Colorectal Cancer

Testosterone therapy is administered following pragmatic diagnostic evaluation and workup to assess whether an adult male is hypogonadal, based on symptoms consistent with androgen deficiency and low morning serum testosterone concentrations on ≥ 2 occasions. Effects of testosterone administration include the development or maintenance of secondary sexual characteristics and increases in libido, muscle strength, fat-free mass, and bone density.

Testosterone prescriptions have markedly increased in the past 20 years, including within the US Department of Veterans Affairs (VA) health care system.^1-3 This trend may be influenced by various factors, including patient perceptions of benefit, an increase in marketing, and the availability of more user-friendly formulations. 

Since 2006, evidence-based clinical practice guidelines have recommended specific clinical and laboratory evaluation and counseling prior to starting testosterone replacement therapy (TRT).^4-8 However, research has shown poor adherence to these recommendations, including at the VA, which raises concerns about inappropriate TRT initiation without proper diagnostic evaluation.^9,10 Observational research has suggested a possible link between testosterone therapy and increased risk of cardiovascular (CV) events. The US Food and Drug Administration prescribing information includes boxed warnings about potential risks of high blood pressure, myocardial infarction, stroke, and CV-related mortality with testosterone treatment, contact transfer of transdermal testosterone, and pulmonary oil microembolism with testosterone undecanoate injections.^11-15

A VA Office of Inspector General (OIG) review of VA clinician adherence to clinical and laboratory evaluation guidelines for testosterone deficiency found poor adherence among VA practitioners and made recommendations for improvement.^4,15 These focused on establishing clinical signs and symptoms consistent with testosterone deficiency, confirming hypogonadism by repeated testosterone testing, determining the etiology of hypogonadism by measuring gonadotropins, initiating a discussion of risks and benefits of TRT, and assessing clinical improvement and obtaining an updated hematocrit test within 3 to 6 months of initiation.

The VA Puget Sound Health Care System (VAPSHCS) developed a local prior authorization template to assist health care practitioners (HCPs) to address the OIG recommendations. This testosterone order template (TOT) aimed to improve the diagnosis, evaluation, and monitoring of TRT in males with hypogonadism, combined with existing VA pharmacy criteria for the use of testosterone based on Endocrine Society guidelines. A version of the VAPSHCS TOT was approved as the national VA Computerized Patient Record System (CPRS) template.

Preliminary evaluation of the TOT suggested improved short-term adherence to guideline recommendations following implementation.¹⁶ This quality improvement study sought to assess the long-term effectiveness of the TOT with respect to clinical practice guideline adherence. The OIG did not address prostate-specific antigen (PSA) monitoring because understanding of the relationship between TRT and the risks of elevated PSA levels remains incomplete.^6,17 This project hypothesized that implementation of a pharmacy-managed TOT incorporated into CPRS would result in higher adherence rates to guideline-recommended clinical and laboratory evaluation, in addition to counseling of men with hypogonadism prior to initiation of TRT.

Methods

Eligible participants were cisgender males who received a new testosterone prescription, had ≥ 2 clinic visits at VAPSHCS, and no previous testosterone prescription in the previous 2 years. Individuals were excluded if they had testosterone administered at VAPSHCS; were prescribed testosterone at another facility (VA or community-based); pilot tested an initial version of the TOT prior to November 30, 2019; or had an International Classification of Diseases, Tenth Revision codes for hypopituitarism, gender identity disorder, history of sexual assignment, or Klinefelter syndrome for which testosterone therapy was already approved. Patients who met the inclusion criteria were identified by an algorithm developed by the VAPSHCS pharmacoeconomist.

This quality improvement project used a retrospective, pre-post experimental design. Electronic chart review and systematic manual review of all eligible patient charts were performed for the pretemplate period (December 1, 2018, to November 30, 2019) and after the template implementation, (December 1, 2021, to November 30, 2022).

An initial version of the TOT was implemented on July 1, 2019, but was not fully integrated into CPRS until early 2020; individuals in whom the TOT was used prior to November 30, 2019, were excluded. Data from the initial period of the COVID-19 pandemic were avoided because of alterations in clinic and prescribing practices. As a quality improvement project, the TOT evaluation was exempt from formal review by the VAPSHCS Institutional Review Board, as determined by the Director of the Office of Transformation/Quality/Safety/Value.

Interventions

Testosterone is a Schedule III controlled substance with potential risks and a propensity for varied prescribing practices. It was designated as a restricted drug requiring a prior authorization drug request (PADR) for which a specific TOT was developed, approved by the VAPSHCS Pharmacy and Therapeutics Committee, and incorporated into CPRS. A team of pharmacists, primary care physicians, geriatricians, endocrinologists, and health informatics experts created and developed the TOT. Pharmacists managed and monitored its completion.

The process for prescribing testosterone via the TOT is outlined in the eAppendix. When an HCP orders testosterone in CPRS, reminders prompt them to use the TOT and indicate required laboratory measurements (an order set is provided). Completion of TOT is not necessary to order testosterone for patients with an existing diagnosis of an organic cause of hypogonadism (eg, Klinefelter syndrome or hypopituitarism) or transgender women (assigned male at birth). In the TOT, the prescriber must also indicate signs and symptoms of testosterone deficiency; required laboratory tests; and counseling regarding potential risks and benefits of TRT. A pharmacist reviews the TOT and either approves or rejects the testosterone prescription and provides follow-up guidance to the prescriber. The completed TOT serves as documentation of guideline adherence in CPRS. The TOT also includes sections for first renewal testosterone prescriptions, addressing guideline recommendations for follow-up laboratory evaluation and clinical response to TRT. Due to limited completion of this section in the posttemplate period, evaluating adherence to follow-up recommendations was not feasible.

Measures

This project assessed the percentage of patients in the posttemplate period vs pretemplate period with an approved PADR. Documentation of specific guideline-recommended measures was assessed: signs and symptoms of testosterone deficiency; ≥ 2 serum testosterone measurements (≥ 2 total, free and total, or 2 free testosterone levels, and ≥ 1 testosterone level before 10 am); serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) tests; discussion of the benefits and risks of testosterone treatment; and hematocrit measurement.

The project also assessed the proportion of patients in the posttemplate period vs pretemplate period who had all hormone tests (≥ 2 serum testosterone and LH and FSH concentrations), all laboratory tests (hormone tests and hematocrit), and all 5 guideline-recommended measures.

Analysis

Statistical comparisons between the proportions of patients in the pretemplate and posttemplate periods for each measure were performed using a χ² test, without correction for multiple comparisons. All analyses were conducted using Stata version 10.0. A P value < .05 was considered significant for all comparisons.

Results

Chart review identified 189 patients in the pretemplate period and 113 patients in the posttemplate period with a new testosterone prescription (Figure). After exclusions, 91 and 49 patients, respectively, met eligibility criteria (Table 1). Fifty-six patients (62%) pretemplate and 40 patients (82%) posttemplate (P = .015) had approved PADRs and comprised the groups that were analyzed (Table 2).

The mean age and body mass index were similar in the pretemplate and posttemplate periods, but there was variation in the proportions of patients aged < 70 years and those with a body mass index < 30 between the groups. The most common diagnosis in both groups was testicular hypofunction, and the most common comorbidity was type 2 diabetes mellitus. Concomitant use of opioids or glucocorticoids that can lower testosterone levels was rare. Most testosterone prescriptions originated from primary care clinics in both periods: 68 (75%) in the pretemplate period and 35 (71%) in the posttemplate period. Most testosterone treatment was delivered by intramuscular injection. 

In the posttemplate period vs pretemplate period, the proportion of patients with an approved PADR (82% vs 62%, P = .02), and documentation of signs and symptoms of hypogonadism (93% vs 71%, P = .002) prior to starting TRT were higher, while the percentage of patients having ≥ 2 testosterone measurements (85% vs 89%, P = .53), ≥ 1 testosterone level before 10 AM (78% vs 75%, P = .70), and hematocrit measured (95% vs 91%, P = .47) were similar. Rates of LH and FSH testing were higher in the posttemplate period (80%) vs the pretemplate period (63%) but did not achieve statistical significance (P = .07), and discussion of the risks and benefits of TRT was higher in the posttemplate period (58%) vs the pretemplate period (34%) (P = .02). The percentage of patients who had all hormone measurements (total and/or free testosterone, LH, and FSH) was higher in the posttemplate period (78%) vs the pretemplate period (59%) but did not achieve statistical significance (P = .06). The rates of all guideline-recommended laboratory test orders were higher in the posttemplate period (78%) vs the pretemplate period (55%) (P = .03), and all 5 guideline-recommended clinical and laboratory measures were higher in the posttemplate period (45%) vs the pretemplate period (18%) (P = .004).

Discussion

The implementation of a pharmacy-managed TOT in CPRS demonstrated higher adherence to evidence-based guidelines for diagnosing and evaluating hypogonadism before TRT. After TOT implementation, a higher proportion of patients had documented signs and symptoms of testosterone deficiency, underwent all recommended laboratory tests, and had discussions about the risks and benefits of TRT. Adherence to 5 clinical and laboratory measures recommended by Endocrine Society guidelines was higher after TOT implementation, indicating improved prescribing practices.⁴

The requirement for TOT completion before testosterone prescription and its management by trained pharmacists likely contributed to higher adherence to guideline recommendations than previously reported. Integration of the TOT into CPRS with pharmacy oversight may have enhanced adherence by summarizing and codifying evidence-based guideline recommendations for clinical and biochemical evaluation prior to TRT initiation, offering relevant education to clinicians and pharmacists, automatically importing pertinent clinical information and laboratory results, and generating CPRS documentation to reduce clinician burden during patient care. 

The proportion of patients with documented signs and symptoms of testosterone deficiency before TRT increased from the pretemplate period (71%) to the posttemplate period (93%), indicating that most patients receiving TRT had clinical manifestations of hypogonadism. This aligns with Endocrine Society guidelines, which define hypogonadism as a clinical disorder characterized by clinical manifestations of testosterone deficiency and persistently low serum testosterone levels on ≥ 2 separate occasions.^4,6 However, recent trends in direct-to-consumer advertising for testosterone and the rise of “low T” clinics may contribute to increased testing, varied practices, and inappropriate testosterone therapy initiation (eg, in men with low testosterone levels who lack symptoms of hypogonadism).¹⁸ Improved adherence in documenting clinical hypogonadism with implementation of the TOT reinforces the value of incorporating educational material, as previously reported.¹¹

Adherence to guideline recommendations following implementation of the TOT in this project was higher than those previously reported. In a study of 111,631 outpatient veterans prescribed testosterone from 2009 to 2012, only 18.3% had ≥ 2 testosterone prescriptions, and 3.5% had ≥ 2 testosterone, LH, and FSH levels measured prior to the initiation of a TRT.⁹ In a report of 63,534 insured patients who received TRT from 2010 to 2012, 40.3% had ≥ 2 testosterone prescriptions, and 12% had LH and/or FSH measured prior to the initiation.⁸

Low rates of guideline-recommended laboratory tests prior to initiation of testosterone treatment were reported in prior non-VA studies.^19,20 Poor guideline adherence reinforces the need for clinician education or other methods to improve TRT and ensure appropriate prescribing practices across health care systems. The TOT described in this project is a sustainable clinical tool with the potential to improve testosterone prescribing practices. 

The high rates of adherence to guideline recommendations at VAPSHCS likely stem from local endocrine expertise and ongoing educational initiatives, as well as the requirement for template completion before testosterone prescription. However, most testosterone prescriptions were initiated by primary care and monitored by pharmacists with varying degrees of training and clinical experience in hypogonadism and TRT.

However, adherence to guideline recommendations was modest, suggesting there is still an opportunity for improvement. The decision to initiate therapy should be made only after appropriate counseling with patients regarding its potential benefits and risks. Reports on the CV risk of TRT have been mixed. The 2023 TRAVERSE study found no increase in major adverse CV events among older men with hypogonadism and pre-existing CV risks undergoing TRT, but noted higher instances of pulmonary embolism, atrial fibrillation, and acute kidney injury.²¹ This highlights the need for clinicians to continue to engage in informed decision-making with patients. Effective pretreatment counseling is important but time-consuming; future TOT monitoring and modifications could consider mandatory checkboxes to document counseling on TRT risks and benefits.

The TOT described in this study could be adapted and incorporated into the prescribing process and electronic health record of larger health care systems. Use of an electronic template allows for automatic real-time dashboard monitoring of organization performance. The TOT described could be modified or simplified for specialty or primary care clinics or individual practitioners to improve adherence to evidence-based guideline recommendations and quality of care.

Strengths

A strength of this study is the multidisciplinary team (composed of stakeholders with experience in VA health care system and subject matter experts in hypogonadism) that developed and incorporated a user-friendly template for testosterone prescriptions; the use of evidence-based guideline recommendations; and the use of a structured chart review permitted accurate assessment of adherence to recommendations to document signs and symptoms of testosterone deficiency and a discussion of potential risks and benefits prior to TRT. To our knowledge, these recommendations have not been assessed in previous reports.

Limitations

The retrospective pre-post design of this study precludes a conclusion that implementation of the TOT caused the increase in adherence to guideline recommendations. Improved adherence could have resulted from the ongoing development of the preauthorization process for testosterone prescriptions or other changes over time. However, the preauthorization process had already been established for many years prior to template implementation. Forty-nine patients had new prescriptions for testosterone in the posttemplate period compared to 91 in the pretemplate period, but TRT was initiated in accordance with guideline recommendations more appropriately in the posttemplate period. The study’s sample size was small, and many eligible patients were excluded; however, exclusions were necessary to evaluate men who had new testosterone prescriptions for which the template was designed. Most men excluded were already taking testosterone.

Conclusions

The implementation of a CPRS-based TOT improved adherence to evidence-based guidelines for the diagnosis, evaluation, and counseling of patients with hypogonadism before starting TRT. While there were improvements in adherence with the TOT, the relatively low proportion of patients with documentation of TRT risks and benefits and all guideline recommendations highlights the need for additional efforts to further strengthen adherence to guideline recommendations and ensure appropriate evaluation, counseling, and prescribing practices before initiating TRT.

Testosterone therapy is administered following pragmatic diagnostic evaluation and workup to assess whether an adult male is hypogonadal, based on symptoms consistent with androgen deficiency and low morning serum testosterone concentrations on ≥ 2 occasions. Effects of testosterone administration include the development or maintenance of secondary sexual characteristics and increases in libido, muscle strength, fat-free mass, and bone density.

Testosterone prescriptions have markedly increased in the past 20 years, including within the US Department of Veterans Affairs (VA) health care system.^1-3 This trend may be influenced by various factors, including patient perceptions of benefit, an increase in marketing, and the availability of more user-friendly formulations. 

Since 2006, evidence-based clinical practice guidelines have recommended specific clinical and laboratory evaluation and counseling prior to starting testosterone replacement therapy (TRT).^4-8 However, research has shown poor adherence to these recommendations, including at the VA, which raises concerns about inappropriate TRT initiation without proper diagnostic evaluation.^9,10 Observational research has suggested a possible link between testosterone therapy and increased risk of cardiovascular (CV) events. The US Food and Drug Administration prescribing information includes boxed warnings about potential risks of high blood pressure, myocardial infarction, stroke, and CV-related mortality with testosterone treatment, contact transfer of transdermal testosterone, and pulmonary oil microembolism with testosterone undecanoate injections.^11-15

A VA Office of Inspector General (OIG) review of VA clinician adherence to clinical and laboratory evaluation guidelines for testosterone deficiency found poor adherence among VA practitioners and made recommendations for improvement.^4,15 These focused on establishing clinical signs and symptoms consistent with testosterone deficiency, confirming hypogonadism by repeated testosterone testing, determining the etiology of hypogonadism by measuring gonadotropins, initiating a discussion of risks and benefits of TRT, and assessing clinical improvement and obtaining an updated hematocrit test within 3 to 6 months of initiation.

The VA Puget Sound Health Care System (VAPSHCS) developed a local prior authorization template to assist health care practitioners (HCPs) to address the OIG recommendations. This testosterone order template (TOT) aimed to improve the diagnosis, evaluation, and monitoring of TRT in males with hypogonadism, combined with existing VA pharmacy criteria for the use of testosterone based on Endocrine Society guidelines. A version of the VAPSHCS TOT was approved as the national VA Computerized Patient Record System (CPRS) template.

Preliminary evaluation of the TOT suggested improved short-term adherence to guideline recommendations following implementation.¹⁶ This quality improvement study sought to assess the long-term effectiveness of the TOT with respect to clinical practice guideline adherence. The OIG did not address prostate-specific antigen (PSA) monitoring because understanding of the relationship between TRT and the risks of elevated PSA levels remains incomplete.^6,17 This project hypothesized that implementation of a pharmacy-managed TOT incorporated into CPRS would result in higher adherence rates to guideline-recommended clinical and laboratory evaluation, in addition to counseling of men with hypogonadism prior to initiation of TRT.

Methods

Eligible participants were cisgender males who received a new testosterone prescription, had ≥ 2 clinic visits at VAPSHCS, and no previous testosterone prescription in the previous 2 years. Individuals were excluded if they had testosterone administered at VAPSHCS; were prescribed testosterone at another facility (VA or community-based); pilot tested an initial version of the TOT prior to November 30, 2019; or had an International Classification of Diseases, Tenth Revision codes for hypopituitarism, gender identity disorder, history of sexual assignment, or Klinefelter syndrome for which testosterone therapy was already approved. Patients who met the inclusion criteria were identified by an algorithm developed by the VAPSHCS pharmacoeconomist.

This quality improvement project used a retrospective, pre-post experimental design. Electronic chart review and systematic manual review of all eligible patient charts were performed for the pretemplate period (December 1, 2018, to November 30, 2019) and after the template implementation, (December 1, 2021, to November 30, 2022).

An initial version of the TOT was implemented on July 1, 2019, but was not fully integrated into CPRS until early 2020; individuals in whom the TOT was used prior to November 30, 2019, were excluded. Data from the initial period of the COVID-19 pandemic were avoided because of alterations in clinic and prescribing practices. As a quality improvement project, the TOT evaluation was exempt from formal review by the VAPSHCS Institutional Review Board, as determined by the Director of the Office of Transformation/Quality/Safety/Value.

Interventions

Testosterone is a Schedule III controlled substance with potential risks and a propensity for varied prescribing practices. It was designated as a restricted drug requiring a prior authorization drug request (PADR) for which a specific TOT was developed, approved by the VAPSHCS Pharmacy and Therapeutics Committee, and incorporated into CPRS. A team of pharmacists, primary care physicians, geriatricians, endocrinologists, and health informatics experts created and developed the TOT. Pharmacists managed and monitored its completion.

The process for prescribing testosterone via the TOT is outlined in the eAppendix. When an HCP orders testosterone in CPRS, reminders prompt them to use the TOT and indicate required laboratory measurements (an order set is provided). Completion of TOT is not necessary to order testosterone for patients with an existing diagnosis of an organic cause of hypogonadism (eg, Klinefelter syndrome or hypopituitarism) or transgender women (assigned male at birth). In the TOT, the prescriber must also indicate signs and symptoms of testosterone deficiency; required laboratory tests; and counseling regarding potential risks and benefits of TRT. A pharmacist reviews the TOT and either approves or rejects the testosterone prescription and provides follow-up guidance to the prescriber. The completed TOT serves as documentation of guideline adherence in CPRS. The TOT also includes sections for first renewal testosterone prescriptions, addressing guideline recommendations for follow-up laboratory evaluation and clinical response to TRT. Due to limited completion of this section in the posttemplate period, evaluating adherence to follow-up recommendations was not feasible.

Measures

This project assessed the percentage of patients in the posttemplate period vs pretemplate period with an approved PADR. Documentation of specific guideline-recommended measures was assessed: signs and symptoms of testosterone deficiency; ≥ 2 serum testosterone measurements (≥ 2 total, free and total, or 2 free testosterone levels, and ≥ 1 testosterone level before 10 am); serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) tests; discussion of the benefits and risks of testosterone treatment; and hematocrit measurement.

The project also assessed the proportion of patients in the posttemplate period vs pretemplate period who had all hormone tests (≥ 2 serum testosterone and LH and FSH concentrations), all laboratory tests (hormone tests and hematocrit), and all 5 guideline-recommended measures.

Analysis

Statistical comparisons between the proportions of patients in the pretemplate and posttemplate periods for each measure were performed using a χ² test, without correction for multiple comparisons. All analyses were conducted using Stata version 10.0. A P value < .05 was considered significant for all comparisons.

Results

Chart review identified 189 patients in the pretemplate period and 113 patients in the posttemplate period with a new testosterone prescription (Figure). After exclusions, 91 and 49 patients, respectively, met eligibility criteria (Table 1). Fifty-six patients (62%) pretemplate and 40 patients (82%) posttemplate (P = .015) had approved PADRs and comprised the groups that were analyzed (Table 2).

The mean age and body mass index were similar in the pretemplate and posttemplate periods, but there was variation in the proportions of patients aged < 70 years and those with a body mass index < 30 between the groups. The most common diagnosis in both groups was testicular hypofunction, and the most common comorbidity was type 2 diabetes mellitus. Concomitant use of opioids or glucocorticoids that can lower testosterone levels was rare. Most testosterone prescriptions originated from primary care clinics in both periods: 68 (75%) in the pretemplate period and 35 (71%) in the posttemplate period. Most testosterone treatment was delivered by intramuscular injection. 

In the posttemplate period vs pretemplate period, the proportion of patients with an approved PADR (82% vs 62%, P = .02), and documentation of signs and symptoms of hypogonadism (93% vs 71%, P = .002) prior to starting TRT were higher, while the percentage of patients having ≥ 2 testosterone measurements (85% vs 89%, P = .53), ≥ 1 testosterone level before 10 AM (78% vs 75%, P = .70), and hematocrit measured (95% vs 91%, P = .47) were similar. Rates of LH and FSH testing were higher in the posttemplate period (80%) vs the pretemplate period (63%) but did not achieve statistical significance (P = .07), and discussion of the risks and benefits of TRT was higher in the posttemplate period (58%) vs the pretemplate period (34%) (P = .02). The percentage of patients who had all hormone measurements (total and/or free testosterone, LH, and FSH) was higher in the posttemplate period (78%) vs the pretemplate period (59%) but did not achieve statistical significance (P = .06). The rates of all guideline-recommended laboratory test orders were higher in the posttemplate period (78%) vs the pretemplate period (55%) (P = .03), and all 5 guideline-recommended clinical and laboratory measures were higher in the posttemplate period (45%) vs the pretemplate period (18%) (P = .004).

Discussion

The implementation of a pharmacy-managed TOT in CPRS demonstrated higher adherence to evidence-based guidelines for diagnosing and evaluating hypogonadism before TRT. After TOT implementation, a higher proportion of patients had documented signs and symptoms of testosterone deficiency, underwent all recommended laboratory tests, and had discussions about the risks and benefits of TRT. Adherence to 5 clinical and laboratory measures recommended by Endocrine Society guidelines was higher after TOT implementation, indicating improved prescribing practices.⁴

The requirement for TOT completion before testosterone prescription and its management by trained pharmacists likely contributed to higher adherence to guideline recommendations than previously reported. Integration of the TOT into CPRS with pharmacy oversight may have enhanced adherence by summarizing and codifying evidence-based guideline recommendations for clinical and biochemical evaluation prior to TRT initiation, offering relevant education to clinicians and pharmacists, automatically importing pertinent clinical information and laboratory results, and generating CPRS documentation to reduce clinician burden during patient care. 

The proportion of patients with documented signs and symptoms of testosterone deficiency before TRT increased from the pretemplate period (71%) to the posttemplate period (93%), indicating that most patients receiving TRT had clinical manifestations of hypogonadism. This aligns with Endocrine Society guidelines, which define hypogonadism as a clinical disorder characterized by clinical manifestations of testosterone deficiency and persistently low serum testosterone levels on ≥ 2 separate occasions.^4,6 However, recent trends in direct-to-consumer advertising for testosterone and the rise of “low T” clinics may contribute to increased testing, varied practices, and inappropriate testosterone therapy initiation (eg, in men with low testosterone levels who lack symptoms of hypogonadism).¹⁸ Improved adherence in documenting clinical hypogonadism with implementation of the TOT reinforces the value of incorporating educational material, as previously reported.¹¹

Adherence to guideline recommendations following implementation of the TOT in this project was higher than those previously reported. In a study of 111,631 outpatient veterans prescribed testosterone from 2009 to 2012, only 18.3% had ≥ 2 testosterone prescriptions, and 3.5% had ≥ 2 testosterone, LH, and FSH levels measured prior to the initiation of a TRT.⁹ In a report of 63,534 insured patients who received TRT from 2010 to 2012, 40.3% had ≥ 2 testosterone prescriptions, and 12% had LH and/or FSH measured prior to the initiation.⁸

Low rates of guideline-recommended laboratory tests prior to initiation of testosterone treatment were reported in prior non-VA studies.^19,20 Poor guideline adherence reinforces the need for clinician education or other methods to improve TRT and ensure appropriate prescribing practices across health care systems. The TOT described in this project is a sustainable clinical tool with the potential to improve testosterone prescribing practices. 

The high rates of adherence to guideline recommendations at VAPSHCS likely stem from local endocrine expertise and ongoing educational initiatives, as well as the requirement for template completion before testosterone prescription. However, most testosterone prescriptions were initiated by primary care and monitored by pharmacists with varying degrees of training and clinical experience in hypogonadism and TRT.

However, adherence to guideline recommendations was modest, suggesting there is still an opportunity for improvement. The decision to initiate therapy should be made only after appropriate counseling with patients regarding its potential benefits and risks. Reports on the CV risk of TRT have been mixed. The 2023 TRAVERSE study found no increase in major adverse CV events among older men with hypogonadism and pre-existing CV risks undergoing TRT, but noted higher instances of pulmonary embolism, atrial fibrillation, and acute kidney injury.²¹ This highlights the need for clinicians to continue to engage in informed decision-making with patients. Effective pretreatment counseling is important but time-consuming; future TOT monitoring and modifications could consider mandatory checkboxes to document counseling on TRT risks and benefits.

The TOT described in this study could be adapted and incorporated into the prescribing process and electronic health record of larger health care systems. Use of an electronic template allows for automatic real-time dashboard monitoring of organization performance. The TOT described could be modified or simplified for specialty or primary care clinics or individual practitioners to improve adherence to evidence-based guideline recommendations and quality of care.

Strengths

A strength of this study is the multidisciplinary team (composed of stakeholders with experience in VA health care system and subject matter experts in hypogonadism) that developed and incorporated a user-friendly template for testosterone prescriptions; the use of evidence-based guideline recommendations; and the use of a structured chart review permitted accurate assessment of adherence to recommendations to document signs and symptoms of testosterone deficiency and a discussion of potential risks and benefits prior to TRT. To our knowledge, these recommendations have not been assessed in previous reports.

Limitations

The retrospective pre-post design of this study precludes a conclusion that implementation of the TOT caused the increase in adherence to guideline recommendations. Improved adherence could have resulted from the ongoing development of the preauthorization process for testosterone prescriptions or other changes over time. However, the preauthorization process had already been established for many years prior to template implementation. Forty-nine patients had new prescriptions for testosterone in the posttemplate period compared to 91 in the pretemplate period, but TRT was initiated in accordance with guideline recommendations more appropriately in the posttemplate period. The study’s sample size was small, and many eligible patients were excluded; however, exclusions were necessary to evaluate men who had new testosterone prescriptions for which the template was designed. Most men excluded were already taking testosterone.

Conclusions

The implementation of a CPRS-based TOT improved adherence to evidence-based guidelines for the diagnosis, evaluation, and counseling of patients with hypogonadism before starting TRT. While there were improvements in adherence with the TOT, the relatively low proportion of patients with documentation of TRT risks and benefits and all guideline recommendations highlights the need for additional efforts to further strengthen adherence to guideline recommendations and ensure appropriate evaluation, counseling, and prescribing practices before initiating TRT.

Testosterone therapy is administered following pragmatic diagnostic evaluation and workup to assess whether an adult male is hypogonadal, based on symptoms consistent with androgen deficiency and low morning serum testosterone concentrations on ≥ 2 occasions. Effects of testosterone administration include the development or maintenance of secondary sexual characteristics and increases in libido, muscle strength, fat-free mass, and bone density.

Testosterone prescriptions have markedly increased in the past 20 years, including within the US Department of Veterans Affairs (VA) health care system.^1-3 This trend may be influenced by various factors, including patient perceptions of benefit, an increase in marketing, and the availability of more user-friendly formulations. 

Since 2006, evidence-based clinical practice guidelines have recommended specific clinical and laboratory evaluation and counseling prior to starting testosterone replacement therapy (TRT).^4-8 However, research has shown poor adherence to these recommendations, including at the VA, which raises concerns about inappropriate TRT initiation without proper diagnostic evaluation.^9,10 Observational research has suggested a possible link between testosterone therapy and increased risk of cardiovascular (CV) events. The US Food and Drug Administration prescribing information includes boxed warnings about potential risks of high blood pressure, myocardial infarction, stroke, and CV-related mortality with testosterone treatment, contact transfer of transdermal testosterone, and pulmonary oil microembolism with testosterone undecanoate injections.^11-15

A VA Office of Inspector General (OIG) review of VA clinician adherence to clinical and laboratory evaluation guidelines for testosterone deficiency found poor adherence among VA practitioners and made recommendations for improvement.^4,15 These focused on establishing clinical signs and symptoms consistent with testosterone deficiency, confirming hypogonadism by repeated testosterone testing, determining the etiology of hypogonadism by measuring gonadotropins, initiating a discussion of risks and benefits of TRT, and assessing clinical improvement and obtaining an updated hematocrit test within 3 to 6 months of initiation.

The VA Puget Sound Health Care System (VAPSHCS) developed a local prior authorization template to assist health care practitioners (HCPs) to address the OIG recommendations. This testosterone order template (TOT) aimed to improve the diagnosis, evaluation, and monitoring of TRT in males with hypogonadism, combined with existing VA pharmacy criteria for the use of testosterone based on Endocrine Society guidelines. A version of the VAPSHCS TOT was approved as the national VA Computerized Patient Record System (CPRS) template.

Preliminary evaluation of the TOT suggested improved short-term adherence to guideline recommendations following implementation.¹⁶ This quality improvement study sought to assess the long-term effectiveness of the TOT with respect to clinical practice guideline adherence. The OIG did not address prostate-specific antigen (PSA) monitoring because understanding of the relationship between TRT and the risks of elevated PSA levels remains incomplete.^6,17 This project hypothesized that implementation of a pharmacy-managed TOT incorporated into CPRS would result in higher adherence rates to guideline-recommended clinical and laboratory evaluation, in addition to counseling of men with hypogonadism prior to initiation of TRT.

Methods

Eligible participants were cisgender males who received a new testosterone prescription, had ≥ 2 clinic visits at VAPSHCS, and no previous testosterone prescription in the previous 2 years. Individuals were excluded if they had testosterone administered at VAPSHCS; were prescribed testosterone at another facility (VA or community-based); pilot tested an initial version of the TOT prior to November 30, 2019; or had an International Classification of Diseases, Tenth Revision codes for hypopituitarism, gender identity disorder, history of sexual assignment, or Klinefelter syndrome for which testosterone therapy was already approved. Patients who met the inclusion criteria were identified by an algorithm developed by the VAPSHCS pharmacoeconomist.

This quality improvement project used a retrospective, pre-post experimental design. Electronic chart review and systematic manual review of all eligible patient charts were performed for the pretemplate period (December 1, 2018, to November 30, 2019) and after the template implementation, (December 1, 2021, to November 30, 2022).

An initial version of the TOT was implemented on July 1, 2019, but was not fully integrated into CPRS until early 2020; individuals in whom the TOT was used prior to November 30, 2019, were excluded. Data from the initial period of the COVID-19 pandemic were avoided because of alterations in clinic and prescribing practices. As a quality improvement project, the TOT evaluation was exempt from formal review by the VAPSHCS Institutional Review Board, as determined by the Director of the Office of Transformation/Quality/Safety/Value.

Interventions

Testosterone is a Schedule III controlled substance with potential risks and a propensity for varied prescribing practices. It was designated as a restricted drug requiring a prior authorization drug request (PADR) for which a specific TOT was developed, approved by the VAPSHCS Pharmacy and Therapeutics Committee, and incorporated into CPRS. A team of pharmacists, primary care physicians, geriatricians, endocrinologists, and health informatics experts created and developed the TOT. Pharmacists managed and monitored its completion.

The process for prescribing testosterone via the TOT is outlined in the eAppendix. When an HCP orders testosterone in CPRS, reminders prompt them to use the TOT and indicate required laboratory measurements (an order set is provided). Completion of TOT is not necessary to order testosterone for patients with an existing diagnosis of an organic cause of hypogonadism (eg, Klinefelter syndrome or hypopituitarism) or transgender women (assigned male at birth). In the TOT, the prescriber must also indicate signs and symptoms of testosterone deficiency; required laboratory tests; and counseling regarding potential risks and benefits of TRT. A pharmacist reviews the TOT and either approves or rejects the testosterone prescription and provides follow-up guidance to the prescriber. The completed TOT serves as documentation of guideline adherence in CPRS. The TOT also includes sections for first renewal testosterone prescriptions, addressing guideline recommendations for follow-up laboratory evaluation and clinical response to TRT. Due to limited completion of this section in the posttemplate period, evaluating adherence to follow-up recommendations was not feasible.

Measures

This project assessed the percentage of patients in the posttemplate period vs pretemplate period with an approved PADR. Documentation of specific guideline-recommended measures was assessed: signs and symptoms of testosterone deficiency; ≥ 2 serum testosterone measurements (≥ 2 total, free and total, or 2 free testosterone levels, and ≥ 1 testosterone level before 10 am); serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) tests; discussion of the benefits and risks of testosterone treatment; and hematocrit measurement.

The project also assessed the proportion of patients in the posttemplate period vs pretemplate period who had all hormone tests (≥ 2 serum testosterone and LH and FSH concentrations), all laboratory tests (hormone tests and hematocrit), and all 5 guideline-recommended measures.

Analysis

Statistical comparisons between the proportions of patients in the pretemplate and posttemplate periods for each measure were performed using a χ² test, without correction for multiple comparisons. All analyses were conducted using Stata version 10.0. A P value < .05 was considered significant for all comparisons.

Results

Chart review identified 189 patients in the pretemplate period and 113 patients in the posttemplate period with a new testosterone prescription (Figure). After exclusions, 91 and 49 patients, respectively, met eligibility criteria (Table 1). Fifty-six patients (62%) pretemplate and 40 patients (82%) posttemplate (P = .015) had approved PADRs and comprised the groups that were analyzed (Table 2).

The mean age and body mass index were similar in the pretemplate and posttemplate periods, but there was variation in the proportions of patients aged < 70 years and those with a body mass index < 30 between the groups. The most common diagnosis in both groups was testicular hypofunction, and the most common comorbidity was type 2 diabetes mellitus. Concomitant use of opioids or glucocorticoids that can lower testosterone levels was rare. Most testosterone prescriptions originated from primary care clinics in both periods: 68 (75%) in the pretemplate period and 35 (71%) in the posttemplate period. Most testosterone treatment was delivered by intramuscular injection. 

In the posttemplate period vs pretemplate period, the proportion of patients with an approved PADR (82% vs 62%, P = .02), and documentation of signs and symptoms of hypogonadism (93% vs 71%, P = .002) prior to starting TRT were higher, while the percentage of patients having ≥ 2 testosterone measurements (85% vs 89%, P = .53), ≥ 1 testosterone level before 10 AM (78% vs 75%, P = .70), and hematocrit measured (95% vs 91%, P = .47) were similar. Rates of LH and FSH testing were higher in the posttemplate period (80%) vs the pretemplate period (63%) but did not achieve statistical significance (P = .07), and discussion of the risks and benefits of TRT was higher in the posttemplate period (58%) vs the pretemplate period (34%) (P = .02). The percentage of patients who had all hormone measurements (total and/or free testosterone, LH, and FSH) was higher in the posttemplate period (78%) vs the pretemplate period (59%) but did not achieve statistical significance (P = .06). The rates of all guideline-recommended laboratory test orders were higher in the posttemplate period (78%) vs the pretemplate period (55%) (P = .03), and all 5 guideline-recommended clinical and laboratory measures were higher in the posttemplate period (45%) vs the pretemplate period (18%) (P = .004).

Discussion

The implementation of a pharmacy-managed TOT in CPRS demonstrated higher adherence to evidence-based guidelines for diagnosing and evaluating hypogonadism before TRT. After TOT implementation, a higher proportion of patients had documented signs and symptoms of testosterone deficiency, underwent all recommended laboratory tests, and had discussions about the risks and benefits of TRT. Adherence to 5 clinical and laboratory measures recommended by Endocrine Society guidelines was higher after TOT implementation, indicating improved prescribing practices.⁴

The requirement for TOT completion before testosterone prescription and its management by trained pharmacists likely contributed to higher adherence to guideline recommendations than previously reported. Integration of the TOT into CPRS with pharmacy oversight may have enhanced adherence by summarizing and codifying evidence-based guideline recommendations for clinical and biochemical evaluation prior to TRT initiation, offering relevant education to clinicians and pharmacists, automatically importing pertinent clinical information and laboratory results, and generating CPRS documentation to reduce clinician burden during patient care. 

The proportion of patients with documented signs and symptoms of testosterone deficiency before TRT increased from the pretemplate period (71%) to the posttemplate period (93%), indicating that most patients receiving TRT had clinical manifestations of hypogonadism. This aligns with Endocrine Society guidelines, which define hypogonadism as a clinical disorder characterized by clinical manifestations of testosterone deficiency and persistently low serum testosterone levels on ≥ 2 separate occasions.^4,6 However, recent trends in direct-to-consumer advertising for testosterone and the rise of “low T” clinics may contribute to increased testing, varied practices, and inappropriate testosterone therapy initiation (eg, in men with low testosterone levels who lack symptoms of hypogonadism).¹⁸ Improved adherence in documenting clinical hypogonadism with implementation of the TOT reinforces the value of incorporating educational material, as previously reported.¹¹

Adherence to guideline recommendations following implementation of the TOT in this project was higher than those previously reported. In a study of 111,631 outpatient veterans prescribed testosterone from 2009 to 2012, only 18.3% had ≥ 2 testosterone prescriptions, and 3.5% had ≥ 2 testosterone, LH, and FSH levels measured prior to the initiation of a TRT.⁹ In a report of 63,534 insured patients who received TRT from 2010 to 2012, 40.3% had ≥ 2 testosterone prescriptions, and 12% had LH and/or FSH measured prior to the initiation.⁸

Low rates of guideline-recommended laboratory tests prior to initiation of testosterone treatment were reported in prior non-VA studies.^19,20 Poor guideline adherence reinforces the need for clinician education or other methods to improve TRT and ensure appropriate prescribing practices across health care systems. The TOT described in this project is a sustainable clinical tool with the potential to improve testosterone prescribing practices. 

The high rates of adherence to guideline recommendations at VAPSHCS likely stem from local endocrine expertise and ongoing educational initiatives, as well as the requirement for template completion before testosterone prescription. However, most testosterone prescriptions were initiated by primary care and monitored by pharmacists with varying degrees of training and clinical experience in hypogonadism and TRT.

However, adherence to guideline recommendations was modest, suggesting there is still an opportunity for improvement. The decision to initiate therapy should be made only after appropriate counseling with patients regarding its potential benefits and risks. Reports on the CV risk of TRT have been mixed. The 2023 TRAVERSE study found no increase in major adverse CV events among older men with hypogonadism and pre-existing CV risks undergoing TRT, but noted higher instances of pulmonary embolism, atrial fibrillation, and acute kidney injury.²¹ This highlights the need for clinicians to continue to engage in informed decision-making with patients. Effective pretreatment counseling is important but time-consuming; future TOT monitoring and modifications could consider mandatory checkboxes to document counseling on TRT risks and benefits.

The TOT described in this study could be adapted and incorporated into the prescribing process and electronic health record of larger health care systems. Use of an electronic template allows for automatic real-time dashboard monitoring of organization performance. The TOT described could be modified or simplified for specialty or primary care clinics or individual practitioners to improve adherence to evidence-based guideline recommendations and quality of care.

Strengths

A strength of this study is the multidisciplinary team (composed of stakeholders with experience in VA health care system and subject matter experts in hypogonadism) that developed and incorporated a user-friendly template for testosterone prescriptions; the use of evidence-based guideline recommendations; and the use of a structured chart review permitted accurate assessment of adherence to recommendations to document signs and symptoms of testosterone deficiency and a discussion of potential risks and benefits prior to TRT. To our knowledge, these recommendations have not been assessed in previous reports.

Limitations

The retrospective pre-post design of this study precludes a conclusion that implementation of the TOT caused the increase in adherence to guideline recommendations. Improved adherence could have resulted from the ongoing development of the preauthorization process for testosterone prescriptions or other changes over time. However, the preauthorization process had already been established for many years prior to template implementation. Forty-nine patients had new prescriptions for testosterone in the posttemplate period compared to 91 in the pretemplate period, but TRT was initiated in accordance with guideline recommendations more appropriately in the posttemplate period. The study’s sample size was small, and many eligible patients were excluded; however, exclusions were necessary to evaluate men who had new testosterone prescriptions for which the template was designed. Most men excluded were already taking testosterone.

Conclusions

The implementation of a CPRS-based TOT improved adherence to evidence-based guidelines for the diagnosis, evaluation, and counseling of patients with hypogonadism before starting TRT. While there were improvements in adherence with the TOT, the relatively low proportion of patients with documentation of TRT risks and benefits and all guideline recommendations highlights the need for additional efforts to further strengthen adherence to guideline recommendations and ensure appropriate evaluation, counseling, and prescribing practices before initiating TRT.

Posttraumatic stress disorder (PTSD) guidelines increasingly are recommending prolonged exposure therapy (PET) and cognitive processing therapy (CPT) as first-line treatments, including the 2023 US Department of Veterans Affairs (VA) and US Department of Defense clinical practice guideline.

Since 2006, > 6000 VA therapists have been trained in PET and CPT; the VA requires all veterans to have access to these treatments. However, despite strong clinical trial evidence supporting PET and CPT for the treatment of PTSD, a 2023 study found that only 11.6% of veterans who received a PTSD diagnosis between 2017 and 2019 initiated Trauma-Focused Evidence-Based Psychotherapy (TF-EBP) in their first year of treatment. Of those who initiated TF-EBP, 67% dropped out. Recent VA programs have attempted to expand the reach of PET with video telehealth to reach rural and remote veterans through virtual group programs.

Recent research has suggested ways to maximize the effectiveness of the programs and assist veterans in receiving the full benefits. Studies have found that swapping traditional longer-term treatments (usually spanning 8 to 15 weeks) for intensified, shorter versions (eg, 6 sessions) may enhance engagement and retention. 

Intensive PET for PTSD is safe and highly effective. A study involving patients with chronic PTSD and complex trauma showed significant reductions in PTSD symptom severity, with large effect sizes and sustained improvements at 3 and 6 months. Multiple 90-minute sessions over consecutive days, supplemented with in vivo exposure or followed by weekly booster sessions, were found to minimize treatment disruptions.

PET is among the most extensively studied treatments for PTSD and is supported by dozens of clinical trials involving thousands of patients. The intervention was originally developed and validated in civilian samples and includes psychoeducation, relaxation through breathing retraining, and in vivo and imaginal exposure to traumatic memories.

A recent study compared treatment outcomes among military veterans and civilian patients receiving treatment in a community setting. Although some studies have compared PET outcomes for military veterans and civilian participants in community settings, none have directly compared outcomes across trauma type (combat, terror, or civilian trauma) and veteran status (military vs civilian) within the same framework. The study notes that combat-related trauma significantly differs from other forms of trauma exposure, as it is typically more prolonged and severe and therefore is more often resistant to treatment. Military personnel also often find themselves both victims and aggressors, a duality that can intensify guilt, shame, anger, disgust, and emotional reactions to moral injury, complicating treatment. 

The study assessed the effects of 8 to 15 PET sessions on PTSD symptoms in 55 civilians and 43 veterans using the PTSD Symptom Scale–Interview Version (PSS-I). Participants showed significant symptom reductions across all trauma types and veteran statuses.

Although veterans and participants in the combat trauma subgroup showed higher levels of baseline symptom severity compared with civilians, all groups experienced similar symptom reductions. These findings differ from some meta-analyses, which have found that PET often produces smaller effect sizes in combat-related PTSD compared to civilian trauma samples.

The study compared treatment outcomes across different groups within the same treatment centers and under consistent supervision. The PET intervention was delivered in community mental health centers to all patients regardless of background. Only 2 prior studies have compared civilian and military veterans within the same locations.

Although the “traditional” number of PET sessions produce evidence-based outcomes, high dropout rates and relapses have catalyzed interest in approaches that boost the power of therapy, such as delivering PET in ever-shorter sequences. 

A study in a Swedish psychiatric outpatient clinic compared the effect of an 8-day intensified treatment program with traditionally spaced treatments on 101 participants with PTSD or complex PTSD. The study reported a significant reduction in PTSD symptoms at posttreatment, with large effect sizes in both conditions. Moreover, symptom reduction was maintained at follow-up. Dropout rates were significantly different between treatment groups: 4.3% in the intensified treatment program and 24.1% in the traditional group.

Another study used VA administrative data to assess the impact of sequenced psychotherapy (≥ 8 sessions of not trauma-focused individual or group psychotherapy delivered before trauma-focused care) on initiation and retention in CPT and PET over 2 years. Roughly 13% of 490,097 veterans who entered care for PTSD between 2014 and 2020 initiated VA-disseminated evidence-based treatment within 21 months (9.5% CPT, 3.4% PE). Among those who initiated treatment, retention was 46% and 42%, respectively. Individual therapy was associated with increased CPT and PET retention of 8.0% and 8.2%. For group therapy, retention increases were 3.4% and 8.7%. 

Another recent study examined the RESET (Reconsolidation, Exposure, and Short-term Emotional Transformation) clinical protocol, an intensive, structured trauma-focused intervention designed to treat PTSD within 6 daily sessions. The protocol includes psychoeducation, targeted exposure, dynamic case formulation, and guided trauma processing. This novel framework ensures therapy moves beyond symptom reduction, fostering a deep understanding of the patient’s core struggles and their broader psychological patterns, and integrates it with the reconsolidation of the index trauma narrative to form a more cohesive sense of self.” 

Clinical studies are ongoing to refine and enhance PET and CPT. They may serve to make therapy more useful and effective in easing—maybe erasing—veterans’ traumatic memories.

Posttraumatic stress disorder (PTSD) guidelines increasingly are recommending prolonged exposure therapy (PET) and cognitive processing therapy (CPT) as first-line treatments, including the 2023 US Department of Veterans Affairs (VA) and US Department of Defense clinical practice guideline.

Since 2006, > 6000 VA therapists have been trained in PET and CPT; the VA requires all veterans to have access to these treatments. However, despite strong clinical trial evidence supporting PET and CPT for the treatment of PTSD, a 2023 study found that only 11.6% of veterans who received a PTSD diagnosis between 2017 and 2019 initiated Trauma-Focused Evidence-Based Psychotherapy (TF-EBP) in their first year of treatment. Of those who initiated TF-EBP, 67% dropped out. Recent VA programs have attempted to expand the reach of PET with video telehealth to reach rural and remote veterans through virtual group programs.

Recent research has suggested ways to maximize the effectiveness of the programs and assist veterans in receiving the full benefits. Studies have found that swapping traditional longer-term treatments (usually spanning 8 to 15 weeks) for intensified, shorter versions (eg, 6 sessions) may enhance engagement and retention. 

Intensive PET for PTSD is safe and highly effective. A study involving patients with chronic PTSD and complex trauma showed significant reductions in PTSD symptom severity, with large effect sizes and sustained improvements at 3 and 6 months. Multiple 90-minute sessions over consecutive days, supplemented with in vivo exposure or followed by weekly booster sessions, were found to minimize treatment disruptions.

PET is among the most extensively studied treatments for PTSD and is supported by dozens of clinical trials involving thousands of patients. The intervention was originally developed and validated in civilian samples and includes psychoeducation, relaxation through breathing retraining, and in vivo and imaginal exposure to traumatic memories.

A recent study compared treatment outcomes among military veterans and civilian patients receiving treatment in a community setting. Although some studies have compared PET outcomes for military veterans and civilian participants in community settings, none have directly compared outcomes across trauma type (combat, terror, or civilian trauma) and veteran status (military vs civilian) within the same framework. The study notes that combat-related trauma significantly differs from other forms of trauma exposure, as it is typically more prolonged and severe and therefore is more often resistant to treatment. Military personnel also often find themselves both victims and aggressors, a duality that can intensify guilt, shame, anger, disgust, and emotional reactions to moral injury, complicating treatment. 

The study assessed the effects of 8 to 15 PET sessions on PTSD symptoms in 55 civilians and 43 veterans using the PTSD Symptom Scale–Interview Version (PSS-I). Participants showed significant symptom reductions across all trauma types and veteran statuses.

Although veterans and participants in the combat trauma subgroup showed higher levels of baseline symptom severity compared with civilians, all groups experienced similar symptom reductions. These findings differ from some meta-analyses, which have found that PET often produces smaller effect sizes in combat-related PTSD compared to civilian trauma samples.

The study compared treatment outcomes across different groups within the same treatment centers and under consistent supervision. The PET intervention was delivered in community mental health centers to all patients regardless of background. Only 2 prior studies have compared civilian and military veterans within the same locations.

Although the “traditional” number of PET sessions produce evidence-based outcomes, high dropout rates and relapses have catalyzed interest in approaches that boost the power of therapy, such as delivering PET in ever-shorter sequences. 

A study in a Swedish psychiatric outpatient clinic compared the effect of an 8-day intensified treatment program with traditionally spaced treatments on 101 participants with PTSD or complex PTSD. The study reported a significant reduction in PTSD symptoms at posttreatment, with large effect sizes in both conditions. Moreover, symptom reduction was maintained at follow-up. Dropout rates were significantly different between treatment groups: 4.3% in the intensified treatment program and 24.1% in the traditional group.

Another study used VA administrative data to assess the impact of sequenced psychotherapy (≥ 8 sessions of not trauma-focused individual or group psychotherapy delivered before trauma-focused care) on initiation and retention in CPT and PET over 2 years. Roughly 13% of 490,097 veterans who entered care for PTSD between 2014 and 2020 initiated VA-disseminated evidence-based treatment within 21 months (9.5% CPT, 3.4% PE). Among those who initiated treatment, retention was 46% and 42%, respectively. Individual therapy was associated with increased CPT and PET retention of 8.0% and 8.2%. For group therapy, retention increases were 3.4% and 8.7%. 

Another recent study examined the RESET (Reconsolidation, Exposure, and Short-term Emotional Transformation) clinical protocol, an intensive, structured trauma-focused intervention designed to treat PTSD within 6 daily sessions. The protocol includes psychoeducation, targeted exposure, dynamic case formulation, and guided trauma processing. This novel framework ensures therapy moves beyond symptom reduction, fostering a deep understanding of the patient’s core struggles and their broader psychological patterns, and integrates it with the reconsolidation of the index trauma narrative to form a more cohesive sense of self.” 

Clinical studies are ongoing to refine and enhance PET and CPT. They may serve to make therapy more useful and effective in easing—maybe erasing—veterans’ traumatic memories.

Posttraumatic stress disorder (PTSD) guidelines increasingly are recommending prolonged exposure therapy (PET) and cognitive processing therapy (CPT) as first-line treatments, including the 2023 US Department of Veterans Affairs (VA) and US Department of Defense clinical practice guideline.

Since 2006, > 6000 VA therapists have been trained in PET and CPT; the VA requires all veterans to have access to these treatments. However, despite strong clinical trial evidence supporting PET and CPT for the treatment of PTSD, a 2023 study found that only 11.6% of veterans who received a PTSD diagnosis between 2017 and 2019 initiated Trauma-Focused Evidence-Based Psychotherapy (TF-EBP) in their first year of treatment. Of those who initiated TF-EBP, 67% dropped out. Recent VA programs have attempted to expand the reach of PET with video telehealth to reach rural and remote veterans through virtual group programs.

Recent research has suggested ways to maximize the effectiveness of the programs and assist veterans in receiving the full benefits. Studies have found that swapping traditional longer-term treatments (usually spanning 8 to 15 weeks) for intensified, shorter versions (eg, 6 sessions) may enhance engagement and retention. 

Intensive PET for PTSD is safe and highly effective. A study involving patients with chronic PTSD and complex trauma showed significant reductions in PTSD symptom severity, with large effect sizes and sustained improvements at 3 and 6 months. Multiple 90-minute sessions over consecutive days, supplemented with in vivo exposure or followed by weekly booster sessions, were found to minimize treatment disruptions.

PET is among the most extensively studied treatments for PTSD and is supported by dozens of clinical trials involving thousands of patients. The intervention was originally developed and validated in civilian samples and includes psychoeducation, relaxation through breathing retraining, and in vivo and imaginal exposure to traumatic memories.

A recent study compared treatment outcomes among military veterans and civilian patients receiving treatment in a community setting. Although some studies have compared PET outcomes for military veterans and civilian participants in community settings, none have directly compared outcomes across trauma type (combat, terror, or civilian trauma) and veteran status (military vs civilian) within the same framework. The study notes that combat-related trauma significantly differs from other forms of trauma exposure, as it is typically more prolonged and severe and therefore is more often resistant to treatment. Military personnel also often find themselves both victims and aggressors, a duality that can intensify guilt, shame, anger, disgust, and emotional reactions to moral injury, complicating treatment. 

The study assessed the effects of 8 to 15 PET sessions on PTSD symptoms in 55 civilians and 43 veterans using the PTSD Symptom Scale–Interview Version (PSS-I). Participants showed significant symptom reductions across all trauma types and veteran statuses.

Although veterans and participants in the combat trauma subgroup showed higher levels of baseline symptom severity compared with civilians, all groups experienced similar symptom reductions. These findings differ from some meta-analyses, which have found that PET often produces smaller effect sizes in combat-related PTSD compared to civilian trauma samples.

The study compared treatment outcomes across different groups within the same treatment centers and under consistent supervision. The PET intervention was delivered in community mental health centers to all patients regardless of background. Only 2 prior studies have compared civilian and military veterans within the same locations.

Although the “traditional” number of PET sessions produce evidence-based outcomes, high dropout rates and relapses have catalyzed interest in approaches that boost the power of therapy, such as delivering PET in ever-shorter sequences. 

A study in a Swedish psychiatric outpatient clinic compared the effect of an 8-day intensified treatment program with traditionally spaced treatments on 101 participants with PTSD or complex PTSD. The study reported a significant reduction in PTSD symptoms at posttreatment, with large effect sizes in both conditions. Moreover, symptom reduction was maintained at follow-up. Dropout rates were significantly different between treatment groups: 4.3% in the intensified treatment program and 24.1% in the traditional group.

Another study used VA administrative data to assess the impact of sequenced psychotherapy (≥ 8 sessions of not trauma-focused individual or group psychotherapy delivered before trauma-focused care) on initiation and retention in CPT and PET over 2 years. Roughly 13% of 490,097 veterans who entered care for PTSD between 2014 and 2020 initiated VA-disseminated evidence-based treatment within 21 months (9.5% CPT, 3.4% PE). Among those who initiated treatment, retention was 46% and 42%, respectively. Individual therapy was associated with increased CPT and PET retention of 8.0% and 8.2%. For group therapy, retention increases were 3.4% and 8.7%. 

Another recent study examined the RESET (Reconsolidation, Exposure, and Short-term Emotional Transformation) clinical protocol, an intensive, structured trauma-focused intervention designed to treat PTSD within 6 daily sessions. The protocol includes psychoeducation, targeted exposure, dynamic case formulation, and guided trauma processing. This novel framework ensures therapy moves beyond symptom reduction, fostering a deep understanding of the patient’s core struggles and their broader psychological patterns, and integrates it with the reconsolidation of the index trauma narrative to form a more cohesive sense of self.” 

Clinical studies are ongoing to refine and enhance PET and CPT. They may serve to make therapy more useful and effective in easing—maybe erasing—veterans’ traumatic memories.

“Moral and mortal stressors may be intertwined in their contribution to the complex symptomatic outcomes” of combat exposure according to a recent study in the European Journal of Psychotraumatology. The study examined the effect moral injury has on Israel Defense Forces (IDF) combat veterans. The resulting trauma may be consolidated in a single category, such as posttraumatic stress disorder (PTSD), but stressors leading to that diagnosis may have been quite different. Properly defining the stressors to assist in better targeted treatment is a challenge.

Moral injury is the emotional distress of being involved in or witnessing actions that conflict with deeply held beliefs. Such experiences could be committing or failing to prevent a transgressive act or learning about or surviving a transgressive act.

The study defines moral injury outcomes as the psychological and emotional consequences that result from exposure to potentially morally injurious events (PMIEs): “This terminology is intended to distinguish the outcomes of moral injury from the broader and sometimes ambiguous use of ‘moral injury’ in the literature, which can refer to either the event, the experience, or the resulting symptoms.”

The study followed 374 male combat veterans for 5 years. Veterans served in the Israel Defense Forces (IDF) in 4 primary combat roles: infantry, armored corps, special forces, and combat engineering. Psychological characteristics were measured 12 months prior to enlistment. PMIE exposure was measured during the final month of military service using the Moral Injury Events Scale. Moral injury outcomes were assessed 6 months postdischarge using the Expressions of Moral Injury Scale-Military Version-Short Form. Posttraumatic stress symptom (PTSS) clusters were evaluated 1 year postdischarge using the PTSD Checklist for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 

Nearly half (49%) of participants reported exposure to PMIEs, while 8% met criteria for probable PTSD. The researchers say elevated PMIE rates observed in their sample may be attributed, in part, to participants’ extended deployments in densely populated urban areas, carrying out operations in close proximity to civilians, where it is difficult to distinguish between combatants and noncombatants. PTSD rates were somewhat lower than those reported in US studies (10% to 30%) among veterans; this may be attributed to the cohort not being engaged in a full-scale war, but deployed mostly in peacekeeping missions.

Longitudinal studies have described the effects of wartime atrocities on PTSD symptom severity. Studies have also linked moral injury outcomes and PTSS clusters (including negative alterations in cognition and mood [NACM]), depression, anxiety, and substance abuse. PMIEs can also include perceptions of betrayal from leaders, colleagues, or trusted others. The study of 374 male combat veterans found a direct effect of PMIE-betrayal on arousal and reactivity as well as NACM clusters. Results also showed indirect associations between exposure to all PMIE dimensions and PTSS clusters via moral injury outcomes. Combat exposure and experiencing PMIEs during military service significantly contributed to the emergence of PTSS during the first year after discharge. The study found 2 distinct paths PMIEs may lead to PTSS among veterans: experiencing acts of transgression and encountering betrayal. 

Betrayal has been linked to feelings of anger and humiliation, emotions thought to have evolved to trigger adaptive behavioral responses, such as aggression and revenge, to threats or transgressions by others. PMIE-betrayal also demonstrated direct effects on the arousal and reactivity and NACM symptom clusters, suggesting partial mediation. Another study (also on IDF veterans) found significant positive correlations between PMIE-betrayal and the NACM cluster, suggesting PMIE-betrayal as a link between PTSD and moral injury. While the link between betrayal and NACM is readily apparent, its connection to arousal and reactivity, a fear-based physiological symptom, is less evident. 

The findings of the study point to the need for assessment tools that separately measure exposure to PMIEs and individual reactions to them. A recent Federal Practitioner study of 100 veterans with a history of incarceration completed the Moral Injury Events Scale and an adapted version for legal-involved persons (MIES-LIP). The authors found that MIES-LIP demonstrated strong psychometric properties, including good reliability and convergent validity for legal-related moral injury.

The study cites a recent review of cognitive-behavioral psychotherapies for individuals experiencing moral injury that challenges the adequacy of existing evidence-based treatments for PTSD for addressing moral injury and its associated symptoms. It is important to evaluate individuals who express feelings of betrayal with tailored, evidence-based interventions such as adaptive disclosure or cognitive-processing therapy. Acceptance and commitment therapy may also help individuals experiencing emotions such as shame, humiliation, guilt, and anger following morally injurious events.

Newer therapy models like Multi-Modal Motion-Assisted Memory Desensitization and Reconsolidation allow clinicians to use personalized trauma cues to facilitate memory processing, reduce avoidance, and aid in emotional reconsolidation. Clinical research has demonstrated this model’s efficacy in reducing PTSD symptoms, depression, and anxiety, with high acceptability and low dropout rates among military personnel, veterans, and first responders.

Regardless of the treatment, the researchers encourage mental health professionals to approach veterans seeking help with the “utmost sensitivity and attentiveness to any expressions of (moral injury) outcomes.”

“Moral and mortal stressors may be intertwined in their contribution to the complex symptomatic outcomes” of combat exposure according to a recent study in the European Journal of Psychotraumatology. The study examined the effect moral injury has on Israel Defense Forces (IDF) combat veterans. The resulting trauma may be consolidated in a single category, such as posttraumatic stress disorder (PTSD), but stressors leading to that diagnosis may have been quite different. Properly defining the stressors to assist in better targeted treatment is a challenge.

Moral injury is the emotional distress of being involved in or witnessing actions that conflict with deeply held beliefs. Such experiences could be committing or failing to prevent a transgressive act or learning about or surviving a transgressive act.

The study defines moral injury outcomes as the psychological and emotional consequences that result from exposure to potentially morally injurious events (PMIEs): “This terminology is intended to distinguish the outcomes of moral injury from the broader and sometimes ambiguous use of ‘moral injury’ in the literature, which can refer to either the event, the experience, or the resulting symptoms.”

The study followed 374 male combat veterans for 5 years. Veterans served in the Israel Defense Forces (IDF) in 4 primary combat roles: infantry, armored corps, special forces, and combat engineering. Psychological characteristics were measured 12 months prior to enlistment. PMIE exposure was measured during the final month of military service using the Moral Injury Events Scale. Moral injury outcomes were assessed 6 months postdischarge using the Expressions of Moral Injury Scale-Military Version-Short Form. Posttraumatic stress symptom (PTSS) clusters were evaluated 1 year postdischarge using the PTSD Checklist for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 

Nearly half (49%) of participants reported exposure to PMIEs, while 8% met criteria for probable PTSD. The researchers say elevated PMIE rates observed in their sample may be attributed, in part, to participants’ extended deployments in densely populated urban areas, carrying out operations in close proximity to civilians, where it is difficult to distinguish between combatants and noncombatants. PTSD rates were somewhat lower than those reported in US studies (10% to 30%) among veterans; this may be attributed to the cohort not being engaged in a full-scale war, but deployed mostly in peacekeeping missions.

Longitudinal studies have described the effects of wartime atrocities on PTSD symptom severity. Studies have also linked moral injury outcomes and PTSS clusters (including negative alterations in cognition and mood [NACM]), depression, anxiety, and substance abuse. PMIEs can also include perceptions of betrayal from leaders, colleagues, or trusted others. The study of 374 male combat veterans found a direct effect of PMIE-betrayal on arousal and reactivity as well as NACM clusters. Results also showed indirect associations between exposure to all PMIE dimensions and PTSS clusters via moral injury outcomes. Combat exposure and experiencing PMIEs during military service significantly contributed to the emergence of PTSS during the first year after discharge. The study found 2 distinct paths PMIEs may lead to PTSS among veterans: experiencing acts of transgression and encountering betrayal. 

Betrayal has been linked to feelings of anger and humiliation, emotions thought to have evolved to trigger adaptive behavioral responses, such as aggression and revenge, to threats or transgressions by others. PMIE-betrayal also demonstrated direct effects on the arousal and reactivity and NACM symptom clusters, suggesting partial mediation. Another study (also on IDF veterans) found significant positive correlations between PMIE-betrayal and the NACM cluster, suggesting PMIE-betrayal as a link between PTSD and moral injury. While the link between betrayal and NACM is readily apparent, its connection to arousal and reactivity, a fear-based physiological symptom, is less evident. 

The findings of the study point to the need for assessment tools that separately measure exposure to PMIEs and individual reactions to them. A recent Federal Practitioner study of 100 veterans with a history of incarceration completed the Moral Injury Events Scale and an adapted version for legal-involved persons (MIES-LIP). The authors found that MIES-LIP demonstrated strong psychometric properties, including good reliability and convergent validity for legal-related moral injury.

The study cites a recent review of cognitive-behavioral psychotherapies for individuals experiencing moral injury that challenges the adequacy of existing evidence-based treatments for PTSD for addressing moral injury and its associated symptoms. It is important to evaluate individuals who express feelings of betrayal with tailored, evidence-based interventions such as adaptive disclosure or cognitive-processing therapy. Acceptance and commitment therapy may also help individuals experiencing emotions such as shame, humiliation, guilt, and anger following morally injurious events.

Newer therapy models like Multi-Modal Motion-Assisted Memory Desensitization and Reconsolidation allow clinicians to use personalized trauma cues to facilitate memory processing, reduce avoidance, and aid in emotional reconsolidation. Clinical research has demonstrated this model’s efficacy in reducing PTSD symptoms, depression, and anxiety, with high acceptability and low dropout rates among military personnel, veterans, and first responders.

Regardless of the treatment, the researchers encourage mental health professionals to approach veterans seeking help with the “utmost sensitivity and attentiveness to any expressions of (moral injury) outcomes.”

“Moral and mortal stressors may be intertwined in their contribution to the complex symptomatic outcomes” of combat exposure according to a recent study in the European Journal of Psychotraumatology. The study examined the effect moral injury has on Israel Defense Forces (IDF) combat veterans. The resulting trauma may be consolidated in a single category, such as posttraumatic stress disorder (PTSD), but stressors leading to that diagnosis may have been quite different. Properly defining the stressors to assist in better targeted treatment is a challenge.

Moral injury is the emotional distress of being involved in or witnessing actions that conflict with deeply held beliefs. Such experiences could be committing or failing to prevent a transgressive act or learning about or surviving a transgressive act.

The study defines moral injury outcomes as the psychological and emotional consequences that result from exposure to potentially morally injurious events (PMIEs): “This terminology is intended to distinguish the outcomes of moral injury from the broader and sometimes ambiguous use of ‘moral injury’ in the literature, which can refer to either the event, the experience, or the resulting symptoms.”

The study followed 374 male combat veterans for 5 years. Veterans served in the Israel Defense Forces (IDF) in 4 primary combat roles: infantry, armored corps, special forces, and combat engineering. Psychological characteristics were measured 12 months prior to enlistment. PMIE exposure was measured during the final month of military service using the Moral Injury Events Scale. Moral injury outcomes were assessed 6 months postdischarge using the Expressions of Moral Injury Scale-Military Version-Short Form. Posttraumatic stress symptom (PTSS) clusters were evaluated 1 year postdischarge using the PTSD Checklist for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. 

Nearly half (49%) of participants reported exposure to PMIEs, while 8% met criteria for probable PTSD. The researchers say elevated PMIE rates observed in their sample may be attributed, in part, to participants’ extended deployments in densely populated urban areas, carrying out operations in close proximity to civilians, where it is difficult to distinguish between combatants and noncombatants. PTSD rates were somewhat lower than those reported in US studies (10% to 30%) among veterans; this may be attributed to the cohort not being engaged in a full-scale war, but deployed mostly in peacekeeping missions.

Longitudinal studies have described the effects of wartime atrocities on PTSD symptom severity. Studies have also linked moral injury outcomes and PTSS clusters (including negative alterations in cognition and mood [NACM]), depression, anxiety, and substance abuse. PMIEs can also include perceptions of betrayal from leaders, colleagues, or trusted others. The study of 374 male combat veterans found a direct effect of PMIE-betrayal on arousal and reactivity as well as NACM clusters. Results also showed indirect associations between exposure to all PMIE dimensions and PTSS clusters via moral injury outcomes. Combat exposure and experiencing PMIEs during military service significantly contributed to the emergence of PTSS during the first year after discharge. The study found 2 distinct paths PMIEs may lead to PTSS among veterans: experiencing acts of transgression and encountering betrayal. 

Betrayal has been linked to feelings of anger and humiliation, emotions thought to have evolved to trigger adaptive behavioral responses, such as aggression and revenge, to threats or transgressions by others. PMIE-betrayal also demonstrated direct effects on the arousal and reactivity and NACM symptom clusters, suggesting partial mediation. Another study (also on IDF veterans) found significant positive correlations between PMIE-betrayal and the NACM cluster, suggesting PMIE-betrayal as a link between PTSD and moral injury. While the link between betrayal and NACM is readily apparent, its connection to arousal and reactivity, a fear-based physiological symptom, is less evident. 

The findings of the study point to the need for assessment tools that separately measure exposure to PMIEs and individual reactions to them. A recent Federal Practitioner study of 100 veterans with a history of incarceration completed the Moral Injury Events Scale and an adapted version for legal-involved persons (MIES-LIP). The authors found that MIES-LIP demonstrated strong psychometric properties, including good reliability and convergent validity for legal-related moral injury.

The study cites a recent review of cognitive-behavioral psychotherapies for individuals experiencing moral injury that challenges the adequacy of existing evidence-based treatments for PTSD for addressing moral injury and its associated symptoms. It is important to evaluate individuals who express feelings of betrayal with tailored, evidence-based interventions such as adaptive disclosure or cognitive-processing therapy. Acceptance and commitment therapy may also help individuals experiencing emotions such as shame, humiliation, guilt, and anger following morally injurious events.

Newer therapy models like Multi-Modal Motion-Assisted Memory Desensitization and Reconsolidation allow clinicians to use personalized trauma cues to facilitate memory processing, reduce avoidance, and aid in emotional reconsolidation. Clinical research has demonstrated this model’s efficacy in reducing PTSD symptoms, depression, and anxiety, with high acceptability and low dropout rates among military personnel, veterans, and first responders.

Regardless of the treatment, the researchers encourage mental health professionals to approach veterans seeking help with the “utmost sensitivity and attentiveness to any expressions of (moral injury) outcomes.”

Screening for colorectal cancer (CRC) with colonoscopy enables the identification and removal of CRC precursors (colonic adenomas) and has been associated with reduced risk of CRC incidence and mortality.^1-3 Furthermore, there is consensus that diet and lifestyle may be associated with forestalling CRC pathogenesis at the intermediate adenoma stages.^4-7 However, studies have shown that US veterans have poorer diet quality and a higher risk for neoplasia compared with nonveterans, reinforcing the need for tailored clinical approaches.^8,9 Combining screening with conversations about modifiable environmental and lifestyle risk factors, such as poor diet, is a highly relevant and possibly easily leveraged prevention for those at high risk. However, there is limited evidence for any particular dietary patterns or dietary features that are most important over time.⁷

Several dietary components have been shown to be associated with CRC risk,10 either as potentially chemopreventive (fiber, fruits and vegetables,¹¹ dairy,¹² supplemental vitamin D,¹³ calcium,¹⁴ and multivitamins¹⁵) or carcinogenic (red meat¹⁶ and alcohol¹⁷). Previous studies of veterans have similarly shown that higher intake of fiber and vitamin D reduced risk, and red meat is associated with an increased risk for finding CRC precursors during colonoscopy.¹⁸ However, these dietary categories are often analyzed in isolation. Studying healthy dietary patterns in aggregate may be more clinically relevant and easier to implement for prevention of CRC and its precursors.^19-21 Healthy dietary patterns, such as the US Dietary Guidelines for Americans represented by the Healthy Eating Index (HEI), the Mediterranean diet (MD), and the Dietary Approaches to Stop Hypertension (DASH) diet, have been associated with lower risk for chronic disease.^22-24 Despite the extant literature, no known studies have compared these dietary patterns for associations with risk of CRC precursor or CRC development among US veterans undergoing long-term screening and follow-up after a baseline colonoscopy.

The objective of this study was to test for associations between baseline scores of healthy dietary patterns and the most severe colonoscopy findings (MSCFs) over ≥ 10 years following a baseline screening colonoscopy in veterans.

Methods

Participants in the Cooperative Studies Program (CSP) #380 cohort study included 3121 asymptomatic veterans aged 50 to 75 years at baseline who had consented to initial screening colonoscopy between 1994 and 1997, with subsequent follow-up and surveillance.²⁵ Prior to their colonoscopy, all participants completed a baseline study survey that included questions about cancer risk factors including family history of CRC, diet, physical activity, and medication use.

Included in this cross-sectional analysis were data from a sample of veteran participants of the CSP #380 cohort with 1 baseline colonoscopy, follow-up surveillance through 2009, a cancer risk factor survey collected at baseline, and complete demographic and clinical indicator data. Excluded from the analysis were 67 participants with insufficient responses to the dietary food frequency questionnaire (FFQ) and 31 participants with missing body mass index (BMI), 3023 veterans.

Measures

MSCF. The outcome of interest in this study was the MSCF recorded across all participant colonoscopies during the study period. MSCF was categorized as either (1) no neoplasia; (2) < 2 nonadvanced adenomas, including small adenomas (diameter < 10 mm) with tubular histology; or (3) advanced neoplasia (AN), which is characterized by adenomas > 10 mm in diameter, with villous histology, with high-grade dysplasia, or CRC.

Dietary patterns. Dietary pattern scores representing dietary quality and calculated based on recommendations of the US Dietary Guidelines for Americans using the HEI, MD, and DASH diets were independent variables.^26-28 These 3 dietary patterns were chosen for their hypothesized relationship with CRC risk, but each weighs food categories differently (Appendix 1).^22-24,29 Dietary pattern scores were calculated using the CSP #380 self-reported responses to 129 baseline survey questions adapted from a well-established and previously validated semiquantitative FFQ.³⁰ The form was administered by mail twice to a sample of 127 participants at baseline and at 1 year. During this interval, men completed 1-week diet records twice, spaced about 6 months apart. Mean values for intake of most nutrients assessed by the 2 methods were similar. Intraclass correlation coefficients for the baseline and 1-year FFQ-assessed nutrient intakes that ranged from 0.47 for vitamin E (without supplements) to 0.80 for vitamin C (with supplements). Correlation coefficients between the energy-adjusted nutrient intakes were measured by diet records and the 1-year FFQ, which asked about diet during the year encompassing the diet records. Higher raw and percent scores indicated better alignment with recommendations from each respective dietary pattern. Percent scores were calculated as a standardizing method and used in analyses for ease of comparing the dietary patterns. Scoring can be found in Appendix 2.

Demographic characteristics and clinical indicators. Demographic characteristics included age categories, sex, and race/ethnicity. Clinical indicators included BMI, the number of comorbid conditions used to calculate the Charlson Comorbidity Index, family history of CRC in first-degree relatives, number of follow-up colonoscopies across the study period, and food-based vitamin D intake.³¹ These variables were chosen for their applicability found in previous CSP #380 cohort studies.^18,32,33 Self-reported race and ethnicity were collapsed due to small numbers in some groups. The authors acknowledge these are distinct concepts and the variable has limited utility other than for controlling for systemic racism in the model.

Statistical Analyses

Descriptive statistics were used to describe distributional assumptions for all variables, including demographics, clinical indicators, colonoscopy results, and dietary patterns. Pairwise correlations between the total dietary pattern scores and food category scores were calculated with Pearson correlation (r).

Multinomial logistic regression models were created using SAS procedure LOGISTIC with the outcome of the categorical MSCF (no neoplasia, nonadvanced adenoma, or AN).³⁴ A model was created for each independent predictor variable of interest (ie, the HEI, MD, or DASH percentage-standardized dietary pattern score and each food category comprising each dietary pattern score). All models were adjusted for age, sex, race/ethnicity, BMI, number of comorbidities, family history of CRC, number of follow-up colonoscopies, and estimated daily food-derived vitamin D intake. The demographic and clinical indicators were included in the models as they are known to be associated with CRC risk.¹⁸ The number of colonoscopies was included to control for surveillance intensity presuming risk for AN is reduced as polyps are removed. Because colonoscopy findings from an initial screening have unique clinical implications compared with follow- up and surveillance, MSCF was observed in 2 ways in sensitivity analyses: (1) baseline and (2) aggregate follow-up and surveillance only, excluding baseline findings.

Adjusted odds ratios (aORs) and 95% CIs for each of the MSCF outcomes with a reference finding of no neoplasia for the models are presented. We chose not to adjust for multiple comparisons across the different dietary patterns given the correlation between dietary pattern total and category scores but did adjust for multiple comparisons for dietary categories within each dietary pattern. Tests for statistical significance used α= .05 for the dietary pattern total scores and P values for the dietary category scores for each dietary pattern controlled for false discovery rate using the MULTTEST SAS procedure.35 All data manipulations and analyses were performed using SAS version 9.4.

Results

The study included 3023 patients. All were aged 50 to 75 years, 2923 (96.7%) were male and 2532 (83.8%) were non-Hispanic White (Table 1). Most participants were overweight or obese (n = 2535 [83.8%]), 2024 (67.0%) had ≤ 2 comorbidities, and 2602 (86.1%) had no family history of CRC. The MSCF for 1628 patients (53.9%) was no neoplasia, 966 patients (32.0%) was nonadvanced adenoma, and 429 participants (14.2%) had AN.

Mean percent scores were 58.5% for HEI, 38.2% for MD, and 63.1% for the DASH diet, with higher percentages indicating greater alignment with the recommendations for each diet (Table 2). All 3 dietary patterns scores standardized to percentages were strongly and significantly correlated in pairwise comparisons: HEI:MD, r = 0.62 (P < .001); HEI:DASH, r = 0.60 (P < .001); and MD:DASH, r = 0.72 (P < .001). Likewise, food category scores were significantly correlated across dietary patterns. For example, whole grain and fiber values from each dietary score were strongly correlated in pairwise comparisons: HEI Whole Grain:MD Grain, r = 0.64 (P < .001); HEI Whole Grain:DASH Fiber, r = 0.71 (P < .001); and MD Grain:DASH Fiber, r = 0.70 (P < .001).

Associations between individual participants' dietary pattern scores and the outcome of their pooled MSCF from baseline screening and ≥ 10 years of surveillance are presented in Table 3. For each single-point increases in dietary pattern scores (reflecting better dietary quality), aORs for nonadvanced adenoma vs no neoplasia were slightly lower but not statistically significantly: HEI, aOR, 1.00 (95% CI, 0.99-1.01); MD, aOR, 0.98 (95% CI, 0.94-1.02); and DASH, aOR, 0.99 (95% CI, 0.99-1.00). aORs for AN vs no neoplasia were slightly lower for each dietary pattern assessed, and only the MD and DASH scores were significantly different from 1.00: HEI, aOR, 1.00 (95% CI, 0.99-1.01); MD, aOR, 0.95 (95% CI, 0.90-1.00); and DASH, aOR, 0.99 (95% CI, 0.98-1.00).

We observed lower odds for nonadvanced adenoma and AN among all these dietary patterns when there was greater alignment with the recommended intake of whole grains and fiber. In separate models conducted using food categories comprising the dietary patterns as independent variables and after correcting for multiple tests, higher scores for the HEI Refined Grain category were associated with higher odds for nonadvanced adenoma (aOR, 1.03 [95% CI, 1.01-1.05]; P = .01) and AN (aOR, 1.05 [95% CI, 1.02-1.08]; P < .001). Higher scores for the HEI Whole Grain category were associated with lower odds for nonadvanced adenoma (aOR, 0.97 [95% CI, 0.95-0.99]; P = .01) and AN (aOR, 0.96 [95% CI, 0.93-0.99]; P = .01). Higher scores for the MD Grain category were significantly associated with lower odds for nonadvanced adenoma (aOR, 0.44 [95% CI, 0.26-0.75]; P = .002) and AN (aOR, 0.29 [95% CI, 0.14-0.62]; P = .001). The DASH Grains category also was significantly associated with lower odds for AN (aOR, 0.86 [95% CI, 0.78-0.95]; P = .002).

Discussion

In this study of 3023 veterans undergoing first-time screening colonoscopy and ≥ 10 years of surveillance, we found that healthy dietary patterns, as assessed by the MD and DASH diet, were significantly associated with lower risk of AN. Additionally, we identified lower odds for AN and nonadvanced adenoma compared with no neoplasia for higher grain scores for all the dietary patterns studied. Other food categories that comprise the dietary pattern scores had mixed associations with the MSCF outcomes. Several other studies have examined associations between dietary patterns and risk for CRC but to our knowledge, no studies have explored these associations among US veterans.

These results also indicate study participants had better than average (based on a 50% threshold) dietary quality according to the HEI and DASH diet scoring methods we used, but poor dietary quality according to the MD scoring method. The mean HEI scores for the present study were higher than a US Department of Agriculture study by Dong et al that compared dietary quality between veterans and nonveterans using the HEI, for which veterans’ expected HEI score was 45.6 of 100.⁸ This could be explained by the fact that the participants needed to be healthy to be eligible and those with healthier behaviors overall may have self-selected into the study due to motivation for screening during a time when screening was not yet commonplace. ³⁶ Similarly, participants of the present study had higher adherence to the DASH diet (63.1%) than adolescents with diabetes in a study by Günther et al. Conversely, firefighters who were coached to use a Mediterranean-style dietary pattern and dietary had higher adherence to MD than did participants in this study.²⁷

A closer examination of specific food category component scores that comprise the 3 distinct dietary patterns revealed mixed results from the multinomial modeling, which may have to do with the guideline thresholds used to calculate the dietary scores. When analyzed separately in the logistic regression models for their associations with nonadvanced adenomas and AN compared with no neoplasia, higher MD and DASH fruit scores (but not HEI fruit scores) were found to be significant. Other studies have had mixed findings when attempting to test for associations of fruit intake with adenoma recurrence.^10,37

This study had some unexpected findings. Vegetable intake was not associated with nonadvanced adenomas or AN risk. Studies of food categories have consistently found vegetable (specifically cruciferous ones) intake to be linked with lower odds for cancers.³⁸ Likewise, the red meat category, which was only a unique food category in the MD score, was not associated with nonadvanced adenomas or AN. Despite consistent literature suggesting higher intake of red meat and processed meats increases CRC risk, in 2019 the Nutritional Recommendations Consortium indicated that the evidence was weak.^39,40 This study showed higher DASH diet scores for low-fat dairy, which were maximized when participants reported at least 50% of their dairy servings per day as being low-fat, had lower odds for AN. Yet, the MD scores for low-fat dairy had no association with either outcome; their calculation was based on total number of servings per week. This difference in findings suggests the fat intake ratio may be more relevant to CRC risk than intake quantity.

The literature is mixed regarding fatty acid intake and CRC risk, which may be relevant to both dairy and meat intake. One systematic review and meta-analysis found dietary fat and types of fatty acid intake had no association with CRC risk.⁴¹ However, a more recent meta-analysis that assessed both dietary intake and plasma levels of fatty acids did find some statistically significant differences for various types of fatty acids and CRC risk.⁴²

The findings in the present study that grain intake is associated with lower odds for more severe colonoscopy findings among veterans are notable.⁴³ Lieberman et al, using the CSP #380 data, found that cereal fiber intake was associated with a lower odds for AN compared with hyperplastic polyps (OR, 0.98 [95% CI, 0.96- 1.00]).¹⁸ Similarly, Hullings et al determined that older adults in the highest quintile of cereal fiber intake had significantly lower odds of CRC than those in lower odds for CRC when compared with lowest quintile (OR, 0.89 [95% CI, 0.83- 0.96]; P < .001).⁴⁴ These findings support existing guidance that prioritizes whole grains as a key source of dietary fiber for CRC prevention.

A recent literature review on fiber, fat, and CRC risk suggested a consensus regarding one protective mechanism: dietary fiber from grains modulates the gut microbiota by promoting butyrate synthesis.⁴⁵ Butyrate is a short-chain fatty acid that supports energy production in colonocytes and has tumor-suppressing properties.⁴⁶ Our findings suggest there could be more to learn about the relationship between butyrate production and reduction of CRC risk through metabolomic studies that use measurements of plasma butyrate. These studies may examine associations between not just a singular food or food category, but rather food patterns that include fruits, vegetables, nuts and seeds, and whole grains known to promote butyrate production and plasma butyrate.⁴⁷

Improved understanding of mechanisms and risk-modifying lifestyle factors such as dietary patterns may enhance prevention strategies. Identifying the collective chemopreventive characteristics of a specific dietary pattern (eg, MD) will be helpful to clinicians and health care staff to promote healthy eating to reduce cancer risk. More studies are needed to understand whether such promotion is more clinically applicable and effective for patients, as compared with eating more or less of specific foods (eg, more whole grains, less red meat). Furthermore, considering important environmental factors collectively beyond dietary patterns may offer a way to better tailor screening and implement a variety of lifestyle interventions. In the literature, this is often referred to as a teachable moment when patients’ attentions are captured and may position them to be more receptive to guidance.⁴⁸

Limitations

This study has several important limitations and leaves opportunities for future studies that explore the role of dietary patterns and AN or CRC risk. First, the FFQ data used to calculate dietary pattern scores used in analysis were only captured at baseline, and there are nearly 3 decades across the study period. However, it is widely assumed that the diets of older adults, like those included in this study, remain stable over time which is appropriate given our sample population was aged 50 to 75 years when the baseline FFQ data were collected.^49-51 Additionally, while the HEI is a well-documented, standard scoring method for dietary quality, there are multitudes of dietary pattern scoring approaches for MD and DASH.^23,52,53 Finally, findings from this study using the sample of veterans may not be generalizable to a broader population. Future longitudinal studies that test for a clinically significant change threshold are warranted.

Conclusion

Results of this study suggest future research should further explore the effects of dietary patterns, particularly intake of specific food groups in combination, as opposed to individual nutrients or food items, on AN and CRC risk. Possible studies might explore these dietary patterns for their mechanistic role in altering the microbiome metabolism, which may influence CRC outcomes or include diet in a more comprehensive, holistic risk score that could be used to predict colonic neoplasia risk or in intervention studies that assess the effects of dietary changes on long-term CRC prevention. We suggest there are differences in people’s dietary intake patterns that might be important to consider when implementing tailored approaches to CRC risk mitigation.

Screening for colorectal cancer (CRC) with colonoscopy enables the identification and removal of CRC precursors (colonic adenomas) and has been associated with reduced risk of CRC incidence and mortality.^1-3 Furthermore, there is consensus that diet and lifestyle may be associated with forestalling CRC pathogenesis at the intermediate adenoma stages.^4-7 However, studies have shown that US veterans have poorer diet quality and a higher risk for neoplasia compared with nonveterans, reinforcing the need for tailored clinical approaches.^8,9 Combining screening with conversations about modifiable environmental and lifestyle risk factors, such as poor diet, is a highly relevant and possibly easily leveraged prevention for those at high risk. However, there is limited evidence for any particular dietary patterns or dietary features that are most important over time.⁷

Several dietary components have been shown to be associated with CRC risk,10 either as potentially chemopreventive (fiber, fruits and vegetables,¹¹ dairy,¹² supplemental vitamin D,¹³ calcium,¹⁴ and multivitamins¹⁵) or carcinogenic (red meat¹⁶ and alcohol¹⁷). Previous studies of veterans have similarly shown that higher intake of fiber and vitamin D reduced risk, and red meat is associated with an increased risk for finding CRC precursors during colonoscopy.¹⁸ However, these dietary categories are often analyzed in isolation. Studying healthy dietary patterns in aggregate may be more clinically relevant and easier to implement for prevention of CRC and its precursors.^19-21 Healthy dietary patterns, such as the US Dietary Guidelines for Americans represented by the Healthy Eating Index (HEI), the Mediterranean diet (MD), and the Dietary Approaches to Stop Hypertension (DASH) diet, have been associated with lower risk for chronic disease.^22-24 Despite the extant literature, no known studies have compared these dietary patterns for associations with risk of CRC precursor or CRC development among US veterans undergoing long-term screening and follow-up after a baseline colonoscopy.

The objective of this study was to test for associations between baseline scores of healthy dietary patterns and the most severe colonoscopy findings (MSCFs) over ≥ 10 years following a baseline screening colonoscopy in veterans.

Methods

Participants in the Cooperative Studies Program (CSP) #380 cohort study included 3121 asymptomatic veterans aged 50 to 75 years at baseline who had consented to initial screening colonoscopy between 1994 and 1997, with subsequent follow-up and surveillance.²⁵ Prior to their colonoscopy, all participants completed a baseline study survey that included questions about cancer risk factors including family history of CRC, diet, physical activity, and medication use.

Included in this cross-sectional analysis were data from a sample of veteran participants of the CSP #380 cohort with 1 baseline colonoscopy, follow-up surveillance through 2009, a cancer risk factor survey collected at baseline, and complete demographic and clinical indicator data. Excluded from the analysis were 67 participants with insufficient responses to the dietary food frequency questionnaire (FFQ) and 31 participants with missing body mass index (BMI), 3023 veterans.

Measures

MSCF. The outcome of interest in this study was the MSCF recorded across all participant colonoscopies during the study period. MSCF was categorized as either (1) no neoplasia; (2) < 2 nonadvanced adenomas, including small adenomas (diameter < 10 mm) with tubular histology; or (3) advanced neoplasia (AN), which is characterized by adenomas > 10 mm in diameter, with villous histology, with high-grade dysplasia, or CRC.

Dietary patterns. Dietary pattern scores representing dietary quality and calculated based on recommendations of the US Dietary Guidelines for Americans using the HEI, MD, and DASH diets were independent variables.^26-28 These 3 dietary patterns were chosen for their hypothesized relationship with CRC risk, but each weighs food categories differently (Appendix 1).^22-24,29 Dietary pattern scores were calculated using the CSP #380 self-reported responses to 129 baseline survey questions adapted from a well-established and previously validated semiquantitative FFQ.³⁰ The form was administered by mail twice to a sample of 127 participants at baseline and at 1 year. During this interval, men completed 1-week diet records twice, spaced about 6 months apart. Mean values for intake of most nutrients assessed by the 2 methods were similar. Intraclass correlation coefficients for the baseline and 1-year FFQ-assessed nutrient intakes that ranged from 0.47 for vitamin E (without supplements) to 0.80 for vitamin C (with supplements). Correlation coefficients between the energy-adjusted nutrient intakes were measured by diet records and the 1-year FFQ, which asked about diet during the year encompassing the diet records. Higher raw and percent scores indicated better alignment with recommendations from each respective dietary pattern. Percent scores were calculated as a standardizing method and used in analyses for ease of comparing the dietary patterns. Scoring can be found in Appendix 2.

Demographic characteristics and clinical indicators. Demographic characteristics included age categories, sex, and race/ethnicity. Clinical indicators included BMI, the number of comorbid conditions used to calculate the Charlson Comorbidity Index, family history of CRC in first-degree relatives, number of follow-up colonoscopies across the study period, and food-based vitamin D intake.³¹ These variables were chosen for their applicability found in previous CSP #380 cohort studies.^18,32,33 Self-reported race and ethnicity were collapsed due to small numbers in some groups. The authors acknowledge these are distinct concepts and the variable has limited utility other than for controlling for systemic racism in the model.

Statistical Analyses

Descriptive statistics were used to describe distributional assumptions for all variables, including demographics, clinical indicators, colonoscopy results, and dietary patterns. Pairwise correlations between the total dietary pattern scores and food category scores were calculated with Pearson correlation (r).

Multinomial logistic regression models were created using SAS procedure LOGISTIC with the outcome of the categorical MSCF (no neoplasia, nonadvanced adenoma, or AN).³⁴ A model was created for each independent predictor variable of interest (ie, the HEI, MD, or DASH percentage-standardized dietary pattern score and each food category comprising each dietary pattern score). All models were adjusted for age, sex, race/ethnicity, BMI, number of comorbidities, family history of CRC, number of follow-up colonoscopies, and estimated daily food-derived vitamin D intake. The demographic and clinical indicators were included in the models as they are known to be associated with CRC risk.¹⁸ The number of colonoscopies was included to control for surveillance intensity presuming risk for AN is reduced as polyps are removed. Because colonoscopy findings from an initial screening have unique clinical implications compared with follow- up and surveillance, MSCF was observed in 2 ways in sensitivity analyses: (1) baseline and (2) aggregate follow-up and surveillance only, excluding baseline findings.

Adjusted odds ratios (aORs) and 95% CIs for each of the MSCF outcomes with a reference finding of no neoplasia for the models are presented. We chose not to adjust for multiple comparisons across the different dietary patterns given the correlation between dietary pattern total and category scores but did adjust for multiple comparisons for dietary categories within each dietary pattern. Tests for statistical significance used α= .05 for the dietary pattern total scores and P values for the dietary category scores for each dietary pattern controlled for false discovery rate using the MULTTEST SAS procedure.35 All data manipulations and analyses were performed using SAS version 9.4.

Results

The study included 3023 patients. All were aged 50 to 75 years, 2923 (96.7%) were male and 2532 (83.8%) were non-Hispanic White (Table 1). Most participants were overweight or obese (n = 2535 [83.8%]), 2024 (67.0%) had ≤ 2 comorbidities, and 2602 (86.1%) had no family history of CRC. The MSCF for 1628 patients (53.9%) was no neoplasia, 966 patients (32.0%) was nonadvanced adenoma, and 429 participants (14.2%) had AN.

Mean percent scores were 58.5% for HEI, 38.2% for MD, and 63.1% for the DASH diet, with higher percentages indicating greater alignment with the recommendations for each diet (Table 2). All 3 dietary patterns scores standardized to percentages were strongly and significantly correlated in pairwise comparisons: HEI:MD, r = 0.62 (P < .001); HEI:DASH, r = 0.60 (P < .001); and MD:DASH, r = 0.72 (P < .001). Likewise, food category scores were significantly correlated across dietary patterns. For example, whole grain and fiber values from each dietary score were strongly correlated in pairwise comparisons: HEI Whole Grain:MD Grain, r = 0.64 (P < .001); HEI Whole Grain:DASH Fiber, r = 0.71 (P < .001); and MD Grain:DASH Fiber, r = 0.70 (P < .001).

Associations between individual participants' dietary pattern scores and the outcome of their pooled MSCF from baseline screening and ≥ 10 years of surveillance are presented in Table 3. For each single-point increases in dietary pattern scores (reflecting better dietary quality), aORs for nonadvanced adenoma vs no neoplasia were slightly lower but not statistically significantly: HEI, aOR, 1.00 (95% CI, 0.99-1.01); MD, aOR, 0.98 (95% CI, 0.94-1.02); and DASH, aOR, 0.99 (95% CI, 0.99-1.00). aORs for AN vs no neoplasia were slightly lower for each dietary pattern assessed, and only the MD and DASH scores were significantly different from 1.00: HEI, aOR, 1.00 (95% CI, 0.99-1.01); MD, aOR, 0.95 (95% CI, 0.90-1.00); and DASH, aOR, 0.99 (95% CI, 0.98-1.00).

We observed lower odds for nonadvanced adenoma and AN among all these dietary patterns when there was greater alignment with the recommended intake of whole grains and fiber. In separate models conducted using food categories comprising the dietary patterns as independent variables and after correcting for multiple tests, higher scores for the HEI Refined Grain category were associated with higher odds for nonadvanced adenoma (aOR, 1.03 [95% CI, 1.01-1.05]; P = .01) and AN (aOR, 1.05 [95% CI, 1.02-1.08]; P < .001). Higher scores for the HEI Whole Grain category were associated with lower odds for nonadvanced adenoma (aOR, 0.97 [95% CI, 0.95-0.99]; P = .01) and AN (aOR, 0.96 [95% CI, 0.93-0.99]; P = .01). Higher scores for the MD Grain category were significantly associated with lower odds for nonadvanced adenoma (aOR, 0.44 [95% CI, 0.26-0.75]; P = .002) and AN (aOR, 0.29 [95% CI, 0.14-0.62]; P = .001). The DASH Grains category also was significantly associated with lower odds for AN (aOR, 0.86 [95% CI, 0.78-0.95]; P = .002).

Discussion

In this study of 3023 veterans undergoing first-time screening colonoscopy and ≥ 10 years of surveillance, we found that healthy dietary patterns, as assessed by the MD and DASH diet, were significantly associated with lower risk of AN. Additionally, we identified lower odds for AN and nonadvanced adenoma compared with no neoplasia for higher grain scores for all the dietary patterns studied. Other food categories that comprise the dietary pattern scores had mixed associations with the MSCF outcomes. Several other studies have examined associations between dietary patterns and risk for CRC but to our knowledge, no studies have explored these associations among US veterans.

These results also indicate study participants had better than average (based on a 50% threshold) dietary quality according to the HEI and DASH diet scoring methods we used, but poor dietary quality according to the MD scoring method. The mean HEI scores for the present study were higher than a US Department of Agriculture study by Dong et al that compared dietary quality between veterans and nonveterans using the HEI, for which veterans’ expected HEI score was 45.6 of 100.⁸ This could be explained by the fact that the participants needed to be healthy to be eligible and those with healthier behaviors overall may have self-selected into the study due to motivation for screening during a time when screening was not yet commonplace. ³⁶ Similarly, participants of the present study had higher adherence to the DASH diet (63.1%) than adolescents with diabetes in a study by Günther et al. Conversely, firefighters who were coached to use a Mediterranean-style dietary pattern and dietary had higher adherence to MD than did participants in this study.²⁷

A closer examination of specific food category component scores that comprise the 3 distinct dietary patterns revealed mixed results from the multinomial modeling, which may have to do with the guideline thresholds used to calculate the dietary scores. When analyzed separately in the logistic regression models for their associations with nonadvanced adenomas and AN compared with no neoplasia, higher MD and DASH fruit scores (but not HEI fruit scores) were found to be significant. Other studies have had mixed findings when attempting to test for associations of fruit intake with adenoma recurrence.^10,37

This study had some unexpected findings. Vegetable intake was not associated with nonadvanced adenomas or AN risk. Studies of food categories have consistently found vegetable (specifically cruciferous ones) intake to be linked with lower odds for cancers.³⁸ Likewise, the red meat category, which was only a unique food category in the MD score, was not associated with nonadvanced adenomas or AN. Despite consistent literature suggesting higher intake of red meat and processed meats increases CRC risk, in 2019 the Nutritional Recommendations Consortium indicated that the evidence was weak.^39,40 This study showed higher DASH diet scores for low-fat dairy, which were maximized when participants reported at least 50% of their dairy servings per day as being low-fat, had lower odds for AN. Yet, the MD scores for low-fat dairy had no association with either outcome; their calculation was based on total number of servings per week. This difference in findings suggests the fat intake ratio may be more relevant to CRC risk than intake quantity.

The literature is mixed regarding fatty acid intake and CRC risk, which may be relevant to both dairy and meat intake. One systematic review and meta-analysis found dietary fat and types of fatty acid intake had no association with CRC risk.⁴¹ However, a more recent meta-analysis that assessed both dietary intake and plasma levels of fatty acids did find some statistically significant differences for various types of fatty acids and CRC risk.⁴²

The findings in the present study that grain intake is associated with lower odds for more severe colonoscopy findings among veterans are notable.⁴³ Lieberman et al, using the CSP #380 data, found that cereal fiber intake was associated with a lower odds for AN compared with hyperplastic polyps (OR, 0.98 [95% CI, 0.96- 1.00]).¹⁸ Similarly, Hullings et al determined that older adults in the highest quintile of cereal fiber intake had significantly lower odds of CRC than those in lower odds for CRC when compared with lowest quintile (OR, 0.89 [95% CI, 0.83- 0.96]; P < .001).⁴⁴ These findings support existing guidance that prioritizes whole grains as a key source of dietary fiber for CRC prevention.

A recent literature review on fiber, fat, and CRC risk suggested a consensus regarding one protective mechanism: dietary fiber from grains modulates the gut microbiota by promoting butyrate synthesis.⁴⁵ Butyrate is a short-chain fatty acid that supports energy production in colonocytes and has tumor-suppressing properties.⁴⁶ Our findings suggest there could be more to learn about the relationship between butyrate production and reduction of CRC risk through metabolomic studies that use measurements of plasma butyrate. These studies may examine associations between not just a singular food or food category, but rather food patterns that include fruits, vegetables, nuts and seeds, and whole grains known to promote butyrate production and plasma butyrate.⁴⁷

Improved understanding of mechanisms and risk-modifying lifestyle factors such as dietary patterns may enhance prevention strategies. Identifying the collective chemopreventive characteristics of a specific dietary pattern (eg, MD) will be helpful to clinicians and health care staff to promote healthy eating to reduce cancer risk. More studies are needed to understand whether such promotion is more clinically applicable and effective for patients, as compared with eating more or less of specific foods (eg, more whole grains, less red meat). Furthermore, considering important environmental factors collectively beyond dietary patterns may offer a way to better tailor screening and implement a variety of lifestyle interventions. In the literature, this is often referred to as a teachable moment when patients’ attentions are captured and may position them to be more receptive to guidance.⁴⁸

Limitations

This study has several important limitations and leaves opportunities for future studies that explore the role of dietary patterns and AN or CRC risk. First, the FFQ data used to calculate dietary pattern scores used in analysis were only captured at baseline, and there are nearly 3 decades across the study period. However, it is widely assumed that the diets of older adults, like those included in this study, remain stable over time which is appropriate given our sample population was aged 50 to 75 years when the baseline FFQ data were collected.^49-51 Additionally, while the HEI is a well-documented, standard scoring method for dietary quality, there are multitudes of dietary pattern scoring approaches for MD and DASH.^23,52,53 Finally, findings from this study using the sample of veterans may not be generalizable to a broader population. Future longitudinal studies that test for a clinically significant change threshold are warranted.

Conclusion

Results of this study suggest future research should further explore the effects of dietary patterns, particularly intake of specific food groups in combination, as opposed to individual nutrients or food items, on AN and CRC risk. Possible studies might explore these dietary patterns for their mechanistic role in altering the microbiome metabolism, which may influence CRC outcomes or include diet in a more comprehensive, holistic risk score that could be used to predict colonic neoplasia risk or in intervention studies that assess the effects of dietary changes on long-term CRC prevention. We suggest there are differences in people’s dietary intake patterns that might be important to consider when implementing tailored approaches to CRC risk mitigation.

Screening for colorectal cancer (CRC) with colonoscopy enables the identification and removal of CRC precursors (colonic adenomas) and has been associated with reduced risk of CRC incidence and mortality.^1-3 Furthermore, there is consensus that diet and lifestyle may be associated with forestalling CRC pathogenesis at the intermediate adenoma stages.^4-7 However, studies have shown that US veterans have poorer diet quality and a higher risk for neoplasia compared with nonveterans, reinforcing the need for tailored clinical approaches.^8,9 Combining screening with conversations about modifiable environmental and lifestyle risk factors, such as poor diet, is a highly relevant and possibly easily leveraged prevention for those at high risk. However, there is limited evidence for any particular dietary patterns or dietary features that are most important over time.⁷

Several dietary components have been shown to be associated with CRC risk,10 either as potentially chemopreventive (fiber, fruits and vegetables,¹¹ dairy,¹² supplemental vitamin D,¹³ calcium,¹⁴ and multivitamins¹⁵) or carcinogenic (red meat¹⁶ and alcohol¹⁷). Previous studies of veterans have similarly shown that higher intake of fiber and vitamin D reduced risk, and red meat is associated with an increased risk for finding CRC precursors during colonoscopy.¹⁸ However, these dietary categories are often analyzed in isolation. Studying healthy dietary patterns in aggregate may be more clinically relevant and easier to implement for prevention of CRC and its precursors.^19-21 Healthy dietary patterns, such as the US Dietary Guidelines for Americans represented by the Healthy Eating Index (HEI), the Mediterranean diet (MD), and the Dietary Approaches to Stop Hypertension (DASH) diet, have been associated with lower risk for chronic disease.^22-24 Despite the extant literature, no known studies have compared these dietary patterns for associations with risk of CRC precursor or CRC development among US veterans undergoing long-term screening and follow-up after a baseline colonoscopy.

The objective of this study was to test for associations between baseline scores of healthy dietary patterns and the most severe colonoscopy findings (MSCFs) over ≥ 10 years following a baseline screening colonoscopy in veterans.

Methods

Participants in the Cooperative Studies Program (CSP) #380 cohort study included 3121 asymptomatic veterans aged 50 to 75 years at baseline who had consented to initial screening colonoscopy between 1994 and 1997, with subsequent follow-up and surveillance.²⁵ Prior to their colonoscopy, all participants completed a baseline study survey that included questions about cancer risk factors including family history of CRC, diet, physical activity, and medication use.

Included in this cross-sectional analysis were data from a sample of veteran participants of the CSP #380 cohort with 1 baseline colonoscopy, follow-up surveillance through 2009, a cancer risk factor survey collected at baseline, and complete demographic and clinical indicator data. Excluded from the analysis were 67 participants with insufficient responses to the dietary food frequency questionnaire (FFQ) and 31 participants with missing body mass index (BMI), 3023 veterans.

Measures

MSCF. The outcome of interest in this study was the MSCF recorded across all participant colonoscopies during the study period. MSCF was categorized as either (1) no neoplasia; (2) < 2 nonadvanced adenomas, including small adenomas (diameter < 10 mm) with tubular histology; or (3) advanced neoplasia (AN), which is characterized by adenomas > 10 mm in diameter, with villous histology, with high-grade dysplasia, or CRC.

Dietary patterns. Dietary pattern scores representing dietary quality and calculated based on recommendations of the US Dietary Guidelines for Americans using the HEI, MD, and DASH diets were independent variables.^26-28 These 3 dietary patterns were chosen for their hypothesized relationship with CRC risk, but each weighs food categories differently (Appendix 1).^22-24,29 Dietary pattern scores were calculated using the CSP #380 self-reported responses to 129 baseline survey questions adapted from a well-established and previously validated semiquantitative FFQ.³⁰ The form was administered by mail twice to a sample of 127 participants at baseline and at 1 year. During this interval, men completed 1-week diet records twice, spaced about 6 months apart. Mean values for intake of most nutrients assessed by the 2 methods were similar. Intraclass correlation coefficients for the baseline and 1-year FFQ-assessed nutrient intakes that ranged from 0.47 for vitamin E (without supplements) to 0.80 for vitamin C (with supplements). Correlation coefficients between the energy-adjusted nutrient intakes were measured by diet records and the 1-year FFQ, which asked about diet during the year encompassing the diet records. Higher raw and percent scores indicated better alignment with recommendations from each respective dietary pattern. Percent scores were calculated as a standardizing method and used in analyses for ease of comparing the dietary patterns. Scoring can be found in Appendix 2.

Demographic characteristics and clinical indicators. Demographic characteristics included age categories, sex, and race/ethnicity. Clinical indicators included BMI, the number of comorbid conditions used to calculate the Charlson Comorbidity Index, family history of CRC in first-degree relatives, number of follow-up colonoscopies across the study period, and food-based vitamin D intake.³¹ These variables were chosen for their applicability found in previous CSP #380 cohort studies.^18,32,33 Self-reported race and ethnicity were collapsed due to small numbers in some groups. The authors acknowledge these are distinct concepts and the variable has limited utility other than for controlling for systemic racism in the model.

Statistical Analyses

Descriptive statistics were used to describe distributional assumptions for all variables, including demographics, clinical indicators, colonoscopy results, and dietary patterns. Pairwise correlations between the total dietary pattern scores and food category scores were calculated with Pearson correlation (r).

Multinomial logistic regression models were created using SAS procedure LOGISTIC with the outcome of the categorical MSCF (no neoplasia, nonadvanced adenoma, or AN).³⁴ A model was created for each independent predictor variable of interest (ie, the HEI, MD, or DASH percentage-standardized dietary pattern score and each food category comprising each dietary pattern score). All models were adjusted for age, sex, race/ethnicity, BMI, number of comorbidities, family history of CRC, number of follow-up colonoscopies, and estimated daily food-derived vitamin D intake. The demographic and clinical indicators were included in the models as they are known to be associated with CRC risk.¹⁸ The number of colonoscopies was included to control for surveillance intensity presuming risk for AN is reduced as polyps are removed. Because colonoscopy findings from an initial screening have unique clinical implications compared with follow- up and surveillance, MSCF was observed in 2 ways in sensitivity analyses: (1) baseline and (2) aggregate follow-up and surveillance only, excluding baseline findings.

Adjusted odds ratios (aORs) and 95% CIs for each of the MSCF outcomes with a reference finding of no neoplasia for the models are presented. We chose not to adjust for multiple comparisons across the different dietary patterns given the correlation between dietary pattern total and category scores but did adjust for multiple comparisons for dietary categories within each dietary pattern. Tests for statistical significance used α= .05 for the dietary pattern total scores and P values for the dietary category scores for each dietary pattern controlled for false discovery rate using the MULTTEST SAS procedure.35 All data manipulations and analyses were performed using SAS version 9.4.

Results

The study included 3023 patients. All were aged 50 to 75 years, 2923 (96.7%) were male and 2532 (83.8%) were non-Hispanic White (Table 1). Most participants were overweight or obese (n = 2535 [83.8%]), 2024 (67.0%) had ≤ 2 comorbidities, and 2602 (86.1%) had no family history of CRC. The MSCF for 1628 patients (53.9%) was no neoplasia, 966 patients (32.0%) was nonadvanced adenoma, and 429 participants (14.2%) had AN.

Mean percent scores were 58.5% for HEI, 38.2% for MD, and 63.1% for the DASH diet, with higher percentages indicating greater alignment with the recommendations for each diet (Table 2). All 3 dietary patterns scores standardized to percentages were strongly and significantly correlated in pairwise comparisons: HEI:MD, r = 0.62 (P < .001); HEI:DASH, r = 0.60 (P < .001); and MD:DASH, r = 0.72 (P < .001). Likewise, food category scores were significantly correlated across dietary patterns. For example, whole grain and fiber values from each dietary score were strongly correlated in pairwise comparisons: HEI Whole Grain:MD Grain, r = 0.64 (P < .001); HEI Whole Grain:DASH Fiber, r = 0.71 (P < .001); and MD Grain:DASH Fiber, r = 0.70 (P < .001).

Associations between individual participants' dietary pattern scores and the outcome of their pooled MSCF from baseline screening and ≥ 10 years of surveillance are presented in Table 3. For each single-point increases in dietary pattern scores (reflecting better dietary quality), aORs for nonadvanced adenoma vs no neoplasia were slightly lower but not statistically significantly: HEI, aOR, 1.00 (95% CI, 0.99-1.01); MD, aOR, 0.98 (95% CI, 0.94-1.02); and DASH, aOR, 0.99 (95% CI, 0.99-1.00). aORs for AN vs no neoplasia were slightly lower for each dietary pattern assessed, and only the MD and DASH scores were significantly different from 1.00: HEI, aOR, 1.00 (95% CI, 0.99-1.01); MD, aOR, 0.95 (95% CI, 0.90-1.00); and DASH, aOR, 0.99 (95% CI, 0.98-1.00).

We observed lower odds for nonadvanced adenoma and AN among all these dietary patterns when there was greater alignment with the recommended intake of whole grains and fiber. In separate models conducted using food categories comprising the dietary patterns as independent variables and after correcting for multiple tests, higher scores for the HEI Refined Grain category were associated with higher odds for nonadvanced adenoma (aOR, 1.03 [95% CI, 1.01-1.05]; P = .01) and AN (aOR, 1.05 [95% CI, 1.02-1.08]; P < .001). Higher scores for the HEI Whole Grain category were associated with lower odds for nonadvanced adenoma (aOR, 0.97 [95% CI, 0.95-0.99]; P = .01) and AN (aOR, 0.96 [95% CI, 0.93-0.99]; P = .01). Higher scores for the MD Grain category were significantly associated with lower odds for nonadvanced adenoma (aOR, 0.44 [95% CI, 0.26-0.75]; P = .002) and AN (aOR, 0.29 [95% CI, 0.14-0.62]; P = .001). The DASH Grains category also was significantly associated with lower odds for AN (aOR, 0.86 [95% CI, 0.78-0.95]; P = .002).

Discussion

In this study of 3023 veterans undergoing first-time screening colonoscopy and ≥ 10 years of surveillance, we found that healthy dietary patterns, as assessed by the MD and DASH diet, were significantly associated with lower risk of AN. Additionally, we identified lower odds for AN and nonadvanced adenoma compared with no neoplasia for higher grain scores for all the dietary patterns studied. Other food categories that comprise the dietary pattern scores had mixed associations with the MSCF outcomes. Several other studies have examined associations between dietary patterns and risk for CRC but to our knowledge, no studies have explored these associations among US veterans.

These results also indicate study participants had better than average (based on a 50% threshold) dietary quality according to the HEI and DASH diet scoring methods we used, but poor dietary quality according to the MD scoring method. The mean HEI scores for the present study were higher than a US Department of Agriculture study by Dong et al that compared dietary quality between veterans and nonveterans using the HEI, for which veterans’ expected HEI score was 45.6 of 100.⁸ This could be explained by the fact that the participants needed to be healthy to be eligible and those with healthier behaviors overall may have self-selected into the study due to motivation for screening during a time when screening was not yet commonplace. ³⁶ Similarly, participants of the present study had higher adherence to the DASH diet (63.1%) than adolescents with diabetes in a study by Günther et al. Conversely, firefighters who were coached to use a Mediterranean-style dietary pattern and dietary had higher adherence to MD than did participants in this study.²⁷

A closer examination of specific food category component scores that comprise the 3 distinct dietary patterns revealed mixed results from the multinomial modeling, which may have to do with the guideline thresholds used to calculate the dietary scores. When analyzed separately in the logistic regression models for their associations with nonadvanced adenomas and AN compared with no neoplasia, higher MD and DASH fruit scores (but not HEI fruit scores) were found to be significant. Other studies have had mixed findings when attempting to test for associations of fruit intake with adenoma recurrence.^10,37

This study had some unexpected findings. Vegetable intake was not associated with nonadvanced adenomas or AN risk. Studies of food categories have consistently found vegetable (specifically cruciferous ones) intake to be linked with lower odds for cancers.³⁸ Likewise, the red meat category, which was only a unique food category in the MD score, was not associated with nonadvanced adenomas or AN. Despite consistent literature suggesting higher intake of red meat and processed meats increases CRC risk, in 2019 the Nutritional Recommendations Consortium indicated that the evidence was weak.^39,40 This study showed higher DASH diet scores for low-fat dairy, which were maximized when participants reported at least 50% of their dairy servings per day as being low-fat, had lower odds for AN. Yet, the MD scores for low-fat dairy had no association with either outcome; their calculation was based on total number of servings per week. This difference in findings suggests the fat intake ratio may be more relevant to CRC risk than intake quantity.

The literature is mixed regarding fatty acid intake and CRC risk, which may be relevant to both dairy and meat intake. One systematic review and meta-analysis found dietary fat and types of fatty acid intake had no association with CRC risk.⁴¹ However, a more recent meta-analysis that assessed both dietary intake and plasma levels of fatty acids did find some statistically significant differences for various types of fatty acids and CRC risk.⁴²

The findings in the present study that grain intake is associated with lower odds for more severe colonoscopy findings among veterans are notable.⁴³ Lieberman et al, using the CSP #380 data, found that cereal fiber intake was associated with a lower odds for AN compared with hyperplastic polyps (OR, 0.98 [95% CI, 0.96- 1.00]).¹⁸ Similarly, Hullings et al determined that older adults in the highest quintile of cereal fiber intake had significantly lower odds of CRC than those in lower odds for CRC when compared with lowest quintile (OR, 0.89 [95% CI, 0.83- 0.96]; P < .001).⁴⁴ These findings support existing guidance that prioritizes whole grains as a key source of dietary fiber for CRC prevention.

A recent literature review on fiber, fat, and CRC risk suggested a consensus regarding one protective mechanism: dietary fiber from grains modulates the gut microbiota by promoting butyrate synthesis.⁴⁵ Butyrate is a short-chain fatty acid that supports energy production in colonocytes and has tumor-suppressing properties.⁴⁶ Our findings suggest there could be more to learn about the relationship between butyrate production and reduction of CRC risk through metabolomic studies that use measurements of plasma butyrate. These studies may examine associations between not just a singular food or food category, but rather food patterns that include fruits, vegetables, nuts and seeds, and whole grains known to promote butyrate production and plasma butyrate.⁴⁷

Improved understanding of mechanisms and risk-modifying lifestyle factors such as dietary patterns may enhance prevention strategies. Identifying the collective chemopreventive characteristics of a specific dietary pattern (eg, MD) will be helpful to clinicians and health care staff to promote healthy eating to reduce cancer risk. More studies are needed to understand whether such promotion is more clinically applicable and effective for patients, as compared with eating more or less of specific foods (eg, more whole grains, less red meat). Furthermore, considering important environmental factors collectively beyond dietary patterns may offer a way to better tailor screening and implement a variety of lifestyle interventions. In the literature, this is often referred to as a teachable moment when patients’ attentions are captured and may position them to be more receptive to guidance.⁴⁸

Limitations

This study has several important limitations and leaves opportunities for future studies that explore the role of dietary patterns and AN or CRC risk. First, the FFQ data used to calculate dietary pattern scores used in analysis were only captured at baseline, and there are nearly 3 decades across the study period. However, it is widely assumed that the diets of older adults, like those included in this study, remain stable over time which is appropriate given our sample population was aged 50 to 75 years when the baseline FFQ data were collected.^49-51 Additionally, while the HEI is a well-documented, standard scoring method for dietary quality, there are multitudes of dietary pattern scoring approaches for MD and DASH.^23,52,53 Finally, findings from this study using the sample of veterans may not be generalizable to a broader population. Future longitudinal studies that test for a clinically significant change threshold are warranted.

Conclusion

Results of this study suggest future research should further explore the effects of dietary patterns, particularly intake of specific food groups in combination, as opposed to individual nutrients or food items, on AN and CRC risk. Possible studies might explore these dietary patterns for their mechanistic role in altering the microbiome metabolism, which may influence CRC outcomes or include diet in a more comprehensive, holistic risk score that could be used to predict colonic neoplasia risk or in intervention studies that assess the effects of dietary changes on long-term CRC prevention. We suggest there are differences in people’s dietary intake patterns that might be important to consider when implementing tailored approaches to CRC risk mitigation.