Association Between Radiation Therapy, Surgery, or Observation for Localized Prostate Cancer and Patient-Reported Outcomes After 3 Years

Abstract

Importance: Understanding the adverse effects of contemporary approaches to localized prostate cancer treatment could inform shared decision making.

Objective: To compare functional outcomes and adverse effects associated with radical prostatectomy, external beam radiation therapy (EBRT), and active surveillance.

Design, setting, and participants: Prospective, population-based, cohort study involving 2550 men (≤80 years) diagnosed in 2011-2012 with clinical stage cT1-2, localized prostate cancer, with prostate-specific antigen levels less than 50 ng/mL, and enrolled within 6 months of diagnosis.

Exposures: Treatment with radical prostatectomy, EBRT, or active surveillance was ascertained within 1 year of diagnosis.

Main outcomes and measures: Patient-reported function on the 26-item Expanded Prostate Cancer Index Composite (EPIC) 36 months after enrollment. Higher domain scores (range, 0-100) indicate better function. Minimum clinically important difference was defined as 10 to 12 points for sexual function, 6 for urinary incontinence, 5 for urinary irritative symptoms, 5 for bowel function, and 4 for hormonal function.

Results: The cohort included 2550 men (mean age, 63.8 years; 74% white, 55% had intermediate- or high-risk disease), of whom 1523 (59.7%) underwent radical prostatectomy, 598 (23.5%) EBRT, and 429 (16.8%) active surveillance. Men in the EBRT group were older (mean age, 68.1 years vs 61.5 years, P < .001) and had worse baseline sexual function (mean score, 52.3 vs 65.2, P < .001) than men in the radical prostatectomy group. At 3 years, the adjusted mean sexual domain score for radical prostatectomy decreased more than for EBRT (mean difference, -11.9 points; 95% CI, -15.1 to -8.7). The decline in sexual domain scores between EBRT and active surveillance was not clinically significant (-4.3 points; 95% CI, -9.2 to 0.7). Radical prostatectomy was associated with worse urinary incontinence than EBRT (-18.0 points; 95% CI, -20.5 to -15.4) and active surveillance (-12.7 points; 95% CI, -16.0 to -9.3) but was associated with better urinary irritative symptoms than active surveillance (5.2 points; 95% CI, 3.2 to 7.2). No clinically significant differences for bowel or hormone function were noted beyond 12 months. No differences in health-related quality of life or disease-specific survival (3 deaths) were noted (99.7%-100%).

Conclusions and relevance: In this cohort of men with localized prostate cancer, radical prostatectomy was associated with a greater decrease in sexual function and urinary incontinence than either EBRT or active surveillance after 3 years and was associated with fewer urinary irritative symptoms than active surveillance; however, no meaningful differences existed in either bowel or hormonal function beyond 12 months or in in other domains of health-related quality-of-life measures. These findings may facilitate counseling regarding the comparative harms of contemporary treatments for prostate cancer.

Figure 1

Association Between Treatment and Sexual Function Outcomes. Outcomes are sexual function domain scores and selected individual items from the Expanded Prostate Cancer Index Composite (EPIC-26). Domain scores range from 0 to 100, with higher score representing better function. Time zero is the date of treatment for radical prostatectomy and external beam radiation therapy patients, and date of diagnosis for active surveillance patients. Minimum clinically important difference for the sexual domain score is 10 points. Individual item probabilities range from 0 to 100, with higher scores representing a higher probability of favorable outcome. Numbers in the legends indicate the number of men who completed baseline and 36-month sexual domain surveys for each treatment group. Longitudinal figures extend to 37 months along the x-axis because the interval between treatment and completion of the 36-month survey was greater than 36 months for some patients. A–C: Unadjusted Mean Expanded Prostate Cancer Index Composite (EPIC-26) Sexual Domain Score (95% CI), Longitudinally by Treatment in All Men (panel A), Men with Excellent Baseline Domain Score (panel B), and Men with Lower Baseline Domain Score (panel C). A baseline domain score of 90 or above was defined as excellent, and a score below 90 was defined as lower, approximating subgroups of the top quartile and all others. D: Adjusted Mean Point Difference (95% CI) in Expanded Prostate Cancer Index Composite (EPIC-26) Sexual Domain Score Between Groups at 3 Years. Forest plots depict the covariate adjusted effect of treatment, baseline sexual domain score, age, and D’Amico risk stratum on domain score at 3 years, estimated from multivariable regression models that controlled for baseline domain score, age, race, comorbidity, prostate cancer risk group, physical function, social support, depression, medical decision-making style and accrual site. Effect size represents the adjusted mean point difference on the EPIC domain score between groups; the group after the colon (:) is the referent, so positive values may be interpreted as better outcome for the group before the colon and negative values indicate a better outcome for the group after the colon. Reference lines indicate the minimum clinically important difference (10 points). eTable 8 contains unadjusted domain scores and number of patients for each subgroup (age, baseline domain score and disease risk group) by treatment. D’Amico risk classification system predicts the risk of recurrence after treatment for clinically localized prostate cancer. Low-risk disease is defined as a clinical stage T2a or less, Gleason Score 6 (3+3) or less, and a prostate-specific antigen less than 10 ng/mL. High-risk disease is defined as T2c or higher, Gleason Score 8 (3+5, 4+4, 5+3) or greater, or a prostate-specific antigen greater than 20 ng/mL. Disease not defined as low or high-risk is defined as intermediate-risk. E: Unadjusted Probability of Reporting Erection Sufficient for Intercourse, Longitudinally by Treatment in All Men. This individual item from the Expanded Prostate Cancer Index Composite (EPIC-26) was selected a priori as a secondary outcome based on its clinical relevance. F. Unadjusted Probability of Reporting No, Very Small or Small Problem with Sexual Function Bother, Longitudinally by Treatment in All Men. This individual item from the Expanded Prostate Cancer Index Composite (EPIC-26) was selected a priori as a secondary outcome based on its clinical relevance.

Figure 2

Association Between Treatment and Urinary Incontinence Outcomes. Outcomes are urinary incontinence domain scores and selected individual items from the Expanded Prostate Cancer Index Composite (EPIC-26). Domain scores range from 0 to 100, with higher score representing better function. Time zero is the date of treatment for radical prostatectomy and external beam radiation therapy patients, and date of diagnosis for active surveillance patients. Minimum clinically important difference for the urinary incontinence domain score is 6 points. Individual item probabilities range from 0 to 100, with higher scores representing a higher probability of favorable outcome. Numbers in the legends indicate the number of men who completed baseline and 36-month urinary incontinence domain surveys for each treatment group. Longitudinal figures extend to 37 months along the x-axis because the interval between treatment and completion of the 36-month survey was greater than 36 months for some patients. A–C: Unadjusted Mean Expanded Prostate Cancer Index Composite (EPIC-26) Urinary Incontinence Domain Score (95% CI), Longitudinally by Treatment in All Men (panel A), Men with Excellent Baseline Domain Score (panel B), and Men with Lower Baseline Domain Score (panel C). A baseline domain score of 100 or above was defined as excellent, and a score below 100 was defined as lower, approximating subgroups of the top quartile and all others. D: Adjusted Mean Point Difference (95% CI) in Expanded Prostate Cancer Index Composite (EPIC-26) Urinary Incontinence Domain Score Between Groups at 3 Years. Forest plots depict the covariate adjusted effect of treatment, baseline urinary incontinence domain score, age, and D’Amico risk stratum on domain score at 3 years, estimated from multivariable regression models that controlled for baseline domain score, age, race, comorbidity, prostate cancer risk group, physical function, social support, depression, medical decision-making style and accrual site. Effect size represents the adjusted mean point difference on the EPIC domain score between groups; the group after the colon (:) is the referent, so positive values may be interpreted as better outcome for the group before the colon and negative values indicate a better outcome for the group after the colon. Reference lines indicate the minimum clinically important difference (6 points). eTable 8 contains unadjusted domain scores and number of patients for each subgroup (age, baseline domain score and disease risk group) by treatment. D’Amico risk classification system predicts the risk of recurrence after treatment for clinically localized prostate cancer. Low-risk disease is defined as a clinical stage T2a or less, Gleason Score 6 (3+3) or less, and a prostate-specific antigen less than 10 ng/mL. High-risk disease is defined as T2c or higher, Gleason Score 8 (3+5, 4+4, 5+3) or greater, or a prostate-specific antigen greater than 20 ng/mL. Disease not defined as low or high-risk is defined as intermediate-risk. E: Unadjusted Probability of Reporting No, Very Small or Small Problem with Urinary Leakage, Longitudinally by Treatment in All Men. This individual item from the Expanded Prostate Cancer Index Composite (EPIC-26) was selected a priori as a secondary outcome based on its clinical relevance. F. Unadjusted Probability of Reporting No, Very Small or Small Problem with Urinary Function Bother, Longitudinally by Treatment in All Men. This individual item from the Expanded Prostate Cancer Index Composite (EPIC-26) was selected a priori as a secondary outcome based on its clinical relevance.

Figure 3

Association Between Treatment and Urinary Irritative Outcomes. Outcomes are urinary irritative domain scores and selected individual items from the Expanded Prostate Cancer Index Composite (EPIC-26). Domain scores range from 0 to 100, with higher score representing better function. Time zero is the date of treatment for radical prostatectomy and external beam radiation therapy patients, and date of diagnosis for active surveillance patients. Minimum clinically important difference for the urinary irritative domain score is 5 points. Individual item probabilities range from 0 to 100, with higher scores representing a higher probability of favorable outcome. Numbers in the legends indicate the number of men who completed baseline and 36-month urinary irritative domain surveys for each treatment group. Longitudinal figures extend to 37 months along the x-axis because the interval between treatment and completion of the 36-month survey was greater than 36 months for some patients. A–C: Unadjusted Mean Expanded Prostate Cancer Index Composite (EPIC-26) Urinary Irritative Domain Score (95% CI), Longitudinally by Treatment in All Men (panel A), Men with Excellent Baseline Domain Score (panel B), and Men with Lower Baseline Domain Score (panel C). A baseline domain score of 100 or above was defined as excellent, and a score below 100 was defined as lower, approximating subgroups of the top quartile and all others. D: Adjusted Mean Point Difference (95% CI) in Expanded Prostate Cancer Index Composite (EPIC-26) Urinary Irritative Domain Score Between Groups at 3 Years. Forest plots depict the covariate adjusted effect of treatment, baseline urinary Irritative domain score, age, and D’Amico risk stratum on domain score at 3 years, estimated from multivariable regression models that controlled for baseline domain score, age, race, comorbidity, prostate cancer risk group, physical function, social support, depression, medical decision-making style and accrual site. Effect size represents the adjusted mean point difference on the EPIC domain score between groups; the group after the colon (:) is the referent, so positive values may be interpreted as better outcome for the group before the colon and negative values indicate a better outcome for the group after the colon. Reference lines indicate the minimum clinically important difference (5 points). eTable 8 contains unadjusted domain scores and number of patients for each subgroup (age, baseline domain score and disease risk group) by treatment. D’Amico risk classification system predicts the risk of recurrence after treatment for clinically localized prostate cancer. Low-risk disease is defined as a clinical stage T2a or less, Gleason Score 6 (3+3) or less, and a prostate-specific antigen less than 10 ng/mL. High-risk disease is defined as T2c or higher, Gleason Score 8 (3+5, 4+4, 5+3) or greater, or a prostate-specific antigen greater than 20 ng/mL. Disease not defined as low or high-risk is defined as intermediate-risk. E: Unadjusted Probability of Reporting No, Very Small or Small Problem with Burning on Urination, Longitudinally by Treatment in All Men. This individual item from the Expanded Prostate Cancer Index Composite (EPIC-26) was selected a priori as a secondary outcome based on its clinical relevance. F. Unadjusted Probability of Reporting No, Very Small or Small Problem with Frequent Urination, Longitudinally by Treatment in All Men. This individual item from the Expanded Prostate Cancer Index Composite (EPIC-26) was selected a priori as a secondary outcome based on its clinical relevance.

Figure 4

Association Between Treatment and Bowel Function Outcomes. Outcomes are bowel function domain scores and selected individual items from the Expanded Prostate Cancer Index Composite (EPIC-26). Domain scores range from 0 to 100, with higher score representing better function. Time zero is the date of treatment for radical prostatectomy and external beam radiation therapy patients, and date of diagnosis for active surveillance patients. Minimum clinically important difference for the bowel function domain score is 4 points. Individual item probabilities range from 0 to 100, with higher scores representing a higher probability of favorable outcome. Numbers in the legends indicate the number of men who completed baseline and 36-month bowel function domain surveys for each treatment group. Longitudinal figures extend to 37 months along the x-axis because the interval between treatment and completion of the 36-month survey was greater than 36 months for some patients. A–C: Unadjusted Mean Expanded Prostate Cancer Index Composite (EPIC-26) Bowel Function Domain Score (95% CI), Longitudinally by Treatment in All Men (panel A), Men with Excellent Baseline Domain Score (panel B), and Men with Lower Baseline Domain Score (panel C). A baseline domain score of 100 or above was defined as excellent, and a score below 100 was defined as lower, approximating subgroups of the top quartile and all others. D: Adjusted Mean Point Difference (95% CI) in Expanded Prostate Cancer Index Composite (EPIC-26) Bowel Function Domain Score Between Groups at 3 Years. Forest plots depict the covariate adjusted effect of treatment, baseline bowel function domain score, age, and D’Amico risk stratum on domain score at 3 years, estimated from multivariable regression models that controlled for baseline domain score, age, race, comorbidity, prostate cancer risk group, physical function, social support, depression, medical decision-making style and accrual site. Effect size represents the adjusted mean point difference on the EPIC domain score between groups; the group after the colon (:) is the referent, so positive values may be interpreted as better outcome for the group before the colon and negative values indicate a better outcome for the group after the colon. Reference lines indicate the minimum clinically important difference (4 points). eTable 8 contains unadjusted domain scores and number of patients for each subgroup (age, baseline domain score and disease risk group) by treatment. D’Amico risk classification system predicts the risk of recurrence after treatment for clinically localized prostate cancer. Low-risk disease is defined as a clinical stage T2a or less, Gleason Score 6 (3+3) or less, and a prostate-specific antigen less than 10 ng/mL. High-risk disease is defined as T2c or higher, Gleason Score 8 (3+5, 4+4, 5+3) or greater, or a prostate-specific antigen greater than 20 ng/mL. Disease not defined as low or high-risk is defined as intermediate-risk. E: Unadjusted Probability of Reporting No, Very Small or Small Problem with Bowel Urgency, Longitudinally by Treatment in All Men. This individual item from the Expanded Prostate Cancer Index Composite (EPIC-26) was selected a priori as a secondary outcome based on its clinical relevance. F. Unadjusted Probability of Reporting No, Very Small or Small Problem with Bowel Function Bother, Longitudinally by Treatment in All Men. This individual item from the Expanded Prostate Cancer Index Composite (EPIC-26) was selected a priori as a secondary outcome based on its clinical relevance.

Figure 5

Association Between Treatment and Hormone Function Outcomes. Outcomes are hormone function domain scores from the Expanded Prostate Cancer Index Composite (EPIC-26). Domain scores range from 0 to 100, with higher score representing better function. Time zero is the date of treatment for radical prostatectomy and external beam radiation therapy patients, and date of diagnosis for active surveillance patients. Minimum clinically important difference for the bowel function domain score is 4 points. Numbers in the legends indicate the number of men who completed baseline and 36-month hormone function domain surveys for each treatment group. Longitudinal figures extend to 37 months along the x-axis because the interval between treatment and completion of the 36-month survey was greater than 36 months for some patients. A–C: Unadjusted Mean Expanded Prostate Cancer Index Composite (EPIC-26) Hormone Function Domain Score (95% CI), Longitudinally by Treatment in All Men (panel A), Men with Excellent Baseline Domain Score (panel B), and Men with Lower Baseline Domain Score (panel C). A baseline domain score of 100 or above was defined as excellent, and a score below 100 was defined as lower, approximating subgroups of the top quartile and all others. D: Adjusted Mean Point Difference (95% CI) in Expanded Prostate Cancer Index Composite (EPIC-26) Hormone Function Domain Score Between Groups at 3 Years. Forest plots depict the covariate adjusted effect of treatment, baseline hormone function domain score, age, and D’Amico risk stratum on domain score at 3 years, estimated from multivariable regression models that controlled for baseline domain score, age, race, comorbidity, prostate cancerrisk group, physical function, social support, depression, medical decision-making style and accrual site. Effect size represents the adjusted mean point difference on the EPIC domain score between groups; the group after the colon (:) is the referent, so positive values may be interpreted as better outcome for the group before the colon and negative values indicate a better outcome for the group after the colon. Reference lines indicate the minimum clinically important difference (4 points). eTable 8 contains unadjusted domain scores and number of patients for each subgroup (age, baseline domain score and disease risk group) by treatment. D’Amico risk classification system predicts the risk of recurrence after treatment for clinically localized prostate cancer. Low-risk disease is defined as a clinical stage T2a or less, Gleason Score 6 (3+3) or less, and a prostate-specific antigen less than 10 ng/mL. High-risk disease is defined as T2c or higher, Gleason Score 8 (3+5, 4+4, 5+3) or greater, or a prostate-specific antigen greater than 20 ng/mL. Disease not defined as low or high-risk is defined as intermediate-risk.

Figure 6

Association Between Treatment and Overall Quality of Life Outcomes. Outcomes are domain scores on the Short Form-36 (physical function, emotional well-being and energy/fatigue). Domain scores range from 0 to 100, with higher score representing better function or less disability. Time zero is the date of treatment for radical prostatectomy and external beam radiation therapy patients, and date of diagnosis for active surveillance patients. Numbers in the legends indicate the number of men who completed baseline and 36-month hormone function domain surveys for each treatment group. Longitudinal figures extend to 37 months along the x-axis because the interval between treatment and completion of the 36-month survey was greater than 36 months for some patients. A–C: Unadjusted Mean Short-Form 36 Overall Quality of Life Domain Scores (95% CI), Longitudinally by Treatment. Physical Function (panel A); Emotional Well-Being (panel B); and Energy/Fatigue (panel C). D–F: Adjusted Mean Point Difference (95% CI) in Short Form 36 (SF-36) Overall Quality of Life Domain Scores Between Groups at 3 Years. Forest plots depict the covariate adjusted effect of treatment, baseline SF-36 domain score, and baseline Expanded Prostate Cancer Index Composite -26 (EPIC-26) sexual and urinary incontinence domain scores, and on SF-36 domain score at 3 years, estimated from multivariable regression models that controlled for age, race, comorbidity, prostate cancer risk group, physical function, social support, depression, medical decision-making style and accrual site. Effect size represents the adjusted mean point difference on the SF-36 domain score between groups; the group after the colon (:) is the referent, so positive values may be interpreted as better outcome for the group before the colon and negative values indicate a better outcome for the group after the colon. Reference lines indicate the minimum clinically important difference for each domain (7 points for Physical Functioning, 6 points for Emotional Well-Being, and 9 points for Energy/Fatigue). eTable 8 contains unadjusted domain scores and number of patients for each subgroup (age, baseline domain score and disease risk group) by treatment.