT regimen. Nevertheless, the results contribute to the growing body of evidence suggesting that SBRT is a safe and convenient treatment option for many patients with localized prostate cancer.