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Association of Age With Risk of Adverse Pathological Findings at Radical Prostatectomy in Men With Gleason Score 6 Prostate Cancer

Association of Age With Risk of Adverse Pathological Findings at Radical Prostatectomy in Men... Research Letter | Oncology Association of Age With Risk of Adverse Pathological Findings at Radical Prostatectomy in Men With Gleason Score 6 Prostate Cancer Daniel W. Kim, MD, MBA; Ming-Hui Chen, PhD; Hartwig Huland, MD; Markus Graefen, MD, PhD; Derya Tilki, MD; Anthony V. D’Amico, MD, PhD Introduction The preferred treatment for men with low-risk prostate cancer, particularly men older than 65 years, Author affiliations and article information are 1 listed at the end of this article. is active surveillance. However, advancing age is associated with upgrading and upstaging at radical prostatectomy. Several factors, including increasing prostate-specific antigen (PSA) level, clinical tumor category, percentage of positive biopsy results, and PSA density, have been noted to be associated with clinically significant prostate cancer at radical prostatectomy. Until now, to our knowledge, no study has incorporated these factors within predefined age strata to ascertain whether a cohort of patients at high risk can be identified for whom additional evaluation and possible treatment is indicated rather than active surveillance. Methods This prospective cohort study included men with Gleason score 6 prostate cancer who were treated with radical prostatectomy from February 28, 1992, to February 15, 2016, at the Martini-Klinik Prostate Cancer Center of the University Hospital Hamburg-Eppendorf in Hamburg, Germany. This study was approved, including waivers of consent owing to deidentified data and a no-risk protocol, by the Ethik-Kommission der Ärztekamme institutional review board in Hamburg, Germany. This study was reported following the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. We investigated whether men older than 65 years had increased odds of adverse pathological findings at radical prostatectomy, defined as TNM category pT3/T4 or R1 or Gleason score 8, 9, or 10, compared with men 65 years and younger. We dichotomized age at 65 years, a commonly used cutoff, to enable clinical utility of the results. Descriptive statistics were used to compare the proportion of clinical characteristics at presentation among men older than 65 years vs 65 years and younger using a Wilcoxon rank sum test for continuous covariates and the Maental-Haenszal χ test for categorical covariates. Univariable and multivariable logistic regressions were used to calculate unadjusted and adjusted odds ratios (ORs) of adverse pathological findings at radical prostatectomy in men older than 65 years vs men 65 years and younger, adjusting for pre–radical prostatectomy PSA level, clinical tumor category, year of diagnosis, percentage of positive biopsy results, and PSA density. SAS statistical software version 9.4 (SAS Institute) was used for all statistical analysis. P values were 2-sided, and statistical significance was set at P < .05. Data were analyzed on May 24, 2019. Results A total of 3191 men (median [interquartile range] age, 62 [32-77] years) were included in the study. The median (interquartile range) PSA level was 6.74 (0.14-187.00) ng/mL (to convert to micrograms per liter, multiply by 1), and 2809 men (88.3%) had T category 1c prostate cancer. Men older than 65 years, compared with men 65 years and younger, had a significantly lower median (interquartile range) percentage of positive biopsy results (16.7% [12.5%-33.3%] vs 20.0% [12.5%-37.5%]; P =.01) and PSA density (0.13 [0.09-0.19] ng/mL vs 0.15 [0.11-0.23] ng/mL; P < .001) (Table 1). While Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(4):e202041. doi:10.1001/jamanetworkopen.2020.2041 (Reprinted) April 2, 2020 1/3 JAMA Network Open | Oncology Age and Risk of Adverse Pathological Findings at Radical Prostatectomy in Men With Prostate Cancer increasing percentage of positive biopsy results (adjusted OR per 1-unit increase, 1.02; 95% CI, 1.01- 1.02; P < .001) and PSA density (adjusted OR per 1-unit increase, 4.28; 95% CI, 1.66-11.01; P = .003) were significantly associated with increased odds of adverse pathological findings at radical prostatectomy (Table 2), men older than 65 years had higher odds of adverse pathological findings at radical prostatectomy compared with men 65 years and younger (adjusted OR, 1.28, 95% CI, 1.00- 1.62; P = .048). Discussion This cohort study found that being older than 65 years was associated with adverse pathological findings at radical prostatectomy. Specifically, if being older than 65 years was not associated with increased risk, one would have expected men older than 65 years to have a lower risk of having adverse pathological findings given the more favorable percentage of positive biopsy results and PSA density levels. Possible explanations for the association of advancing age with risk of adverse pathological features include sampling error and undergrading owing to benign prostatic hyperplasia that occurs normally with advancing age. Another possible explanation is that most men undergo andropause starting at approximately age 40 years continuing to the end of life. Therefore, older men are more likely to have lower testosterone levels at prostate cancer diagnosis compared with younger men, and it is known that prostate cancer in men who are hypogonadal can be more aggressive compared with prostate cancer in men who are eugonadal. This study has some limitations, such as that we chose age 65 years as our cutoff for age, as it is commonly used in prostate cancer studies when Table 1. Baseline Distribution of Factors Associated with Adverse Pathological Findings at Radical Prostatectomy Stratified by Age Median (IQR) Characteristic Men aged >65 y (n = 1075) Men aged ≤65 y (n = 2116) P value PSA, ng/mL 6.90 (5.00-10.00) 6.65 (4.92-9.74) .17 T category, No. (%) ≥2a 126 (11.7) 256 (12.1) 1c 949 (88.3) 1860 (87.9) Abbreviations: IQR, interquartile range; PSA, prostate- Year of diagnosis 2008 (2004-2011) 2008 (2003-2011) .92 specific antigen; T, tumor. Positive biopsy results, % 16.7 (12.5-33.3) 20.0 (12.5-37.5) .01 SI conversion factor: To convert PSA level to PSA density, ng/mL/cc 0.13 (0.09-0.19) 0.15 (0.11-0.23) <.001 micrograms per liter, multiple by 1. Table 2. Unadjusted and Adjusted Odds Ratio of Adverse Pathological Findings at Radical Prostatectomy for Each Clinical Characteristic Univariable analysis Multivariable analysis Characteristic Men, No. Events, No. Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value b b Age 3191 377 1.01 (1.00-1.03) .09 1.02 (1.00-1.04) .07 >65 y 1075 133 1.08 (0.87-1.36) .49 1.28 (1.00-1.62) .048 ≤65 y 2116 244 1 [Reference] NA 1 [Reference] NA b b PSA level 3191 377 1.02 (1.01-1.036) .004 0.99 (0.97-1.01) .95 T category ≥2a 382 84 2.42 (1.85-3.17) <.001 1.26 (0.93-1.71) .13 1c 2809 293 1 [Reference] NA 1 [Reference] NA b b Year of diagnosis 3191 377 0.87 (0.85-0.89) <.001 0.89 (0.87-0.91) <.001 b b Positive biopsy results, % 3191 377 1.03 (1.02-1.039) <.001 1.02 (1.01-1.02) <.001 b b PSA density 3191 377 3.23 (1.95-5.35) <.001 4.28 (1.66-11.01) .003 Abbreviations: NA, not applicable; OR, odds ratio; PSA, prostate-specific antigen; Per 1-unit increase. T, tumor. Includes adverse pathological findings at prostatectomy, including T3/T4, R1, and/or Gleason score 8, 9, or 10. JAMA Network Open. 2020;3(4):e202041. doi:10.1001/jamanetworkopen.2020.2041 (Reprinted) April 2, 2020 2/3 JAMA Network Open | Oncology Age and Risk of Adverse Pathological Findings at Radical Prostatectomy in Men With Prostate Cancer distinguishing men of older vs younger age; however, life expectancy using a validated metric, such as the Adult Comorbidity Evaluation-27, may be preferred rather than a specific age cutoff. These findings suggest that men older than 65 years with biopsy-confirmed Gleason score 6 prostate cancer may benefit from additional testing, such as multiparametric magnetic resonance imaging and targeted biopsy before proceeding with active surveillance. If higher grade or stage disease is detected, this information could be used to guide the use and duration of androgen deprivation therapy in men considering radiotherapy. ARTICLE INFORMATION Accepted for Publication: February 2, 2020. Published: April 2, 2020. doi:10.1001/jamanetworkopen.2020.2041 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Kim DW et al. JAMA Network Open. Corresponding Author: Daniel W. Kim, MD, MBA, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, 75 Francis St, ASBI-L2, Boston, MA 02115 (dkim20@partners.org). Author Affiliations: Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, Massachusetts (Kim, D’Amico); Department of Statistics, University of Connecticut, Storrs (Chen); Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany (Huland, Graefen, Tilki); Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (Tilki). Author Contributions: Drs Kim and D’Amico had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Tilki and D’Amico share senior authorship. Concept and design: Graefen, D’Amico. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Kim, Graefen, D’Amico. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Chen, Tilki. Administrative, technical, or material support: Kim, D’Amico. Supervision: Huland, Graefen, D’Amico. Conflict of Interest Disclosures: None reported. REFERENCES 1. Hamdy FC, Donovan JL, Lane JA, et al; ProtecT Study Group. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375(15):1415-1424. doi:10.1056/NEJMoa1606220 2. Klotz L. Active surveillance: patient selection. Curr Opin Urol. 2013;23(3):239-244. doi:10.1097/00042307- 200005000-00010 3. Moore DS, Alwan LC, McCabe GP, Duckworth WM. The Practice of Business Statistics: Using Data for Decisions. 2nd ed. W. H. Freeman; 2008. 4. Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci. 2002;57(2):M76-M99. doi:10.1093/gerona/57.2.M76 5. Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less. Urology. 2006;68(6):1263-1267. doi:10.1016/j.urology.2006.08.1058 6. Piccirillo JF, Tierney RM, Costas I, Grove L, Spitznagel EL Jr. Prognostic importance of comorbidity in a hospital- based cancer registry. JAMA. 2004;291(20):2441-2447. doi:10.1001/jama.291.20.2441 JAMA Network Open. 2020;3(4):e202041. doi:10.1001/jamanetworkopen.2020.2041 (Reprinted) April 2, 2020 3/3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

Association of Age With Risk of Adverse Pathological Findings at Radical Prostatectomy in Men With Gleason Score 6 Prostate Cancer

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Publisher
American Medical Association
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Copyright 2020 Kim DW et al. JAMA Network Open.
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2574-3805
DOI
10.1001/jamanetworkopen.2020.2041
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Abstract

Research Letter | Oncology Association of Age With Risk of Adverse Pathological Findings at Radical Prostatectomy in Men With Gleason Score 6 Prostate Cancer Daniel W. Kim, MD, MBA; Ming-Hui Chen, PhD; Hartwig Huland, MD; Markus Graefen, MD, PhD; Derya Tilki, MD; Anthony V. D’Amico, MD, PhD Introduction The preferred treatment for men with low-risk prostate cancer, particularly men older than 65 years, Author affiliations and article information are 1 listed at the end of this article. is active surveillance. However, advancing age is associated with upgrading and upstaging at radical prostatectomy. Several factors, including increasing prostate-specific antigen (PSA) level, clinical tumor category, percentage of positive biopsy results, and PSA density, have been noted to be associated with clinically significant prostate cancer at radical prostatectomy. Until now, to our knowledge, no study has incorporated these factors within predefined age strata to ascertain whether a cohort of patients at high risk can be identified for whom additional evaluation and possible treatment is indicated rather than active surveillance. Methods This prospective cohort study included men with Gleason score 6 prostate cancer who were treated with radical prostatectomy from February 28, 1992, to February 15, 2016, at the Martini-Klinik Prostate Cancer Center of the University Hospital Hamburg-Eppendorf in Hamburg, Germany. This study was approved, including waivers of consent owing to deidentified data and a no-risk protocol, by the Ethik-Kommission der Ärztekamme institutional review board in Hamburg, Germany. This study was reported following the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. We investigated whether men older than 65 years had increased odds of adverse pathological findings at radical prostatectomy, defined as TNM category pT3/T4 or R1 or Gleason score 8, 9, or 10, compared with men 65 years and younger. We dichotomized age at 65 years, a commonly used cutoff, to enable clinical utility of the results. Descriptive statistics were used to compare the proportion of clinical characteristics at presentation among men older than 65 years vs 65 years and younger using a Wilcoxon rank sum test for continuous covariates and the Maental-Haenszal χ test for categorical covariates. Univariable and multivariable logistic regressions were used to calculate unadjusted and adjusted odds ratios (ORs) of adverse pathological findings at radical prostatectomy in men older than 65 years vs men 65 years and younger, adjusting for pre–radical prostatectomy PSA level, clinical tumor category, year of diagnosis, percentage of positive biopsy results, and PSA density. SAS statistical software version 9.4 (SAS Institute) was used for all statistical analysis. P values were 2-sided, and statistical significance was set at P < .05. Data were analyzed on May 24, 2019. Results A total of 3191 men (median [interquartile range] age, 62 [32-77] years) were included in the study. The median (interquartile range) PSA level was 6.74 (0.14-187.00) ng/mL (to convert to micrograms per liter, multiply by 1), and 2809 men (88.3%) had T category 1c prostate cancer. Men older than 65 years, compared with men 65 years and younger, had a significantly lower median (interquartile range) percentage of positive biopsy results (16.7% [12.5%-33.3%] vs 20.0% [12.5%-37.5%]; P =.01) and PSA density (0.13 [0.09-0.19] ng/mL vs 0.15 [0.11-0.23] ng/mL; P < .001) (Table 1). While Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(4):e202041. doi:10.1001/jamanetworkopen.2020.2041 (Reprinted) April 2, 2020 1/3 JAMA Network Open | Oncology Age and Risk of Adverse Pathological Findings at Radical Prostatectomy in Men With Prostate Cancer increasing percentage of positive biopsy results (adjusted OR per 1-unit increase, 1.02; 95% CI, 1.01- 1.02; P < .001) and PSA density (adjusted OR per 1-unit increase, 4.28; 95% CI, 1.66-11.01; P = .003) were significantly associated with increased odds of adverse pathological findings at radical prostatectomy (Table 2), men older than 65 years had higher odds of adverse pathological findings at radical prostatectomy compared with men 65 years and younger (adjusted OR, 1.28, 95% CI, 1.00- 1.62; P = .048). Discussion This cohort study found that being older than 65 years was associated with adverse pathological findings at radical prostatectomy. Specifically, if being older than 65 years was not associated with increased risk, one would have expected men older than 65 years to have a lower risk of having adverse pathological findings given the more favorable percentage of positive biopsy results and PSA density levels. Possible explanations for the association of advancing age with risk of adverse pathological features include sampling error and undergrading owing to benign prostatic hyperplasia that occurs normally with advancing age. Another possible explanation is that most men undergo andropause starting at approximately age 40 years continuing to the end of life. Therefore, older men are more likely to have lower testosterone levels at prostate cancer diagnosis compared with younger men, and it is known that prostate cancer in men who are hypogonadal can be more aggressive compared with prostate cancer in men who are eugonadal. This study has some limitations, such as that we chose age 65 years as our cutoff for age, as it is commonly used in prostate cancer studies when Table 1. Baseline Distribution of Factors Associated with Adverse Pathological Findings at Radical Prostatectomy Stratified by Age Median (IQR) Characteristic Men aged >65 y (n = 1075) Men aged ≤65 y (n = 2116) P value PSA, ng/mL 6.90 (5.00-10.00) 6.65 (4.92-9.74) .17 T category, No. (%) ≥2a 126 (11.7) 256 (12.1) 1c 949 (88.3) 1860 (87.9) Abbreviations: IQR, interquartile range; PSA, prostate- Year of diagnosis 2008 (2004-2011) 2008 (2003-2011) .92 specific antigen; T, tumor. Positive biopsy results, % 16.7 (12.5-33.3) 20.0 (12.5-37.5) .01 SI conversion factor: To convert PSA level to PSA density, ng/mL/cc 0.13 (0.09-0.19) 0.15 (0.11-0.23) <.001 micrograms per liter, multiple by 1. Table 2. Unadjusted and Adjusted Odds Ratio of Adverse Pathological Findings at Radical Prostatectomy for Each Clinical Characteristic Univariable analysis Multivariable analysis Characteristic Men, No. Events, No. Unadjusted OR (95% CI) P value Adjusted OR (95% CI) P value b b Age 3191 377 1.01 (1.00-1.03) .09 1.02 (1.00-1.04) .07 >65 y 1075 133 1.08 (0.87-1.36) .49 1.28 (1.00-1.62) .048 ≤65 y 2116 244 1 [Reference] NA 1 [Reference] NA b b PSA level 3191 377 1.02 (1.01-1.036) .004 0.99 (0.97-1.01) .95 T category ≥2a 382 84 2.42 (1.85-3.17) <.001 1.26 (0.93-1.71) .13 1c 2809 293 1 [Reference] NA 1 [Reference] NA b b Year of diagnosis 3191 377 0.87 (0.85-0.89) <.001 0.89 (0.87-0.91) <.001 b b Positive biopsy results, % 3191 377 1.03 (1.02-1.039) <.001 1.02 (1.01-1.02) <.001 b b PSA density 3191 377 3.23 (1.95-5.35) <.001 4.28 (1.66-11.01) .003 Abbreviations: NA, not applicable; OR, odds ratio; PSA, prostate-specific antigen; Per 1-unit increase. T, tumor. Includes adverse pathological findings at prostatectomy, including T3/T4, R1, and/or Gleason score 8, 9, or 10. JAMA Network Open. 2020;3(4):e202041. doi:10.1001/jamanetworkopen.2020.2041 (Reprinted) April 2, 2020 2/3 JAMA Network Open | Oncology Age and Risk of Adverse Pathological Findings at Radical Prostatectomy in Men With Prostate Cancer distinguishing men of older vs younger age; however, life expectancy using a validated metric, such as the Adult Comorbidity Evaluation-27, may be preferred rather than a specific age cutoff. These findings suggest that men older than 65 years with biopsy-confirmed Gleason score 6 prostate cancer may benefit from additional testing, such as multiparametric magnetic resonance imaging and targeted biopsy before proceeding with active surveillance. If higher grade or stage disease is detected, this information could be used to guide the use and duration of androgen deprivation therapy in men considering radiotherapy. ARTICLE INFORMATION Accepted for Publication: February 2, 2020. Published: April 2, 2020. doi:10.1001/jamanetworkopen.2020.2041 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Kim DW et al. JAMA Network Open. Corresponding Author: Daniel W. Kim, MD, MBA, Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, 75 Francis St, ASBI-L2, Boston, MA 02115 (dkim20@partners.org). Author Affiliations: Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston, Massachusetts (Kim, D’Amico); Department of Statistics, University of Connecticut, Storrs (Chen); Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany (Huland, Graefen, Tilki); Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany (Tilki). Author Contributions: Drs Kim and D’Amico had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Tilki and D’Amico share senior authorship. Concept and design: Graefen, D’Amico. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Kim, Graefen, D’Amico. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Chen, Tilki. Administrative, technical, or material support: Kim, D’Amico. Supervision: Huland, Graefen, D’Amico. Conflict of Interest Disclosures: None reported. REFERENCES 1. Hamdy FC, Donovan JL, Lane JA, et al; ProtecT Study Group. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375(15):1415-1424. doi:10.1056/NEJMoa1606220 2. Klotz L. Active surveillance: patient selection. Curr Opin Urol. 2013;23(3):239-244. doi:10.1097/00042307- 200005000-00010 3. Moore DS, Alwan LC, McCabe GP, Duckworth WM. The Practice of Business Statistics: Using Data for Decisions. 2nd ed. W. H. Freeman; 2008. 4. Matsumoto AM. Andropause: clinical implications of the decline in serum testosterone levels with aging in men. J Gerontol A Biol Sci Med Sci. 2002;57(2):M76-M99. doi:10.1093/gerona/57.2.M76 5. Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less. Urology. 2006;68(6):1263-1267. doi:10.1016/j.urology.2006.08.1058 6. Piccirillo JF, Tierney RM, Costas I, Grove L, Spitznagel EL Jr. Prognostic importance of comorbidity in a hospital- based cancer registry. JAMA. 2004;291(20):2441-2447. doi:10.1001/jama.291.20.2441 JAMA Network Open. 2020;3(4):e202041. doi:10.1001/jamanetworkopen.2020.2041 (Reprinted) April 2, 2020 3/3

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Published: Apr 2, 2020

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