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Who Bears the Greatest Burden of Aggressive Treatment of Indolent Prostate Cancer?

Published:January 30, 2015DOI:https://doi.org/10.1016/j.amjmed.2014.12.030

      Abstract

      Purpose

      The long-term prostate cancer-specific survival for patients initially managed with active surveillance for low-risk prostate cancer ranges from 97% to 100%. We characterized factors that are associated with aggressive treatment with radical prostatectomy or radiation for indolent prostate cancer (defined as screening-detected, low-risk disease).

      Methods

      The Surveillance, Epidemiology, and End Results Program was used to extract a cohort of 39,803 men diagnosed with prostate-specific antigen–detected, low-risk prostate cancer (clinical category T1c, Gleason score ≤6, and prostate-specific antigen <10) from 2004 to 2010. After socioeconomic profiles were generated from county-linked education and income data, multivariable logistic regression was used to determine whether there were any factors associated with high rates of aggressive treatment.

      Results

      The rate of aggressive treatment among all men with indolent prostate cancer was 64.3%. Greater rates of aggressive treatment were experienced by men with high socioeconomic status, Caucasian men, and married men (P < .001 for all cases). The increased adjusted odds for receipt of aggressive therapy were 1.25 (95% confidence interval [CI], 1.17-1.32; P < .001), 1.26 (95% CI, 1.21-1.32; P < .001), and 1.88 (95% CI, 1.80-1.97; P < .001) for men with high socioeconomic status, Caucasian men, and married men, respectively, compared with men with low socioeconomic status, non-Caucasian men, and unmarried men, respectively.

      Conclusions

      Although men with high socioeconomic status, Caucasian men, and married men often receive the highest quality health care and have the best outcomes for many cancers, it seems that they are most at risk for the avoidable potential harms of aggressive treatment of indolent prostate cancer. Future policy should encourage more stringent guidelines for deferred treatment and culturally and sociodemographically competent counseling of active surveillance.

      Keywords

      Clinical Significance
      • Despite 97% to 100% long-term prostate cancer-specific survival for patients managed with active surveillance, the rate of aggressive treatment among men with indolent prostate cancer remains high.
      • Although men with high socioeconomic status, Caucasian men, and married men often receive the highest quality health care, they are the most at risk groups for overtreatment of indolent prostate cancer.
      • Policy should encourage more stringent guidelines for deferred treatment and culturally and sociodemographically competent counseling of active surveillance.
      Prostate cancer represents the most common noncutaneous malignancy in developed nations, with 650,000 new diagnoses and 136,500 deaths due to disease in 2008.
      • Jemal A.
      • Bray F.
      • Center M.M.
      • Ferlay J.
      • Ward E.
      • Forman D.
      Global cancer statistics.
      Although prostate-specific antigen screening reduces prostate cancer-specific mortality, overuse and misuse of prostate-specific antigen screening could lead to diagnoses of indolent low-risk tumors that would have otherwise not become life threatening.
      • Cooperberg M.R.
      • Broering J.M.
      • Kantoff P.W.
      • Carroll P.R.
      Contemporary trends in low risk prostate cancer: risk assessment and treatment.
      An increasing proportion of prostate cancer diagnoses are characterized as nonpalpable clinical T1c disease with ongoing trends toward low-risk features at presentation.
      • Cooperberg M.R.
      • Broering J.M.
      • Kantoff P.W.
      • Carroll P.R.
      Contemporary trends in low risk prostate cancer: risk assessment and treatment.
      Overdiagnosis of prostate-specific antigen-detected low-risk disease has led to high rates of overtreatment, resulting in many unnecessary side effects and detriments in quality of life, attenuating the aggregate benefits of prostate-specific antigen-based screening.
      • Heijnsdijk E.A.
      • Wever E.M.
      • Auvinen A.
      • et al.
      Quality-of-life effects of prostate-specific antigen screening.
      • Loeb S.
      • Bjurlin M.A.
      • Nicholson J.
      • et al.
      Overdiagnosis and overtreatment of prostate cancer.
      Deferred treatment with watchful waiting or active surveillance represents an important alternative to definitive therapy for indolent disease that may minimize the burden of overdiagnosis and harms of overtreatment.
      • Cooperberg M.R.
      • Carroll P.R.
      • Klotz L.
      Active surveillance for prostate cancer: progress and promise.
      • Ganz P.A.
      • Barry J.M.
      • Burke W.
      • et al.
      National Institutes of Health State-of-the-Science Conference: role of active surveillance in the management of men with localized prostate cancer.
      Several studies have reported less than 3% prostate cancer-specific mortality at up to 10 years among men who undergo active surveillance as initial management for localized prostate cancer.
      • Stattin P.
      • Holmberg E.
      • Johansson J.E.
      • et al.
      Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study.
      • Godtman R.A.
      • Holmberg E.
      • Khatami A.
      • et al.
      Outcome following active surveillance of men with screen-detected prostate cancer. Results from the Goteborg randomised population-based prostate cancer screening trial.
      • Bul M.
      • Zhu X.
      • Valdagni R.
      • et al.
      Active surveillance for low-risk prostate cancer worldwide: the PRIAS study.
      Although the use of surveillance is increasing in developed nations, treatment of prostate-specific antigen-detected low-risk disease still occurs at high rates, and overtreatment of clinically indolent prostate cancer remains a global concern.
      • Loeb S.
      • Bjurlin M.A.
      • Nicholson J.
      • et al.
      Overdiagnosis and overtreatment of prostate cancer.
      • Cooperberg M.R.
      • Carroll P.R.
      • Klotz L.
      Active surveillance for prostate cancer: progress and promise.
      • Godtman R.A.
      • Holmberg E.
      • Khatami A.
      • et al.
      Outcome following active surveillance of men with screen-detected prostate cancer. Results from the Goteborg randomised population-based prostate cancer screening trial.
      • Loeb S.
      • Berglund A.
      • Stattin P.
      Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer.
      Although interventions targeting groups that are susceptible to overtreatment may be effective in reducing rates of unnecessary treatment for low-risk disease, there is little literature that characterizes the patients most likely to be treated aggressively for indolent disease.
      • Loeb S.
      • Berglund A.
      • Stattin P.
      Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer.
      • Miller D.C.
      • Gruber S.B.
      • Hollenbeck B.K.
      • et al.
      Incidence of initial local therapy among men with lower-risk prostate cancer in the United States.
      • Harlan S.R.
      • Cooperberg M.R.
      • Elkin E.
      • et al.
      Time trends and characteristics of men choosing watchful waiting for initial treatment of localized prostate cancer: results from CaPSURE.
      • Cooperberg M.R.
      • Broering J.M.
      • Carroll P.R.
      Time trends and local variation in primary treatment of localized prostate cancer.
      The aim of this study was to determine whether sociodemographic factors, such as socioeconomic status, marital status, and race, are associated with aggressive treatment among men with indolent, prostate-specific antigen-detected low-risk prostate cancer using the national US Surveillance, Epidemiology, and End Results (SEER) database.

      Surveillance, Epidemiology, and End Results (SEER) Program: Research Data (1973-2010), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, based on November 2012 SEER data submission, posted to the SEER web site. Available at: www.seer.cancer.gov. Accessed April 15, 2013.

      Materials and Methods

      Patient Population and Study Design

      Sponsored by the National Cancer Institute, the SEER program collects and publishes cancer incidence, survival, and treatment data from population-based cancer registries; the 17 tumor registries encompass approximately 28% of the US population and capture approximately 97% of incident cancers.

      Surveillance, Epidemiology, and End Results (SEER) Program: Research Data (1973-2010), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, based on November 2012 SEER data submission, posted to the SEER web site. Available at: www.seer.cancer.gov. Accessed April 15, 2013.

      The SEER program was used to identify 39,803 men diagnosed with prostate-specific antigen-detected, low-risk prostate (clinical category T1c, Gleason score ≤6, and prostate-specific antigen <10)

      NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer 2014. Available at: http://www.nccn.org. Accessed December 30, 2013.

      from 2004 to 2010. The inclusion period was limited to 2004 to 2010, because 2004 represents the year that SEER initiated collection of prostate-specific antigen data and 2010 represents the most recent year for which full information is available. As provided by SEER, Gleason scores represent the highest Gleason score identified at surgery or at biopsy for nonsurgically managed patients, whereas stage was determined using the American Joint Committee on Cancer 6th edition.

      Surveillance, Epidemiology, and End Results (SEER) Program: Research Data (1973-2010), National Cancer Institute, DCCPS, Surveillance Research Program, Surveillance Systems Branch, based on November 2012 SEER data submission, posted to the SEER web site. Available at: www.seer.cancer.gov. Accessed April 15, 2013.

      Of note, the number of cores obtained at biopsy and prostate-specific antigen density are not recorded by the registries.
      Patient composite socioeconomic status was evaluated using income (computed as median household income) and educational status (computed as the percentage of residents aged ≥25 years with at least a high school education), which were both determined at the county level by linking to the 2000 US Census.

      US Census Bureau. Census 2000 Gateway. [online database]. Available at: http://www.census.gov/main/www/cen2000html. Accessed December 27, 2013.

      Specifically, socioeconomic status profiles were generated from income and educational status data to analyze treatment trends by socioeconomic strata. This was done by separately stratifying income and educational status into quartiles and assigning the following values to each quartile: first quartile = 1; second quartile = 2; third quartile = 3; and fourth quartile = 4. These values were subsequently added across income and education quartiles creating a composite (income + educational status) socioeconomic score ranging from 2 to 8. These scores were then translated into the following socioeconomic status profiles: income + educational status scores of 2 to 3 represented low socioeconomic status, 4 to 6 represented middle socioeconomic status, and 7 to 8 represented high socioeconomic status.
      Residence type (urban vs rural) also was determined at the county level by linking to the 2003 US Department of Agriculture rural-urban continuum codes.

      US Department of Agriculture Rural-Urban Continuum Codes. [online database] Available at: http://www.ers.usda.gov/data-products/rural-urban-continuum-codes.aspx. Accessed December 27, 2013.

      The demographics of race and marital status were classified as Caucasian vs other race (African American, Spanish/Hispanic/Latino, Asian or Pacific Islander, Native American) and married vs unmarried, respectively. Last, initial management was defined as aggressive treatment vs nonaggressive management. Aggressive treatment consisted of definitive therapy as classified according to the National Comprehensive Cancer Network guidelines and included radical prostatectomy, external beam radiation therapy, brachytherapy, or any combination thereof.

      NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer 2014. Available at: http://www.nccn.org. Accessed December 30, 2013.

      SEER only documents treatments that are received within 12 months of cancer diagnosis as first-course therapies.

      Statistical Analyses

      The primary outcome measure of interest was receipt of aggressive definitive therapy. Baseline clinical and demographic characteristics were compared using the Wilcoxon rank-sum test for continuous variables, chi-square test for categoric variables, and Mantel-Haenszel test for ordinal variables. Univariable and multivariable logistic regression analyses were used to model the probability of receiving aggressive therapy. The covariates of interest included in the logistic regression models were socioeconomic status (low [reference] vs middle vs high), race (Caucasian vs other [reference]), marital status (married vs unmarried [reference]), residence (urban vs rural [reference]), age at diagnosis (analyzed as a continuous variable), and prostate-specific antigen (analyzed as a continuous variable). The following multivariable sensitivity logistic regression analyses were also applied to account for life expectancy: (1) a model adjusting for other-cause (nonprostate) mortality within 5 years of prostate cancer diagnosis as a proxy for comorbidity, as previously reported
      • Mahal B.A.
      • Aizer A.A.
      • Ziehr D.R.
      • et al.
      Trends in disparate treatment of African American men with localized prostate cancer across NCCN Risk Groups.
      ; (2) a model limiting the cohort to life expectancy <20 years based on Social Security actuarial life tables, because active surveillance is recommended for patients with very low-risk disease and less than 20-year life expectancy

      NCCN Clinical Practice Guidelines in Oncology. Prostate Cancer 2014. Available at: http://www.nccn.org. Accessed December 30, 2013.

      Social Security Actuarial Life Table. [online database]. Available at: www.ssa.gov/OACT/STATS/table4c6.html. Accessed April 1, 2014.

      ; and (3) a model adjusting for insurance status (data on insurance data were introduced recently to SEER and are only available from 2007-2010). Furthermore, a multiplicative multivariable logistic regression model was used to test for an interaction between race and socioeconomic status to determine whether any potential association of socioeconomic status on receipt of aggressive therapy differed by race. Men were only included (N = 39,779) in analyses if data on the covariates defined were available (N = 24 excluded because of missing sociodemographic information).
      All P values were 2 sided. The threshold of .05 was used to determine statistical significance. Statistical analyses were completed using STATA 13.0 (StataCorp LP, College Station, Tex) for all analyses. This study was approved by the institutional review board; a waiver for informed consent was obtained.

      Results

      Baseline patient clinical and demographic characteristics stratified by initial management type are shown in Table 1. Of note, patients initially managed with aggressive treatment were more likely to be younger, Caucasian, and married, and to come from areas of higher median household income and education status, compared with patients who were not managed aggressively (P ≤ .01 for all comparisons) (Table 1). Baseline prostate-specific antigen values stratified by socioeconomic status, race, and marital status are displayed in Table 2.
      Table 1Baseline Clinical and Demographic Characteristics
      CharacteristicReceived Aggressive Treatment
      Aggressive treatment included radical prostatectomy, external beam radiation therapy, brachytherapy, or any combination thereof.
      (N = 25,590)
      Did Not Receive Aggressive Treatment
      Aggressive treatment included radical prostatectomy, external beam radiation therapy, brachytherapy, or any combination thereof.
      (N = 14,189)
      P Value
      Age, y, mean (SD)65 (8)66 (9)<.001
      Income, US dollars, mean (SD)
      County-level data.
      48,100 (12,100)47,800 (12,000).01
      Percent who completed high school, mean (SD)
      County-level data.
      80.1 (7.4)79.5 (7.5)<.001
      Race, N (%)<.001
       Caucasian18,496 (72.3)9386 (66.1)
       Non-Caucasian7094 (27.7)4803 (33.9)
      Married, N (%)<.001
       Yes18,792 (73.4)8413 (59.3)
       No6798 (26.6)5776 (40.7)
      Residence, N (%)
      County-level data.
      .30
       Rural2756 (10.8)1478 (10.4)
       Urban22,834 (89.2)12,711 (89.6)
      Socioeconomic status, N (%)
      County-level data.
      <.001
       Low8322 (32.5)5094 (35.9)
       Middle9898 (38.7)5694 (40.1)
       High7370 (28.8)3401 (24.0)
      PSA, ng/mL, median (IQR)5.5 (4.5-6.9)5.5 (4.5-7.0).21
      IQR = interquartile range; PSA = prostate-specific antigen; SD = standard deviation.
      Aggressive treatment included radical prostatectomy, external beam radiation therapy, brachytherapy, or any combination thereof.
      County-level data.
      Table 2Baseline Prostate-Specific Antigen for the Significant Predictors of Receipt of Aggressive Treatment (Socioeconomic Status, Race, Marital Status) (N = 39,779)
      CharacteristicPSA, ng/mL, Median (IQR)P Value
      Socioeconomic Status<.001
       Low5.6 (4.6-7.0)
       Middle5.6 (4.5-7.0)
       High5.4 (4.4-6.8)
      Race<.001
       Caucasian5.5 (4.5-6.9)
       Non-Caucasian5.6 (4.6-7.1)
      Married.75
       Yes5.5 (4.5-7.0)
       No5.5 (4.5-7.0)
      IQR = interquartile range; PSA = prostate-specific antigen.
      Among the entire cohort of men with indolent disease, the rate of receipt of aggressive therapy was 64.3%. Men who received higher rates of aggressive treatment for indolent disease were more likely to have a high socioeconomic status, to be married, and to be Caucasian (P < .001 in all cases). Specifically, men with high socioeconomic status received treatment at a rate of 68.4% compared with 62.0% of men with low socioeconomic status (odds ratio [OR], 1.33; 95% confidence interval [CI], 1.26-1.40; P < .001), 66.3% of Caucasians underwent aggressive therapy as opposed to 59.6% of non-Caucasians (OR, 1.33; 95% CI, 1.28-1.39; P < .001), and married men were treated at a rate of 69.1% vs 54.1% among unmarried men (OR, 1.90; 95% CI, 1.82-1.98; P < .001) (Table 3). After adjusting for all covariates, the adjusted odds of receiving aggressive therapy were 1.25 (95% CI, 1.17-1.32; P < .001), 1.26 (95% CI, 1.21-1.32; P < .001), and 1.88 (95% CI, 1.80-1.97; P < .001) among men with high socioeconomic status, Caucasian men, and married men, respectively (Table 3). When adjusting for the comorbidity proxy or insurance status—although the comorbidity proxy was strongly negatively associated with receipt of aggressive therapy and being insured was strongly positively associated with receipt of aggressive therapy—associations among high socioeconomic status, Caucasian, and married status with receipt of aggressive therapy remained significant and nearly unchanged (Table 4). Also, when limiting the analysis to patients with <20-year life expectancy, all previously mentioned associations remained significant (P < .001 for all cases) (Table 4). Of note, among cases diagnosed from 2007 to 2010, we found that patients with high socioeconomic status were slightly more likely to be insured compared with patients with low socioeconomic status (99.0% vs 98.4%; P = .007), married patients were slightly more likely to be insured compared with nonmarried patients (99.1% vs 98.1%; P < .001), and Caucasian patients were slightly more likely to be insured compared with nonwhite minorities (99.2% vs 97.9%; P < .001).
      Table 3Univariable and Multivariable Logistic Regression for Receipt of Aggressive Therapy (Radical Prostatectomy or Radiation) Among Men with Indolent Prostate Cancer (Clinical Category T1c, Gleason Score ≤6, and Prostate-Specific Antigen <10) (N = 39,779)
      CharacteristicUnivariable AnalysisMultivariable Analysis
      OR (95% CI)P ValueAdjusted OR (95% CI)P Value
      Race
       Non-Caucasian1.0 (ref)1.0 (ref)
       Caucasian1.33 (1.28-1.39)<.0011.26 (1.21-1.32)<.001
      Socioeconomic Status
       Low1.0 (ref)1.0 (ref)
       Middle1.07 (1.02-1.12).0091.04 (0.99-1.10).101
       High1.33 (1.26-1.40)<.0011.25 (1.17-1.32)<.001
      Marital Status
       Not married1.0 (ref)1.0 (ref)
       Married1.90 (1.82-1.98)<.0011.88 (1.80-1.97)<.001
      Residence
       Rural1.0 (ref)1.0 (ref)
       Urban0.96 (0.90-1.03).270.93 (0.86-0.99).040
      Age (per year increase)0.99 (0.98-0.99)<.0010.98 (0.98-0.99)<.001
      PSA (per ng/mL increase)0.99 (0.99-1.00).211.0 (0.99-1.00).097
      OR = odds ratio; PSA = prostate-specific antigen.
      Table 4Multivariable Sensitivity Logistic Regression Analyses for Receipt of Aggressive Therapy (Radical Prostatectomy or Radiation) Among Men with Indolent Prostate Cancer (Clinical Category T1c, Gleason Score ≤6, and Prostate-Specific Antigen <10)
      CharacteristicSensitivity Analysis (1)
      Sensitivity analysis (1) adjusts for other cause (nonprostate) mortality within 5 years of prostate cancer diagnosis as a proxy for comorbidity; N = 39,779.
      Sensitivity Analysis (2)
      Sensitivity analysis (2) limits the cohort to life expectancy <20 years based on Social Security actuarial life tables; N = 27,481.
      Sensitivity Analysis (3)
      Sensitivity analysis (3) adjusts for insurance status (data only available from 2007-2010); N = 18,806.
      OR (95% CI)P ValueAdjusted OR (95% CI)P ValueAdjusted OR (95% CI)P Value
      Other Cause Mortality/Comorbidity Proxy
       No comorbidity1.0 (ref)N/AN/A
       Comorbidity0.62 (0.56-0.70)<.001N/AN/A
      Insurance Status
       UninsuredN/AN/A1.0 (ref)
       InsuredN/AN/A1.49 (1.14-1.94).003
      Race
       Non-Caucasian1.0 (ref)1.0 (ref)1.0 (ref)
       Caucasian1.26 (1.21-1.32)<.0011.27 (1.20-1.34)<.0011.27 (1.18-1.34)<.001
      Socioeconomic Status
       Low1.0 (ref)1.0 (ref)1.0 (ref)
       Middle1.04 (0.99-1.09).131.04 (0.98-1.11).170.91 (0.85-0.98).01
       High1.24 (1.17-1.31)<.0011.20 (1.12-1.28)<.0011.10 (1.01-1.19).027
      Marital Status
       Not married1.0 (ref)1.0 (ref)1.0 (ref)
       Married1.87 (1.79-1.95)<.0011.91 (1.81-2.02)<.0011.61 (1.51-1.72)<.001
      Residence
       Rural1.0 (ref)1.0 (ref)1.0 (ref)
       Urban0.92 (0.86-0.99).030.94 (0.86-1.02).150.84 (0.76-0.93).001
      Age (per year increase)0.98 (0.98-0.99)<.0010.95 (0.94-0.95)<.0010.99 (0.98-0.99)<.001
      PSA (per ng/mL increase)1.00 (0.99-1.00).061.00 (0.99-1.00).811.00 (0.99-1.00).01
      CI = confidence interval; N/A = not applicable; OR = odds ratio; PSA = prostate-specific antigen.
      Sensitivity analysis (1) adjusts for other cause (nonprostate) mortality within 5 years of prostate cancer diagnosis as a proxy for comorbidity; N = 39,779.
      Sensitivity analysis (2) limits the cohort to life expectancy <20 years based on Social Security actuarial life tables; N = 27,481.
      Sensitivity analysis (3) adjusts for insurance status (data only available from 2007-2010); N = 18,806.
      Furthermore, a significant interaction between race and high socioeconomic status was found (Pinteraction = .048) such that high socioeconomic status had a higher impact on the odds of receiving aggressive treatment among non-Caucasians compared with Caucasians (Table 5). Specifically, although Caucasian men of high socioeconomic status received treatment at a higher rate than Caucasian men of low socioeconomic status (adjusted OR, 1.14; 95% CI, 1.07-1.23; P < .001), the effect of high socioeconomic status vs low socioeconomic status on receipt of aggressive treatment was significantly greater among non-Caucasian minority men (adjusted OR, 1.46; 95% CI, 1.32-1.62; P < .001).
      Table 5Assessment of Effect Modification Between Socioeconomic Status (High vs Low) and Race (Caucasian vs non-Caucasian) for the Outcome of Receipt of Aggressive Therapy (Radical Prostatectomy or Radiation)
      CharacteristicMultivariable Analysis
      Multivariable analyses are adjusted for race, socioeconomic status, age, residence (urban vs rural), marital status (married vs not married), and prostate-specific antigen.
      Adjusted OR (95% CI)P Value
      Interaction for Employment of Aggressive Therapy
      P value for interaction term tests whether there is a significant difference in the OR between Caucasian men of high socioeconomic status and non-Caucasian men of high socioeconomic status.
      .048
      P value for interaction term tests whether there is a significant difference in the OR between Caucasian men of high socioeconomic status and non-Caucasian men of high socioeconomic status.
       Caucasian Men
      Low SESReference (1.0)<.001
      High SES1.14 (1.07-1.23)
       Non-Caucasian Men
      Low SESReference (1.0)<.001
      High SES1.46 (1.32-1.62)
      All men were diagnosed with indolent prostate cancer (clinical category T1c, Gleason score ≤6, and prostate-specific antigen <10); N = 39,779.
      CI = confidence interval; OR = odds ratio; SES = socioeconomic status.
      Multivariable analyses are adjusted for race, socioeconomic status, age, residence (urban vs rural), marital status (married vs not married), and prostate-specific antigen.
      P value for interaction term tests whether there is a significant difference in the OR between Caucasian men of high socioeconomic status and non-Caucasian men of high socioeconomic status.

      Discussion

      By using a large contemporary cohort of patients from the SEER database, we found that 64.3% of patients with prostate-specific antigen-detected low-risk prostate cancer diagnosed from 2004 to 2010 were treated aggressively with radical prostatectomy or radiation. After adjusting for pertinent covariates, we found that men with high socioeconomic status, Caucasian men, and married men were 25%, 26%, and 88% more likely to receive aggressive treatment compared with men if low socioeconomic status, non-Caucasian men, and unmarried men, respectively.
      Men with high socioeconomic status, Caucasian men, and married men with aggressive cancers typically benefit from more guideline concordant cancer care, better cancer outcomes, and care at higher quality and volume centers.
      • Underwood W.
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      However, in the case of indolent prostate cancer, our results demonstrate that these factors are associated with high rates of potentially detrimental aggressive treatment. Specifically, given that patients with indolent prostate cancer are unlikely to die of the disease, those who are treated aggressively may unnecessarily experience the morbidities associated with surgery or radiation,
      • Resnick M.J.
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      • Fan K.H.
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      Long-term functional outcomes after treatment for localized prostate cancer.
      with little to no benefit from treatment.
      • Stattin P.
      • Holmberg E.
      • Johansson J.E.
      • et al.
      Outcomes in localized prostate cancer: National Prostate Cancer Register of Sweden follow-up study.
      • Godtman R.A.
      • Holmberg E.
      • Khatami A.
      • et al.
      Outcome following active surveillance of men with screen-detected prostate cancer. Results from the Goteborg randomised population-based prostate cancer screening trial.
      • Bul M.
      • Zhu X.
      • Valdagni R.
      • et al.
      Active surveillance for low-risk prostate cancer worldwide: the PRIAS study.
      Men of high socioeconomic status and Caucasian men with prostate cancer have greater access to healthcare and health insurance coverage compared with men of low socioeconomic status and minority men,
      • Rundle A.
      • Neckerman K.M.
      • Sheehan D.
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      which may be the underlying driver of high rates of aggressive therapy for their indolent prostate cancer. Our results demonstrated that men of high socioeconomic status, Caucasian men, and married men were only slightly more likely to be insured compared with men of low socioeconomic status, non-Caucasian men, and unmarried men, respectively, indicating that differences in rates of insurance coverage probably were not a major contributor to the sociodemographic differences in receipt of aggressive therapy observed in our study. However, SEER does not provide information on coverage periods or the details of the insurance plans that patients have, thus differences in insurance policies, coverage, network, and so on could have contributed to sociodemographic differences in receipt of aggressive treatment such that men of low socioeconomic status, non-Caucasian men, and unmarried men were shunted toward less costly alternatives.
      Furthermore, individual-level patient and provider characteristics, including cultural beliefs, social support networks, medical trust or mistrust, and willingness to take the risks of treatment rather than tolerate the uncertainty associated with surveillance could lead to higher rates of aggressive therapy among men of high socioeconomic status, Caucasian men, or married men.
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      For example, studies from European populations have suggested that men of higher education level or from more affluent areas were more likely to seek aggressive treatment for prostate cancer—a behavior that may be driven by trust in provider-delivered therapies and willingness to receive treatment despite potential risks and side effects.
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      • Berglund A.
      • Stattin P.
      Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer.
      • McVey G.P.
      • McPhail S.
      • Fowler S.
      • et al.
      Initial management of low-risk localized prostate cancer in the UK: analysis of the British Association of Urological Surgeons Cancer Registry.
      Schulman et al
      • Schulman K.A.
      • Berlin J.A.
      • Harless W.
      • et al.
      The effect of race and sex on physicians' recommendations for cardiac catheterization.
      found that patient race independently influences physician treatment recommendations, with physicians more likely to recommend aggressive therapy for white patients compared with black patients when presented with hypothetical cases of chest pain. Thus, it is possible that physicians may be more likely to recommend aggressive therapy for more affluent, Caucasian, or married patients with low-risk prostate cancer. Last, being married has been suggested to reflect greater social support, and married patients receive higher rates of treatment for cancer likely as a result of encouragement by spouses or partners.
      • Aizer A.A.
      • Chen M.H.
      • McCarthy E.P.
      • et al.
      Marital status and survival in patients with cancer.
      Although beneficial in most settings, encouragement from a spouse or partner might provoke an individual with otherwise indolent disease to undergo potentially unnecessary treatment.
      As stated earlier, previous European studies have found that men with higher socioeconomic status are more likely to seek immediate treatment for prostate cancer,
      • Loeb S.
      • Berglund A.
      • Stattin P.
      Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer.
      • McVey G.P.
      • McPhail S.
      • Fowler S.
      • et al.
      Initial management of low-risk localized prostate cancer in the UK: analysis of the British Association of Urological Surgeons Cancer Registry.
      but because the majority of patients were Caucasian, the interaction of socioeconomic status with race was unknown. Our study found a novel significant interaction between socioeconomic status and race such that high socioeconomic status led to greater increases in the odds of receiving treatment among non-Caucasian men compared with Caucasian men. Specifically, Caucasian men of high socioeconomic status were 14% more likely to receive aggressive treatment compared with Caucasian men of low socioeconomic status, whereas non-Caucasian men of high socioeconomic status were 46% more likely to be managed aggressively compared with non-Caucasians of low socioeconomic status. Because Caucasians may already have a relatively high level of access to care, increasing socioeconomic status may affect the treatment patterns of Caucasians less than it would for non-Caucasians. Furthermore, the greater increase in receipt of aggressive treatment among minority men of high socioeconomic status compared with Caucasian men (in whom high socioeconomic status is likely associated with greater access to care) may be driven by the higher rates of prostate cancer and a higher risk for prostate cancer mortality among African American men compared with white men.
      • Jemal A.
      • Bray F.
      • Center M.M.
      • Ferlay J.
      • Ward E.
      • Forman D.
      Global cancer statistics.
      The existing literature is sparse with regard to overtreatment trends by race and marital status. Studies looking at low-risk deferred treatment trends in European populations were unable to report results by race due to relatively homogenous study cohorts.
      • Loeb S.
      • Berglund A.
      • Stattin P.
      Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer.
      • McVey G.P.
      • McPhail S.
      • Fowler S.
      • et al.
      Initial management of low-risk localized prostate cancer in the UK: analysis of the British Association of Urological Surgeons Cancer Registry.
      Furthermore, an earlier SEER study did not report results by race.
      • Miller D.C.
      • Gruber S.B.
      • Hollenbeck B.K.
      • et al.
      Incidence of initial local therapy among men with lower-risk prostate cancer in the United States.
      Therefore, our findings that Caucasian men are more susceptible to aggressive treatment for indolent disease are novel and should guide future efforts that seek to reduce unnecessary aggressive treatment rates. Furthermore, although one study found a modest association between initial management type for indolent prostate cancer and marital status in a Swedish cohort,
      • Loeb S.
      • Berglund A.
      • Stattin P.
      Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer.
      our findings demonstrated that being married was associated strongly with high rates of aggressive treatment for indolent disease. This finding is particularly important because it highlights the need not only to counsel patients about the option and potential benefits of active surveillance but also to share this information with social support and family members who may share in the treatment decision process.
      Although differences in the adjusted odds of aggressive treatment by socioeconomic status, race, and marital status ranged from 25% to 88%, absolute rates of aggressive treatment by the aforementioned sociodemographics only differed by 2.4% to 15.0%. Such small differences in absolute rates of aggressive treatment by sociodemographics suggest that the overall treatment rate of 64.3% may be indicative of overtreatment among all men with newly diagnosed indolent prostate cancer. In the setting of our findings, it is important to note that although deferred treatment represents an important alternative management approach for indolent prostate cancer and may be more effective and less costly compared with initial aggressive management with definitive treatment among men aged 65 to 75 years,
      • Hayes J.H.
      • Ollendorf D.A.
      • Pearson S.D.
      • et al.
      Active surveillance compared with initial treatment for men with low-risk prostate cancer: a decision analysis.
      widespread acceptance of surveillance has been difficult to achieve among all men regardless of sociodemographics.
      • Ganz P.A.
      • Barry J.M.
      • Burke W.
      • et al.
      National Institutes of Health State-of-the-Science Conference: role of active surveillance in the management of men with localized prostate cancer.
      • Barocas D.A.
      • Cowan J.E.
      • Smith J.A.
      • Carroll P.R.
      What percentage of patients with newly diagnosed carcinoma of the prostate are candidates for surveillance? An analysis of the CaPSURE database.
      Because there are no guarantees that men will not progress on surveillance and there are concerns of undersampling and undergrading/staging of low-risk disease, some men with higher access to care may be reluctant to pursue a surveillance strategy.
      • Dianat S.S.
      • Carter H.B.
      • Macura K.J.
      Performance of multiparametric magnetic resonance imaging in the evaluation and management of clinically low-risk prostate cancer.
      More accurate identification of precisely which men are appropriate for surveillance may lead to more widespread acceptance of deferred treatment among both patients and physicians. Specifically, methods for selecting those appropriate for surveillance for indolent disease could include more personalized risk stratification as afforded by tools such as the University of California, San Francisco Cancer of the Prostate Risk Assessment score, use of magnetic resonance imaging to rule out potentially higher-grade lesions that could be targeted for biopsy, and novel clinical and molecular markers as they become available.
      • Cooperberg M.R.
      • Broering J.M.
      • Kantoff P.W.
      • Carroll P.R.
      Contemporary trends in low risk prostate cancer: risk assessment and treatment.
      • Cooperberg M.R.
      • Carroll P.R.
      • Klotz L.
      Active surveillance for prostate cancer: progress and promise.
      • Dianat S.S.
      • Carter H.B.
      • Macura K.J.
      Performance of multiparametric magnetic resonance imaging in the evaluation and management of clinically low-risk prostate cancer.
      • van den Bergh R.C.
      • Ahmed H.U.
      • Bangma C.H.
      • et al.
      Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review.
      • Cooperberg M.R.
      • Broering J.M.
      • Carroll P.R.
      Risk assessment for prostate cancer metastasis and mortality at the time of diagnosis.
      Magnetic resonance imaging has a high specificity for low-risk prostate cancer, and currently available imaging techniques hold promise for improving patient selection for surveillance.
      • Cooperberg M.R.
      • Broering J.M.
      • Carroll P.R.
      Risk assessment for prostate cancer metastasis and mortality at the time of diagnosis.
      Likewise, currently available novel markers have the potential to improve current surveillance protocols, increase the number of patients suitable for surveillance, and reduce the burden of monitoring while on surveillance.
      • Cooperberg M.R.
      • Broering J.M.
      • Carroll P.R.
      Risk assessment for prostate cancer metastasis and mortality at the time of diagnosis.
      Still, the use of magnetic resonance imaging and novel markers should be assessed in prospective clinical trials before widespread adoption.

      Study Limitations

      First, SEER does not report information on comorbidity. However, when we adjusted for other-cause mortality within 5 years of cancer diagnosis as a proxy for comorbidity, all associations remained nearly unchanged. Also, when limiting our analysis to life expectancy <20 years based on Social Security actuarial life tables (given that active surveillance is recommended for those with very low risk disease and <20-year life expectancy),

      Social Security Actuarial Life Table. [online database]. Available at: www.ssa.gov/OACT/STATS/table4c6.html. Accessed April 1, 2014.

      all associations with high rates of treatment remained significant. The results of our sensitivity analyses suggest that our findings hold even after adjusting for life expectancy and comorbidity. Furthermore, SEER provides income and educational status information at the county level, which may lack the precision of individual or ZIP code level data. Last, SEER does not provide information on prostate-specific antigen density, perineural invasion, or number/percent of positive cores, so we were not able to further stratify our low-risk cohort on the basis of those parameters. Specifically, given the inability of the SEER dataset to distinguish between National Comprehensive Cancer Network low and very low risk disease, our definition of indolent disease included patients with both low risk and very low risk disease, which may have different risks of progression without therapy. So, a theoretic concern is that perhaps men with high socioeconomic status, Caucasian men, and married men have more advanced disease than men with low socioeconomic status, nonwhite men, and unmarried men. However, we found that men with high socioeconomic status and Caucasian men have significantly lower prostate-specific antigens than men with low to mid socioeconomic status and non-Caucasian men, and married and unmarried men have nearly identical prostate-specific antigens (Table 2), indicating that the men presenting with lower prostate-specific antigens are actually the ones being aggressively treated.

      Conclusions

      Our study identifies several factors associated with high rates of aggressive treatment among men with prostate-specific antigen-detected low-risk prostate cancer. Our findings suggest that men from groups that typically receive the highest quality care and benefit from the best cancer outcomes (ie, Caucasian, married, high socioeconomic status) may be the patients who are most at risk from the harms of aggressive overtreatment of prostate-specific antigen-detected low-risk disease. Future interventions and policy should encourage culturally and sociodemographically competent counseling of active surveillance and more stringent guidelines for active surveillance based on sensitive and personalized risk stratification to prevent groups from being disproportionately affected by unnecessary and potentially morbid treatment.

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