Oncology

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.

The role of hereditary syndromes in renal cell carcinoma (RCC) might be easily missed, a kidney cancer specialist said during a recent Association of VA Hematology and Oncology (AVAHO) seminar in Long Beach, California, though careful clinical evaluation can uncover genetic traits that may affect treatment and familial risk.

“The importance of finding or identifying hereditary forms of kidney cancer really should not be underestimated,” said urologist Brian Shuch, MD, director of the UCLA Kidney Cancer Program, on treating veterans with kidney cancer. 

According to Shuch, recent data suggest that about 4.5% of patients with RCC have a hereditary syndrome: “A lot of times, these hide in plain sight. You have to really look deep and try to figure things out and understand that maybe they have a hereditary form of kidney cancer.”

It is important to consider early genetic testing, Shuch said. Red flags for hereditary syndromes include early-onset RCC (age ≤ 45 years), multifocal tumors, bilateral tumors (especially in younger individuals), or a relevant family personal history, he said. 

Unusual skin conditions are also potential signs, Shuch said. These can include leiomyomas, fibrofolliculomas, and angiofibromas: “Patients have lots of lumps or bumps.”

“When I look at a patient, I go head to toe and ask if there any issues with your vision, any issues with your hearing, any issues swallowing,” he explained at the meeting. “Do you have any problems with heart issues, adrenal issues? You’ve got to go through each organ, and it can lead you to different things.”

Shuch highlighted Von Hippel-Lindau (VHL) syndrome, which affects 1 in 25,000 people. About 80% to 90% of these patients have a family history, Shuch said.

But the others do not. “Unfortunately, some get diagnosed later in life because they don’t get cascade testing starting at aged 2, which is recommended. These are the patients who might be coming into the ER with a hemangioblastoma or picking up the phone and all of a sudden being deaf in one ear due to an endolymphatic sac tumor.

“We want to limit metastatic spread and preserve the kidneys,” Shuch said. “We don’t want to be doing radical nephrectomies. We want to avoid chronic kidney disease, prevent end-stage renal disease, and maximize quality of life.”

It’s a good idea to avoid surgical removal unless a patient’s tumor grows to be > 3 cm, a line that indicates risk of metastases, he said. 

In terms of treatment, Shuch highlighted a 2021 study that showed benefit in VHL from belzutifan (Welireg), an oral HIF-2 α inhibitor approved by the US Food and Drug Administration. The medication significantly reduced the need for surgical intervention. 

“Patients go on this drug, and surgeons are putting their scalpels down,” said Shuch, who worked on the 2021 study. 

Other hereditary syndromes include the rare hereditary papillary RCC, and Birt-Hogg-Dubé syndrome, believed to affect 1 in 200,000 people but may be more common, he said. 

Birt-Hogg-Dubé syndrome is linked to lung cysts, lung collapse, and skin manifestations. The 3 cm surgery rule is appropriate in these cases, Shuch said, and metastases are rare.

Another condition, hereditary leiomyomatosis and RCC, is the most dangerous hereditary form. Originally thought to affect 1 in 200,000 people, hereditary leiomyomatosis and RCC is similar to Birt-Hogg-Dubé syndrome in that it is believed to be more common.

“You will see this,” Shuch predicted. 

Shuch advised colleagues to intervene early and take a large margin during surgery.

He also highlighted familial paraganglioma syndrome, which is associated with gastrointestinal stromal tumors, and Cowden syndrome, which is linked to skin manifestations and breast, thyroid, and endometrial cancer. 

Shuch reported that he had no disclosures.

The role of hereditary syndromes in renal cell carcinoma (RCC) might be easily missed, a kidney cancer specialist said during a recent Association of VA Hematology and Oncology (AVAHO) seminar in Long Beach, California, though careful clinical evaluation can uncover genetic traits that may affect treatment and familial risk.

“The importance of finding or identifying hereditary forms of kidney cancer really should not be underestimated,” said urologist Brian Shuch, MD, director of the UCLA Kidney Cancer Program, on treating veterans with kidney cancer. 

According to Shuch, recent data suggest that about 4.5% of patients with RCC have a hereditary syndrome: “A lot of times, these hide in plain sight. You have to really look deep and try to figure things out and understand that maybe they have a hereditary form of kidney cancer.”

It is important to consider early genetic testing, Shuch said. Red flags for hereditary syndromes include early-onset RCC (age ≤ 45 years), multifocal tumors, bilateral tumors (especially in younger individuals), or a relevant family personal history, he said. 

Unusual skin conditions are also potential signs, Shuch said. These can include leiomyomas, fibrofolliculomas, and angiofibromas: “Patients have lots of lumps or bumps.”

“When I look at a patient, I go head to toe and ask if there any issues with your vision, any issues with your hearing, any issues swallowing,” he explained at the meeting. “Do you have any problems with heart issues, adrenal issues? You’ve got to go through each organ, and it can lead you to different things.”

Shuch highlighted Von Hippel-Lindau (VHL) syndrome, which affects 1 in 25,000 people. About 80% to 90% of these patients have a family history, Shuch said.

But the others do not. “Unfortunately, some get diagnosed later in life because they don’t get cascade testing starting at aged 2, which is recommended. These are the patients who might be coming into the ER with a hemangioblastoma or picking up the phone and all of a sudden being deaf in one ear due to an endolymphatic sac tumor.

“We want to limit metastatic spread and preserve the kidneys,” Shuch said. “We don’t want to be doing radical nephrectomies. We want to avoid chronic kidney disease, prevent end-stage renal disease, and maximize quality of life.”

It’s a good idea to avoid surgical removal unless a patient’s tumor grows to be > 3 cm, a line that indicates risk of metastases, he said. 

In terms of treatment, Shuch highlighted a 2021 study that showed benefit in VHL from belzutifan (Welireg), an oral HIF-2 α inhibitor approved by the US Food and Drug Administration. The medication significantly reduced the need for surgical intervention. 

“Patients go on this drug, and surgeons are putting their scalpels down,” said Shuch, who worked on the 2021 study. 

Other hereditary syndromes include the rare hereditary papillary RCC, and Birt-Hogg-Dubé syndrome, believed to affect 1 in 200,000 people but may be more common, he said. 

Birt-Hogg-Dubé syndrome is linked to lung cysts, lung collapse, and skin manifestations. The 3 cm surgery rule is appropriate in these cases, Shuch said, and metastases are rare.

Another condition, hereditary leiomyomatosis and RCC, is the most dangerous hereditary form. Originally thought to affect 1 in 200,000 people, hereditary leiomyomatosis and RCC is similar to Birt-Hogg-Dubé syndrome in that it is believed to be more common.

“You will see this,” Shuch predicted. 

Shuch advised colleagues to intervene early and take a large margin during surgery.

He also highlighted familial paraganglioma syndrome, which is associated with gastrointestinal stromal tumors, and Cowden syndrome, which is linked to skin manifestations and breast, thyroid, and endometrial cancer. 

Shuch reported that he had no disclosures.

The role of hereditary syndromes in renal cell carcinoma (RCC) might be easily missed, a kidney cancer specialist said during a recent Association of VA Hematology and Oncology (AVAHO) seminar in Long Beach, California, though careful clinical evaluation can uncover genetic traits that may affect treatment and familial risk.

“The importance of finding or identifying hereditary forms of kidney cancer really should not be underestimated,” said urologist Brian Shuch, MD, director of the UCLA Kidney Cancer Program, on treating veterans with kidney cancer. 

According to Shuch, recent data suggest that about 4.5% of patients with RCC have a hereditary syndrome: “A lot of times, these hide in plain sight. You have to really look deep and try to figure things out and understand that maybe they have a hereditary form of kidney cancer.”

It is important to consider early genetic testing, Shuch said. Red flags for hereditary syndromes include early-onset RCC (age ≤ 45 years), multifocal tumors, bilateral tumors (especially in younger individuals), or a relevant family personal history, he said. 

Unusual skin conditions are also potential signs, Shuch said. These can include leiomyomas, fibrofolliculomas, and angiofibromas: “Patients have lots of lumps or bumps.”

“When I look at a patient, I go head to toe and ask if there any issues with your vision, any issues with your hearing, any issues swallowing,” he explained at the meeting. “Do you have any problems with heart issues, adrenal issues? You’ve got to go through each organ, and it can lead you to different things.”

Shuch highlighted Von Hippel-Lindau (VHL) syndrome, which affects 1 in 25,000 people. About 80% to 90% of these patients have a family history, Shuch said.

But the others do not. “Unfortunately, some get diagnosed later in life because they don’t get cascade testing starting at aged 2, which is recommended. These are the patients who might be coming into the ER with a hemangioblastoma or picking up the phone and all of a sudden being deaf in one ear due to an endolymphatic sac tumor.

“We want to limit metastatic spread and preserve the kidneys,” Shuch said. “We don’t want to be doing radical nephrectomies. We want to avoid chronic kidney disease, prevent end-stage renal disease, and maximize quality of life.”

It’s a good idea to avoid surgical removal unless a patient’s tumor grows to be > 3 cm, a line that indicates risk of metastases, he said. 

In terms of treatment, Shuch highlighted a 2021 study that showed benefit in VHL from belzutifan (Welireg), an oral HIF-2 α inhibitor approved by the US Food and Drug Administration. The medication significantly reduced the need for surgical intervention. 

“Patients go on this drug, and surgeons are putting their scalpels down,” said Shuch, who worked on the 2021 study. 

Other hereditary syndromes include the rare hereditary papillary RCC, and Birt-Hogg-Dubé syndrome, believed to affect 1 in 200,000 people but may be more common, he said. 

Birt-Hogg-Dubé syndrome is linked to lung cysts, lung collapse, and skin manifestations. The 3 cm surgery rule is appropriate in these cases, Shuch said, and metastases are rare.

Another condition, hereditary leiomyomatosis and RCC, is the most dangerous hereditary form. Originally thought to affect 1 in 200,000 people, hereditary leiomyomatosis and RCC is similar to Birt-Hogg-Dubé syndrome in that it is believed to be more common.

“You will see this,” Shuch predicted. 

Shuch advised colleagues to intervene early and take a large margin during surgery.

He also highlighted familial paraganglioma syndrome, which is associated with gastrointestinal stromal tumors, and Cowden syndrome, which is linked to skin manifestations and breast, thyroid, and endometrial cancer. 

Shuch reported that he had no disclosures.

This transcript has been edited for clarity.

Hello. I’m Dr Maurie Markman, from City of Hope. I’d like to discuss what I consider to be an absolutely fascinating paper, and one that I will say has very interesting results but raises many more questions than it answers. I think that was the intent of the authors.

The paper is entitled, “Addition of metastasis-directed therapy to systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): a multicenter, randomized phase 2 trial,” published in the Journal of Clinical Oncology.

You might ask what metastasis-directed therapy in pancreatic cancer means. Have we really made much of an impact on pancreatic cancer? In fact, in my earlier years of training, if somebody came up with the idea, or suggested as part of a trial or treatment of an individual patient, that they would focus on metastases in pancreas cancer, you might say they’re crazy, or you might say: “Yeah, but they probably don’t know anything about the disease and its natural history.” 

Now, fast forward several decades. Even with the recognized, modest advances in systemic therapy, what we see are tremendous, really remarkable advances in innovations in radiation therapy. Of course, this includes not only the use of radiation itself but also the imaging technology that is used to direct the radiation therapy. These advances have permitted asking the questions that are addressed in the current study. 

Again, this study is fascinating. They randomized a very small number. Again, it’s a randomized phase 2 study. It’s really more of a proof of principle here. They randomized 41 patients with five or fewer metastatic lesions — with oligometastatic disease, they could have numerous lesions — to undergo what they’ve described as comprehensive metastases-directed therapy.

Most of this was external beam radiation therapy and stereotactic radiation therapy, but there were some localized radiation implants as well, plus chemotherapy. This was comprehensive metastases-directed therapy to each of these sites plus chemotherapy vs chemotherapy alone.

What was shown in this trial? The progression-free survival (PFS) in the metastases-directed therapy group was 10.3 months vs 2.5 months in the group of patients who received chemotherapy only, with a hazard ratio of 0.43 and statistical significance.

Remember, this was a very small study, but we see more than a tripling in the PFS. There was no difference in overall survival, which is not at all surprising because it was a very small sample size. 

Very importantly — and essential to doing this trial ethically — a crossover was permitted at the time of progression, meaning that if a patient received chemotherapy only and progressed, they could potentially get stereotactic radiation to sites of metastatic disease. They might have also benefited from that kind of strategy to the metastasis-[therapy] so that overall survival in the small population may not be different. Again, there was a tripling of the time to disease progression.

Clearly, a larger study will be required to be more definitive. We would need more centers involved and maybe some modification in the study design in this trial because of any issues that the investigators may have identified. Of course, overall survival would be a fair endpoint to look at, but again, crossover would be essential, and that might influence an ultimate outcome. PFS is a very valid endpoint.

The only other point to mention is, with these results — and as I mentioned, advances in radiation and imaging — is it reasonable to potentially consider this type of approach for individual patients as a component of aggressive standard of care? Of course, this would be with very adequate informed consent from patients, because we don’t know what the impact will be. 

With the limited morbidity associated with the radiation, for an individual patient with pancreatic cancer who has an adequate performance status and limited metastases, if we give them chemotherapy and also directed radiation, is it reasonable to consider that as an appropriate treatment option outside the setting of a clinical trial?

I think this is a very valid question that needs to be addressed. In my opinion, the answer in some settings should be yes, but that needs to be discussed much more widely than simply in this randomized phase 2 trial.

Thank you for your attention.

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

This transcript has been edited for clarity.

Hello. I’m Dr Maurie Markman, from City of Hope. I’d like to discuss what I consider to be an absolutely fascinating paper, and one that I will say has very interesting results but raises many more questions than it answers. I think that was the intent of the authors.

The paper is entitled, “Addition of metastasis-directed therapy to systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): a multicenter, randomized phase 2 trial,” published in the Journal of Clinical Oncology.

You might ask what metastasis-directed therapy in pancreatic cancer means. Have we really made much of an impact on pancreatic cancer? In fact, in my earlier years of training, if somebody came up with the idea, or suggested as part of a trial or treatment of an individual patient, that they would focus on metastases in pancreas cancer, you might say they’re crazy, or you might say: “Yeah, but they probably don’t know anything about the disease and its natural history.” 

Now, fast forward several decades. Even with the recognized, modest advances in systemic therapy, what we see are tremendous, really remarkable advances in innovations in radiation therapy. Of course, this includes not only the use of radiation itself but also the imaging technology that is used to direct the radiation therapy. These advances have permitted asking the questions that are addressed in the current study. 

Again, this study is fascinating. They randomized a very small number. Again, it’s a randomized phase 2 study. It’s really more of a proof of principle here. They randomized 41 patients with five or fewer metastatic lesions — with oligometastatic disease, they could have numerous lesions — to undergo what they’ve described as comprehensive metastases-directed therapy.

Most of this was external beam radiation therapy and stereotactic radiation therapy, but there were some localized radiation implants as well, plus chemotherapy. This was comprehensive metastases-directed therapy to each of these sites plus chemotherapy vs chemotherapy alone.

What was shown in this trial? The progression-free survival (PFS) in the metastases-directed therapy group was 10.3 months vs 2.5 months in the group of patients who received chemotherapy only, with a hazard ratio of 0.43 and statistical significance.

Remember, this was a very small study, but we see more than a tripling in the PFS. There was no difference in overall survival, which is not at all surprising because it was a very small sample size. 

Very importantly — and essential to doing this trial ethically — a crossover was permitted at the time of progression, meaning that if a patient received chemotherapy only and progressed, they could potentially get stereotactic radiation to sites of metastatic disease. They might have also benefited from that kind of strategy to the metastasis-[therapy] so that overall survival in the small population may not be different. Again, there was a tripling of the time to disease progression.

Clearly, a larger study will be required to be more definitive. We would need more centers involved and maybe some modification in the study design in this trial because of any issues that the investigators may have identified. Of course, overall survival would be a fair endpoint to look at, but again, crossover would be essential, and that might influence an ultimate outcome. PFS is a very valid endpoint.

The only other point to mention is, with these results — and as I mentioned, advances in radiation and imaging — is it reasonable to potentially consider this type of approach for individual patients as a component of aggressive standard of care? Of course, this would be with very adequate informed consent from patients, because we don’t know what the impact will be. 

With the limited morbidity associated with the radiation, for an individual patient with pancreatic cancer who has an adequate performance status and limited metastases, if we give them chemotherapy and also directed radiation, is it reasonable to consider that as an appropriate treatment option outside the setting of a clinical trial?

I think this is a very valid question that needs to be addressed. In my opinion, the answer in some settings should be yes, but that needs to be discussed much more widely than simply in this randomized phase 2 trial.

Thank you for your attention.

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

This transcript has been edited for clarity.

Hello. I’m Dr Maurie Markman, from City of Hope. I’d like to discuss what I consider to be an absolutely fascinating paper, and one that I will say has very interesting results but raises many more questions than it answers. I think that was the intent of the authors.

The paper is entitled, “Addition of metastasis-directed therapy to systemic therapy for oligometastatic pancreatic ductal adenocarcinoma (EXTEND): a multicenter, randomized phase 2 trial,” published in the Journal of Clinical Oncology.

You might ask what metastasis-directed therapy in pancreatic cancer means. Have we really made much of an impact on pancreatic cancer? In fact, in my earlier years of training, if somebody came up with the idea, or suggested as part of a trial or treatment of an individual patient, that they would focus on metastases in pancreas cancer, you might say they’re crazy, or you might say: “Yeah, but they probably don’t know anything about the disease and its natural history.” 

Now, fast forward several decades. Even with the recognized, modest advances in systemic therapy, what we see are tremendous, really remarkable advances in innovations in radiation therapy. Of course, this includes not only the use of radiation itself but also the imaging technology that is used to direct the radiation therapy. These advances have permitted asking the questions that are addressed in the current study. 

Again, this study is fascinating. They randomized a very small number. Again, it’s a randomized phase 2 study. It’s really more of a proof of principle here. They randomized 41 patients with five or fewer metastatic lesions — with oligometastatic disease, they could have numerous lesions — to undergo what they’ve described as comprehensive metastases-directed therapy.

Most of this was external beam radiation therapy and stereotactic radiation therapy, but there were some localized radiation implants as well, plus chemotherapy. This was comprehensive metastases-directed therapy to each of these sites plus chemotherapy vs chemotherapy alone.

What was shown in this trial? The progression-free survival (PFS) in the metastases-directed therapy group was 10.3 months vs 2.5 months in the group of patients who received chemotherapy only, with a hazard ratio of 0.43 and statistical significance.

Remember, this was a very small study, but we see more than a tripling in the PFS. There was no difference in overall survival, which is not at all surprising because it was a very small sample size. 

Very importantly — and essential to doing this trial ethically — a crossover was permitted at the time of progression, meaning that if a patient received chemotherapy only and progressed, they could potentially get stereotactic radiation to sites of metastatic disease. They might have also benefited from that kind of strategy to the metastasis-[therapy] so that overall survival in the small population may not be different. Again, there was a tripling of the time to disease progression.

Clearly, a larger study will be required to be more definitive. We would need more centers involved and maybe some modification in the study design in this trial because of any issues that the investigators may have identified. Of course, overall survival would be a fair endpoint to look at, but again, crossover would be essential, and that might influence an ultimate outcome. PFS is a very valid endpoint.

The only other point to mention is, with these results — and as I mentioned, advances in radiation and imaging — is it reasonable to potentially consider this type of approach for individual patients as a component of aggressive standard of care? Of course, this would be with very adequate informed consent from patients, because we don’t know what the impact will be. 

With the limited morbidity associated with the radiation, for an individual patient with pancreatic cancer who has an adequate performance status and limited metastases, if we give them chemotherapy and also directed radiation, is it reasonable to consider that as an appropriate treatment option outside the setting of a clinical trial?

I think this is a very valid question that needs to be addressed. In my opinion, the answer in some settings should be yes, but that needs to be discussed much more widely than simply in this randomized phase 2 trial.

Thank you for your attention.

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

Mrs G.O. is an 80-year-old retired teacher who was widowed a decade ago. With no close relatives, she lives alone, accompanied by only two cats and a dog that she has rescued. “I am alone,” she told Gustavo Kusminsky, MD, consultant in Hematology and Hematopoietic Transplant Service at Austral University Hospital and lecturer in medicine at the Hospital Universitario Austral, Buenos Aires, Argentina. She said this calmly while refusing treatment for life-threatening multiple myeloma. “Doctor, I would rather not,” she added — her words lingering in the quiet consulting room. That moment is now the focus of a recent article in the journal Medicina.

In the article, Kusminsky described how he made an effort to clarify to the patient that she needed cancer treatment. He explained that the treatment was mostly oral, required no initial hospitalization, and that consultations could be spaced out. However, Mrs G.O. maintained her position.

“The patient had no signs of depression, and her argument was logical. Mrs G.O. was already receiving several medications for high blood pressure, was on anticoagulation therapy for atrial fibrillation, and managed dyslipidemia with fenofibrate. But she preferred not to receive treatment for her multiple myeloma.” Kusminsky noted.

“Doctor, I have lived my life. I am old. I am already taking too many medications. I do not have a family, and it would be very difficult to deal with the side effects and be dependent on the hospital. As long as I can take care of myself, I do not want any more treatment, at least not for now. We will talk in a few months if I am still here,” she told him before leaving.

The article mentioned that responses such as Mrs G.O. spark perplexity in modern medicine to the extent that clinicians initiate protocols to rule out depression or other psychological factors when a patient rejects treatments that could prolong their life. On the contrary, no such checks are made when patients agree to treatment, because acceptance is deemed “normal.”

Because of collective assumptions and the war metaphors often used in oncology, Mrs G.O. risked being labeled a “deserter from the battalion” of patients with cancer. 

In truth, her decision invites reflection on the doctor-patient relationship, respect for autonomy, and the benefits of modern cancer care offered today, Kusminsky said.

This provides an opportunity to consider the patient’s perspective rather than a purely medical perspective.

Jennifer Hincapié Sánchez, PhD, professor in the Faculty of Medicine at the National Autonomous University of Mexico (UNAM). She is the director of the UNAM University Bioethics Program and coordinates its Institutional Ethics and Bioethics Program for the Faculty of Medicine in Mexico. Although not involved in the article, she regards it as vital. “It’s crucial to remind medical staff that their role is to promote patients’ well-being and that this is related to the life plan that patients have set for themselves, even though this vision is sometimes not aligned with biomedical progress,” she said.

 

Patient Autonomy

Science-guided medicine aims to prolong life, improve quality, and relieve suffering. However, acceptance or refusal of treatment remains a personal choice for anyone with cancer.

Some evidence showed that patients who decline treatment do not always experience rapid decline. Many can live acceptable, even fulfilling, lives on their own for varying periods, even though they know that there is a possibility of shorter survival. Valuing fewer side effects and better quality of life. This suggested that quality of life is subjective and cannot be measured solely by biomedical standards but also by the meaning each person finds in their existence, even in the face of serious illness.

“There is a myth that quality of life is only valid when defined by objective success. Our task is to explain that it is subjective, and life can be meaningful despite limitations.” Kusminsky said.

Mrs G.O. knew her prognosis and treatment options but chose not to pursue treatment, which, while medically advisable, did not align with her values or vision of life.

Hincapié Sánchez stated that the priority is always to honor the patient’s choice. Clinicians must ensure that the patient has all necessary information that is always appropriate to their sociocultural context before making the decision.

“If the decision persists despite being informed and aware of the effects of the patient’s choice, all we can do is provide support, manage the pain, and seek the patient’s comfort,” she emphasized.

 

Medical Omnipotence 

Physicians should not view the refusal of treatment as an abandonment of the fundamental principles of the profession. Rather, it means respecting patient priorities and recognizing medicine as a dialogue between science and humanity, not as an exercise of control.

However, many clinicians struggle with such decisions because they conflict with their impulse to act and a sense of medical omnipotence. Hincapié Sánchez attributed these difficulties to medical training.

“We are taught to preserve life at all costs. If treatment even slightly prolongs life, many doctors continue to recommend it. The question becomes: Is it valid to extend life when its quality is in doubt?” she asked.

“Medicine is more than a science; it is an art. It is the most human in the sciences and the most scientific in the humanities. Let us not lose sight of the human element that allows us to see the patient as a person, not just a disease to be treated,” Hincapié Sánchez urges.

Kusminsky describes a common therapeutic obstinacy — doctors’ reluctance to stop “doing something,” to avoid “throwing in the towel,” or to uphold “hope is the last thing to be lost.”

“But physicians are growing more aware of these situations, and change is slowly coming,” he said. However, he added: “Of course, there is the issue of the perceived omnipotence of doctors — their words descending with authority to ‘prescribe’ treatment, issue ‘medical orders,’ or dictate ‘pharmacological’ therapy.

For the specialist, such terminology reflects a view of the doctor-patient relationship not as a mutual, two-way exchange, but as a vertical, paternalistic dynamic.

He suggested looking at ancient Greece for perspective. “Hippocrates, or rather the Hippocratic school, taught that the doctor-patient encounter is inherently one of compassion. We must approach this in that way. Reflecting on that bond, improving communication, humanizing relationships, and, above all, being available to listen are key,” Kusminsky said.

Another intersection that has long fascinated Kusminsky is between literature and medicine. This interest led him to explore the field of narrative medicine, serve on the board of directors of the Argentine Society of Narrative Medicine (SAMEN), and join the roster of speakers at the upcoming second SAMEN Conference in Buenos Aires on July 10 and 11, 2025.

“Narrative medicine uses storytelling tools to absorb, process, acknowledge, and empathize with patients’ illness narratives, aiming to restore humanism to practice,” he explained.

According to Kusminsky, the circumstances under which Mrs G.O. expressed her wish not to begin treatment immediately reminded him of a text by Melville’s famous “I would prefer not to” from Bartleby, the Scrivener.

This reflection inspired him to publish an article cited at its beginning. At the same time, it reinforced his belief that what patients say can itself be a form of narrative that extends beyond the confines of clinical history.

Mrs G.O. chose not to pursue treatment for multiple myeloma. However, she returned to Kusminsky’s office approximately 2 months ago. She felt well, and her disease slowly progressed; however, she still had no clinical signs or symptoms.

Kusminsky and Hincapié Sánchez have declared no relevant financial conflicts of interest.

This story was translated from Medscape’s Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

Mrs G.O. is an 80-year-old retired teacher who was widowed a decade ago. With no close relatives, she lives alone, accompanied by only two cats and a dog that she has rescued. “I am alone,” she told Gustavo Kusminsky, MD, consultant in Hematology and Hematopoietic Transplant Service at Austral University Hospital and lecturer in medicine at the Hospital Universitario Austral, Buenos Aires, Argentina. She said this calmly while refusing treatment for life-threatening multiple myeloma. “Doctor, I would rather not,” she added — her words lingering in the quiet consulting room. That moment is now the focus of a recent article in the journal Medicina.

In the article, Kusminsky described how he made an effort to clarify to the patient that she needed cancer treatment. He explained that the treatment was mostly oral, required no initial hospitalization, and that consultations could be spaced out. However, Mrs G.O. maintained her position.

“The patient had no signs of depression, and her argument was logical. Mrs G.O. was already receiving several medications for high blood pressure, was on anticoagulation therapy for atrial fibrillation, and managed dyslipidemia with fenofibrate. But she preferred not to receive treatment for her multiple myeloma.” Kusminsky noted.

“Doctor, I have lived my life. I am old. I am already taking too many medications. I do not have a family, and it would be very difficult to deal with the side effects and be dependent on the hospital. As long as I can take care of myself, I do not want any more treatment, at least not for now. We will talk in a few months if I am still here,” she told him before leaving.

The article mentioned that responses such as Mrs G.O. spark perplexity in modern medicine to the extent that clinicians initiate protocols to rule out depression or other psychological factors when a patient rejects treatments that could prolong their life. On the contrary, no such checks are made when patients agree to treatment, because acceptance is deemed “normal.”

Because of collective assumptions and the war metaphors often used in oncology, Mrs G.O. risked being labeled a “deserter from the battalion” of patients with cancer. 

In truth, her decision invites reflection on the doctor-patient relationship, respect for autonomy, and the benefits of modern cancer care offered today, Kusminsky said.

This provides an opportunity to consider the patient’s perspective rather than a purely medical perspective.

Jennifer Hincapié Sánchez, PhD, professor in the Faculty of Medicine at the National Autonomous University of Mexico (UNAM). She is the director of the UNAM University Bioethics Program and coordinates its Institutional Ethics and Bioethics Program for the Faculty of Medicine in Mexico. Although not involved in the article, she regards it as vital. “It’s crucial to remind medical staff that their role is to promote patients’ well-being and that this is related to the life plan that patients have set for themselves, even though this vision is sometimes not aligned with biomedical progress,” she said.

 

Patient Autonomy

Science-guided medicine aims to prolong life, improve quality, and relieve suffering. However, acceptance or refusal of treatment remains a personal choice for anyone with cancer.

Some evidence showed that patients who decline treatment do not always experience rapid decline. Many can live acceptable, even fulfilling, lives on their own for varying periods, even though they know that there is a possibility of shorter survival. Valuing fewer side effects and better quality of life. This suggested that quality of life is subjective and cannot be measured solely by biomedical standards but also by the meaning each person finds in their existence, even in the face of serious illness.

“There is a myth that quality of life is only valid when defined by objective success. Our task is to explain that it is subjective, and life can be meaningful despite limitations.” Kusminsky said.

Mrs G.O. knew her prognosis and treatment options but chose not to pursue treatment, which, while medically advisable, did not align with her values or vision of life.

Hincapié Sánchez stated that the priority is always to honor the patient’s choice. Clinicians must ensure that the patient has all necessary information that is always appropriate to their sociocultural context before making the decision.

“If the decision persists despite being informed and aware of the effects of the patient’s choice, all we can do is provide support, manage the pain, and seek the patient’s comfort,” she emphasized.

 

Medical Omnipotence 

Physicians should not view the refusal of treatment as an abandonment of the fundamental principles of the profession. Rather, it means respecting patient priorities and recognizing medicine as a dialogue between science and humanity, not as an exercise of control.

However, many clinicians struggle with such decisions because they conflict with their impulse to act and a sense of medical omnipotence. Hincapié Sánchez attributed these difficulties to medical training.

“We are taught to preserve life at all costs. If treatment even slightly prolongs life, many doctors continue to recommend it. The question becomes: Is it valid to extend life when its quality is in doubt?” she asked.

“Medicine is more than a science; it is an art. It is the most human in the sciences and the most scientific in the humanities. Let us not lose sight of the human element that allows us to see the patient as a person, not just a disease to be treated,” Hincapié Sánchez urges.

Kusminsky describes a common therapeutic obstinacy — doctors’ reluctance to stop “doing something,” to avoid “throwing in the towel,” or to uphold “hope is the last thing to be lost.”

“But physicians are growing more aware of these situations, and change is slowly coming,” he said. However, he added: “Of course, there is the issue of the perceived omnipotence of doctors — their words descending with authority to ‘prescribe’ treatment, issue ‘medical orders,’ or dictate ‘pharmacological’ therapy.

For the specialist, such terminology reflects a view of the doctor-patient relationship not as a mutual, two-way exchange, but as a vertical, paternalistic dynamic.

He suggested looking at ancient Greece for perspective. “Hippocrates, or rather the Hippocratic school, taught that the doctor-patient encounter is inherently one of compassion. We must approach this in that way. Reflecting on that bond, improving communication, humanizing relationships, and, above all, being available to listen are key,” Kusminsky said.

Another intersection that has long fascinated Kusminsky is between literature and medicine. This interest led him to explore the field of narrative medicine, serve on the board of directors of the Argentine Society of Narrative Medicine (SAMEN), and join the roster of speakers at the upcoming second SAMEN Conference in Buenos Aires on July 10 and 11, 2025.

“Narrative medicine uses storytelling tools to absorb, process, acknowledge, and empathize with patients’ illness narratives, aiming to restore humanism to practice,” he explained.

According to Kusminsky, the circumstances under which Mrs G.O. expressed her wish not to begin treatment immediately reminded him of a text by Melville’s famous “I would prefer not to” from Bartleby, the Scrivener.

This reflection inspired him to publish an article cited at its beginning. At the same time, it reinforced his belief that what patients say can itself be a form of narrative that extends beyond the confines of clinical history.

Mrs G.O. chose not to pursue treatment for multiple myeloma. However, she returned to Kusminsky’s office approximately 2 months ago. She felt well, and her disease slowly progressed; however, she still had no clinical signs or symptoms.

Kusminsky and Hincapié Sánchez have declared no relevant financial conflicts of interest.

This story was translated from Medscape’s Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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

Mrs G.O. is an 80-year-old retired teacher who was widowed a decade ago. With no close relatives, she lives alone, accompanied by only two cats and a dog that she has rescued. “I am alone,” she told Gustavo Kusminsky, MD, consultant in Hematology and Hematopoietic Transplant Service at Austral University Hospital and lecturer in medicine at the Hospital Universitario Austral, Buenos Aires, Argentina. She said this calmly while refusing treatment for life-threatening multiple myeloma. “Doctor, I would rather not,” she added — her words lingering in the quiet consulting room. That moment is now the focus of a recent article in the journal Medicina.

In the article, Kusminsky described how he made an effort to clarify to the patient that she needed cancer treatment. He explained that the treatment was mostly oral, required no initial hospitalization, and that consultations could be spaced out. However, Mrs G.O. maintained her position.

“The patient had no signs of depression, and her argument was logical. Mrs G.O. was already receiving several medications for high blood pressure, was on anticoagulation therapy for atrial fibrillation, and managed dyslipidemia with fenofibrate. But she preferred not to receive treatment for her multiple myeloma.” Kusminsky noted.

“Doctor, I have lived my life. I am old. I am already taking too many medications. I do not have a family, and it would be very difficult to deal with the side effects and be dependent on the hospital. As long as I can take care of myself, I do not want any more treatment, at least not for now. We will talk in a few months if I am still here,” she told him before leaving.

The article mentioned that responses such as Mrs G.O. spark perplexity in modern medicine to the extent that clinicians initiate protocols to rule out depression or other psychological factors when a patient rejects treatments that could prolong their life. On the contrary, no such checks are made when patients agree to treatment, because acceptance is deemed “normal.”

Because of collective assumptions and the war metaphors often used in oncology, Mrs G.O. risked being labeled a “deserter from the battalion” of patients with cancer. 

In truth, her decision invites reflection on the doctor-patient relationship, respect for autonomy, and the benefits of modern cancer care offered today, Kusminsky said.

This provides an opportunity to consider the patient’s perspective rather than a purely medical perspective.

Jennifer Hincapié Sánchez, PhD, professor in the Faculty of Medicine at the National Autonomous University of Mexico (UNAM). She is the director of the UNAM University Bioethics Program and coordinates its Institutional Ethics and Bioethics Program for the Faculty of Medicine in Mexico. Although not involved in the article, she regards it as vital. “It’s crucial to remind medical staff that their role is to promote patients’ well-being and that this is related to the life plan that patients have set for themselves, even though this vision is sometimes not aligned with biomedical progress,” she said.

 

Patient Autonomy

Science-guided medicine aims to prolong life, improve quality, and relieve suffering. However, acceptance or refusal of treatment remains a personal choice for anyone with cancer.

Some evidence showed that patients who decline treatment do not always experience rapid decline. Many can live acceptable, even fulfilling, lives on their own for varying periods, even though they know that there is a possibility of shorter survival. Valuing fewer side effects and better quality of life. This suggested that quality of life is subjective and cannot be measured solely by biomedical standards but also by the meaning each person finds in their existence, even in the face of serious illness.

“There is a myth that quality of life is only valid when defined by objective success. Our task is to explain that it is subjective, and life can be meaningful despite limitations.” Kusminsky said.

Mrs G.O. knew her prognosis and treatment options but chose not to pursue treatment, which, while medically advisable, did not align with her values or vision of life.

Hincapié Sánchez stated that the priority is always to honor the patient’s choice. Clinicians must ensure that the patient has all necessary information that is always appropriate to their sociocultural context before making the decision.

“If the decision persists despite being informed and aware of the effects of the patient’s choice, all we can do is provide support, manage the pain, and seek the patient’s comfort,” she emphasized.

 

Medical Omnipotence 

Physicians should not view the refusal of treatment as an abandonment of the fundamental principles of the profession. Rather, it means respecting patient priorities and recognizing medicine as a dialogue between science and humanity, not as an exercise of control.

However, many clinicians struggle with such decisions because they conflict with their impulse to act and a sense of medical omnipotence. Hincapié Sánchez attributed these difficulties to medical training.

“We are taught to preserve life at all costs. If treatment even slightly prolongs life, many doctors continue to recommend it. The question becomes: Is it valid to extend life when its quality is in doubt?” she asked.

“Medicine is more than a science; it is an art. It is the most human in the sciences and the most scientific in the humanities. Let us not lose sight of the human element that allows us to see the patient as a person, not just a disease to be treated,” Hincapié Sánchez urges.

Kusminsky describes a common therapeutic obstinacy — doctors’ reluctance to stop “doing something,” to avoid “throwing in the towel,” or to uphold “hope is the last thing to be lost.”

“But physicians are growing more aware of these situations, and change is slowly coming,” he said. However, he added: “Of course, there is the issue of the perceived omnipotence of doctors — their words descending with authority to ‘prescribe’ treatment, issue ‘medical orders,’ or dictate ‘pharmacological’ therapy.

For the specialist, such terminology reflects a view of the doctor-patient relationship not as a mutual, two-way exchange, but as a vertical, paternalistic dynamic.

He suggested looking at ancient Greece for perspective. “Hippocrates, or rather the Hippocratic school, taught that the doctor-patient encounter is inherently one of compassion. We must approach this in that way. Reflecting on that bond, improving communication, humanizing relationships, and, above all, being available to listen are key,” Kusminsky said.

Another intersection that has long fascinated Kusminsky is between literature and medicine. This interest led him to explore the field of narrative medicine, serve on the board of directors of the Argentine Society of Narrative Medicine (SAMEN), and join the roster of speakers at the upcoming second SAMEN Conference in Buenos Aires on July 10 and 11, 2025.

“Narrative medicine uses storytelling tools to absorb, process, acknowledge, and empathize with patients’ illness narratives, aiming to restore humanism to practice,” he explained.

According to Kusminsky, the circumstances under which Mrs G.O. expressed her wish not to begin treatment immediately reminded him of a text by Melville’s famous “I would prefer not to” from Bartleby, the Scrivener.

This reflection inspired him to publish an article cited at its beginning. At the same time, it reinforced his belief that what patients say can itself be a form of narrative that extends beyond the confines of clinical history.

Mrs G.O. chose not to pursue treatment for multiple myeloma. However, she returned to Kusminsky’s office approximately 2 months ago. She felt well, and her disease slowly progressed; however, she still had no clinical signs or symptoms.

Kusminsky and Hincapié Sánchez have declared no relevant financial conflicts of interest.

This story was translated from Medscape’s Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

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