Frequency of Gleason Score 7 to 10 in 5100 Elderly Prostate Cancer Patients

Cancer Screening Update

Cancer Screening Update Frequency of Gleason Score 7 to 10 in 5100 Elderly Prostate Cancer Patients Navin Shah, MD,1 Vladimir Ioffe, MD2 1Mid-Atlantic Urology Associates, Greenbelt, MD; 221st Century Oncology, Greenbelt, MD Men 70 to 80 years of age are known to have an increased incidence of high-grade (Gleason sum score [GSS] 7-10) prostate cancer. We determined the frequency of highgrade prostate cancer among men 70 to 80 years old in our practice. We retrospectively reviewed our 5100 prostate cancer patients who are 70 to 80 years old and who opted for radiation therapy (external radiation, brachytherapy, or combination). Data were gathered on race, prostate-specific antigen value, digital rectal examination (DRE) results, and GSS. Patients were further subdivided by age in two categories, those 70 to 75 years and 76 to 80 years, and also by time period: 2006-2010 and 2011-2015. In patients 70 to 75 years, 1426 patients had a GSS of 6 (41%) and 2042 patients had a GSS of 7 to 10 (59%). In patients 76 to 80 years old, 553 had a GSS of 6 (34%) and 1079 had a GSS of 7 to 10 (66%). In 1432 patients with an abnormal DRE result, the GSS was 6 in 376 (26%) and GSS was 7 to 10 in 1059 (74%). Based on analysis of 5100 prostate cancer patients in our practice, we determined that 61% of patients age 70 to 80 have a high-grade prostate cancer, as do 59% of patients age 70 to 75 years, and 66% of patients between age 76 and 80 years. Because biopsy underestimates the grade in GSS 6 patients by 50%, the actual frequency is approximately 80%. In patients with prostate cancer who had an abnormal DRE result, 74% had a GSS of 7 to 10—approximately 85% when accounting for biopsy under-grading. [Rev Urol. 2016;18(4):181-187 doi: 10.3909/riu0732] ® © 2016 MedReviews , LLC Key words Prostate cancer • Age • Gleason score Vol. 18 No. 4 • 2016 • Reviews in Urology • 181 05_4004170006_RIU0732.indd 181 12/12/16 11:55 am Frequency of Gleason Score 7-10 in Elderly Prostate Cancer Patients continued P rostate cancer is the second leading cause of cancer-related death in American men. In 2015, the American Cancer Society estimated that there would be 220,800 new cases of prostate cancer and 30,000 deaths due to prostate cancer.1 One in seven men will be diagnosed with prostate cancer during his lifetime. Nearly 66% of prostate cancer cases are diagnosed in men age 65 years and older. If prostate cancer is diagnosed early and treated it has a 99% 5-year survival rate.1,2 Early diagnosis of prostate cancer by prostate-specific antigen (PSA) level and digital rectal examination (DRE), and with treatment, has decreased the number of prostate cancer deaths by 40% in the past two decades. There are 3 million prostate cancer survivors living in the United States.3-5 In 2012, the US Preventive Task Force recommended against prostate cancer screening.6 In 2013, the American Urological Association recommended against prostate cancer screening in men 70 years and older.7 These recommendations have led to a 30% reduction in PSA screening.8,9 Currently, at least 50% of primary care physicians do not recommend PSA screening in men 70 years and older.10 Among men ages 75 to 80 years, the PSA screening rate was almost 50% lower in 2013 than in 2008.11 Since 2012, there has been a rise in the number of patients presenting with advanced prostate cancer and it is estimated that, in 2015, 1400 additional prostate cancer deaths will occur.12 Using a simulation model, Gulati and colleagues13 predicted that compared to continuing screening, completely discontinuing screening in the United States will increase prostate cancer mortality by 13% to 20%, which translates to 3900 to 6000 more deaths due to prostate cancer annually. Multiple studies in peer-reviewed journals document that men 70 years and older have more prevalence of prostate cancer, more highgrade disease, more metastases, and Board-certified urologists performed DRE and biopsies in all patients. All patients were medically cleared for the procedure by their primary care doctors, were Multiple studies in peer-reviewed journals document that men 70 years and older have more prevalence of prostate cancer, more high-grade disease, more metastases, and more prostate ­cancer-specific deaths compared with men under 70 years. more prostate cancer-specific deaths compared with men under 70 years. Among 402 consecutive biopsy proven prostate cancer patients, we previously found that men 70 years and older had an incidence of Gleason sum score (GSS) of 7 to 10 of 60.7% and 46% in men under age 70. The present study documents the frequency of high-grade tumors (GSS 7-10) in our 5100 prostate cancer patients that are age 70 to 80 years. Materials and Methods The study consisted of 5100 prostate cancer patients who opted for treatment with radiation therapy— external radiation, brachytherapy (high-dose rate and/or low-dose rate), or a combination. We completed a retrospective analysis in these men with prostate cancer who were age 70 to 80 years. Data were collected on age, race, PSA level, DRE result, and GSS, in 5100 prostate cancer patients who had transrectal ultrasound-guided prostate biopsy for either elevated PSA level (over 2.5 ng/mL), positive DRE result, or both during a 10-year period (2006-2015). The charts of patients from our practice were systematically reviewed and the information was entered in to a database. The data were analyzed to determine the incidence of highgrade prostate cancer by age 70 to 75 years and 76 to 80 years and also by time period (2006-2010 and 2011-2015). ambulatory, and received treatment on an outpatient basis. The Gleason pattern 4 component confers aggressive characteristics associated with cancer progression. We grouped all patients into two groups: GSS of 7 to 10 (those containing Gleason pattern 4 or higher) and GSS 6 (Gleason pattern 3 only). This grouping was intended for comparison of highgrade versus low-grade cancers. A recent study of 1691 localized prostate cancer patients who underwent radical prostatectomy found that a Gleason score 4 component was a significant predictor of adverse pathology.14 χ2 tests were used to compare frequencies. All analyses were conducted using the SAS software system (Cary, NC). The study was approved by the Western Institutional Review Board (Philadelphia, PA; study number 1087891). Results Patient Characteristics The study consisted of 5100 prostate cancer patients who were diagnosed by prostate biopsy and who opted for treatment with external radiation, brachytherapy (high-dose rate and/or low-dose rate) or a combination. All patients had either a PSA value . 2.5 ng/mL, an abnormal DRE result, or both. Among 5100 patients 67% where white, 19% were African-American, and 14% were of other race (Table 1). A detailed 182 • Vol. 18 No. 4 • 2016 • Reviews in Urology 05_4004170006_RIU0732.indd 182 12/12/16 11:55 am Frequency of Gleason Score 7-10 in Elderly Prostate Cancer Patients TABLE 1 Racial Demographic, Gleason Sum Score, and Time Period Breakdown                       Race White (%) 1644 (59) 1753 (75) 3397 (67) 2006-2010 (n = 2775) 2011-2015 (n = 2325) Total (N = 5100) African American (%) 658 (24) 310 (13) 968 (19) Other (%) 473 (17) 262 (11) 735 (14) Gleason Sum Score GSS 6 GSS 7 (%) GSS 8 (%) GSS 9 (%) GSS 10 (%) 1979 (39%) 2224 (43.5) 527 (10) 340 (6.5) 30 (1) Time Period 2006-2010 2011-2015 Total (N 5 5100) Patients (%) 2775 (54) 2325 (46) 5100 GSS, Gleason sum score. breakdown of Gleason sum scores is shown in Table 1; 54% of the 5100 patients were diagnosed and treated during the time between 2006 and 2010, and 46% during the time between 2011 and 2015. PSA For the entire group, 21% had a PSA value below 4 ng/mL, and 65% had a PSA value between 4 and 10 ng/ mL; 11% had a PSA value of 11 to 20 ng/mL and 3% had a PSA value of 21 to 50 ng/mL. In all, 86% of patients had a PSA value of 10 ng/ mL or less. The PSA value did not differ significantly based on further age stratification (Table 2). Review of the data stratified by years indicates no change in the PSA value between 2011 and 2015, as compared with 2006 to 2010. Digital Rectal Examination In 5100 patients aged 70 to 80 years, 72% had normal DRE results and 28% had abnormal DRE results. In patients aged 70 to 75 years, 27% had abnormal DRE results, and in patients 76 to 80 years, 31% had abnormal DRE results (Table 3). Review of the data stratified by years indicates no change in the incidence of abnormal DRE result between 2011 and 2015, as compared with 2006 to 2010. GSS GSS of 7 to 10 were grouped together in order to compare highgrade cancers with low-grade cancers (GSS 6). In 5100 patients age 70 to 80 years, 39% had a GSS of 6 and 61% had a GSS of 7 to 10. In 3468 patients age 70 to 75, 1426 patients had a GSS of 6 (41%) and 2042 patients had a GSS of 7 to 10 (59%). In 1632 patients age 76 to 80 years, 553 had a GSS of 6 (34%) and 1079 had a GSS of 7 to 10 (66%; Table 4). A multivariate analysis indicated that patients with prostate cancer who were age 70 to 80 had a statistically significant higher rate of GSS from 7 to 10. Review of the data stratified by years indicates that no significant change in the incidence of GSS 7 to 10 occurred between 2011 and 2015, as compared with 2006 to 2010. This indicates that updates to the Gleason grading system in 2014 did not affect our results.14 In 1435 patients age 70 to 80 years with an abnormal DRE result, 26% had a GSS of 6 and 74% had a GSS of 7 to 10. Patients 76 to 80 years with an abnormal DRE result had a 77% incidence of a GSS 7-10 prostate cancer (Table 5). A multivariate analysis confirmed that patients with prostate cancer who were age 70 to 80 years with an abnormal DRE result had a statistically significant higher rate of GSS 7-10 cancer. Review of the data stratified by years indicates no change in GSS with abnormal DRE Vol. 18 No. 4 • 2016 • Reviews in Urology • 183 05_4004170006_RIU0732.indd 183 12/12/16 11:55 am Frequency of Gleason Score 7-10 in Elderly Prostate Cancer Patients continued TABLE 2 Prostate-specific Antigen Stratified by Age and Year PSA , 4 ng/mL (%) PSA 4-10 ng/mL (%) PSA 11-20 ng/mL (%) PSA 21-50 ng/mL (%) Age Age 70-75 (n 5 3468) 798 (23) 2220 (64) 347 (10) 104 (3) Age 76-80 (n 5 1632) 261 (16) 1126 (69) 196 (12) 49 (3) Total 70-80 (N 5 5100) 1071 (21) 3315 (65) 561 (11) 153 (3) Year 2006-2010 (n 5 2775) 21 65 10 3 2011-2015 (n 5 2325) 20 66 11 3 Total (N 5 5100) 21 65 11 3 PSA, prostate-specific antigen. result between 2011 and 2015, as compared with 2006 to 2010. Overall, patients in their seventh decade demonstrated a 61% frequency of high-grade prostate ­cancer. Men age 70 to 75 years had a 59% frequency of high-grade prostate cancer and men age 76 to 80 years had a 66% frequency of high-grade prostate cancer. Advancing age in the seventh decade resulted in a higher frequency of abnormal DRE results: 31% for men 76 to 80 years and 27% for men 70 to 75 years. Discussion In 2014, we published a review of our 402 patients age 50 to 78 years with biopsy-diagnosed prostate cancer; 61% of men  70 years old had a GSS of 7 to 10; of those with a positive DRE result, 69% had a GSS of 7 to 10. The incidence of high-grade cancer was 60.7% in men 70 years and older compared with 41% in men younger than age 70. Multivariable statistical analysis showed that higher age correlated to higher GSS.15 TABLE 3 Digital Rectal Examination Results Stratified by Age and Year Normal (%) Abnormal (%) Age 70-75 (n 5 3468) Age 2531 (73) 937 (27) Age 76-80 (n 5 1632) 1134 (69) 498 (31) Total 70-80 (N 5 5100) 3665 (72) 1435 (28) 2006-2010 (n 5 2775) Year 1982 (72) 793 (28) 2011-2015 (n 5 2325) 1682 (72) 643 (28) Total (N 5 5100) 3665 (72) 1435 (28) The current study confirms our earlier results by reviewing 5100 biopsy-graded men with prostate cancer. We found that men in their seventh decade have a disproportionately high frequency of GSS 7-10 prostate cancer (61%), and the frequency increases with age, as patients 76 to 80 years had a 66% frequency of high-grade cancer. Moreover, septuagenarians with an abnormal DRE result have a 74% frequency of high-grade cancer. The results hold during the time period between 2011 and 2015 as compared with 2006 to 2010, indicating that updates to the Gleason grading system in 2014 did not affect our results.16 The majority of the patients had PSA level of  10 ng/mL (86%). This suggests that these patients were not high risk based on prebiopsy characteristics. The American Urological Association issued guidelines in 2013 recommending against screening men  70 years for prostate cancer.7 The prostate cancer literature has an abundance of data that indicate that men 70 years and older suffer disproportionately with 184 • Vol. 18 No. 4 • 2016 • Reviews in Urology 05_4004170006_RIU0732.indd 184 12/12/16 11:55 am Frequency of Gleason Score 7-10 in Elderly Prostate Cancer Patients TABLE 4 Gleason Sum Score Stratified by Age and Year Gleason Sum Score 6 (%) Gleason Sum Score 7-10 (%) Age Age 70-75 (n 5 3468) 1426 (41) 2042 (59) Age 76-80 (n 5 1632) 553 (34) 1079 (66) Total 70-80 (N 5 5100) 1979 (39) 3121 (61) (Statistically significant P , .0001 for GSS 7-10 higher than GSS 6 in all age groups and the total.) Year 2006-2010 (n 5 2775) 1143 (41) 1632 (59) 2011-2015 (n 5 2325) 836 (36) 1489 (64) Total (N 5 5100) 1979 (39) 3121 (61) GSS, Gleason sum score. TABLE 5 Gleason Sum Score With Abnormal Digital Rectal Examination Results Stratified by Age and Year Gleason Sum Score 6 (%) Gleason Sum Score 7-10 (%) Age Age 70-75 (n = 937) Age 76-80 (n = 1632) Total 70-80 (N = 1435) 263 (28) 113 (23) 376 (26) 674 (72) 385 (77) 1059 (74) (Statistically significant P , .0001 for GSS 7-10 higher than GSS 6 in all age groups and the total.) Year 2006-2010 (n = 793) 2011-2015 (n = 642) Total (N = 1435) 223 (28) 153 (24) 376 (26) 570 (72) 489 (76) 1059 (74) GSS, Gleason sum score. advanced prostate cancer. Scosyrev and colleagues17 analyzed 46,498 patients who were diagnosed with prostate cancer from 1998 to 2007. They reported that the frequency of metastatic prostate cancer was 3% for the group below 75 years versus 33% in the group over 75 years. The 5-year cumulative death from prostate cancer was 3% in those below 75 years versus 70% in patients over 75 years. Although patients age 75 years and older represented 26% of all prostate cancer cases, they contributed 48% of metastatic cases and 53% of all prostate cancer deaths. Richstone and colleagues18 reviewed patients who underwent radical prostatectomy for prostate cancer. The group included 258 men who were  70 years old, and 3777 men younger than 70 years. Comparison between these two groups showed that patients over 70 years had higher-stage disease, higher GSS, and lower frequency of organ-confined disease compared with their younger counterparts. In addition, upgrading and upstaging was more frequent (40.2%) in patients older than 70 years compared with younger men (29.3%). Sun and associates19 reported a study of 4561 men who underwent radical prostatectomy. They found that men over 70 years had a higher proportion of pathologic tumors (stage 3 and 4), higher GSS (. 7), and larger tumor volume. Loeb and associates20 found that in 8968 men who underwent radical prostatectomy, patients who were 70 years or older had the highest frequency of GSS between 8 and 10, positive surgical margins, extracapsular extension, seminal vesical invasion, and lymph node metastasis. They concluded that age over 70 years was associated with poorer tumor histopathology and poorer survival rate. A recent study by Vellekoop and coworkers21 reviewed 13,159 men diagnosed with GSS 6 prostate cancer. Of the men that met the most stringent active surveillance criteria, 4500 underwent radical prostatectomy; 50% had adverse pathology at prostatectomy for which older age was a predictor. Another study by Dinh and coworkers22 found that, among 5581 patients with low-risk prostate cancer treated with prostatectomy, 44% were upgraded (Gleason 7 or higher) and 10% were upstaged Vol. 18 No. 4 • 2016 • Reviews in Urology • 185 05_4004170006_RIU0732.indd 185 12/12/16 11:55 am Frequency of Gleason Score 7-10 in Elderly Prostate Cancer Patients continued (pT3 or greater). Multivariable analysis showed that older age was significantly associated with both upgrading and upstaging. Muralidhar and coauthors23 analyzed 383,039 men diagnosed with prostate cancer in the Surveillance, Epidemiology, and End Results a GSS of 7 to 10. For GSS between 8 and 10, 25% were  70 years and 3% were 55 to 69 years. Multiple studies have documented that men with a GSS of 6 are upgraded at a rate of 50% at prostatectomy. Therefore, we believe that the true incidence of high-grade Multivariable analysis showed that older age was significantly ­associated with both upgrading and upstaging. database. This study’s racial breakdown was 81% white, 11% AfricanAmerican, and 8% other race; the current study shows 67%, 19%, and 14%, respectively. They demonstrated that older men have a higher probability of harboring highgrade and high-risk disease. The percentage of Gleason score 8-10 disease among men age 50 to 54, 70 to 74, and 80 to 84 was 8.9%, 16.2%, and 28.5%, respectively, and the percentage of high-risk disease was 14.3%, 22.4%, and 38.7% (P , .001). They found a significantly higher rate of high-grade Gleason scores and high-risk disease among older men after 2009 compared with before 2009 based on a decrease in screening practices. Moreover, our current study shows an 8% reduction in patient population between 2011 and 2015 compared with 2006 to 2010. We believe the reduction may be due to decreased prostate cancer screening in men 70 years and older. The Miraco Life Sciences Laboratory (Irving, TX), a national pathology facility, reviewed their pathology data on biopsy-positive prostate cancer. Through personal communication, in 2014, they reviewed their 621 consecutive prostate cancer-biopsied patients with regard to age versus GSS. For the age group from 55 to 69 years (n 5 317), 48% had a GSS of 6, and 52% had a GSS of 7 to 10. For the age group  70 years (n 5 251), 26% had a GSS of 6 and 74% had prostate cancer in our patients age 70 to 80 years is approximately 80%. Two epidemiologic principles are cited to argue against prostate cancer screening: length-time bias and lead-time bias. Length-time bias suggests that annual screening is more likely to detect slow-­growing tumors, whereas fast-growing and potentially lethal tumors are less likely to be detected. Our data argue against length-time bias in men age 70 to 80 years because the data indicate that men in this age group have a high incidence of lethal cancer. Lead-time bias suggests that the natural history of the disease is not truly affected by screening. Although a long-term randomized trial for this age group is required to definitively address lead-time bias, most healthy men age 70 to 80 years and their physicians do not support withholding treatment for advanced tumors. As the life expectancy for men age 70 to 80 years old is 14.1 to 8.1 years, an increasing number of men in this age group will be at risk for high-grade prostate cancer.24 Withholding screening is especially harmful to high-risk populations such as African-American men, men with a family history of prostate cancer, and men over 70 years. In the United States, AfricanAmerican men are at increased risk for prostate cancer, as their incidence is 208.7 per 100,000 compared with 123.0 per 100,000 in white men. African-American men also have a higher prostate cancer mortality (47.2 per 100,000 compared with 19.9 per 100,000 in white men).25 It also harms men from poor socioeconomic strata who frequently seek medical attention only when symptomatic, usually representing metastatic and incurable disease. New genetic tests and imaging studies (such as multiparametric magnetic resonance imaging) are being incorporated to determine which patients are candidates for active surveillance or treatment. We should not abandon diagnosis by limiting screening, even in men 70 years and older, in fear that it will necessarily lead to treatment. Such approaches are obsolete in light of newer, more specific stratification tools to aid treatment decisions. Conclusions In this study, septuagenarians with prostate cancer have a 61% frequency of GSS 7-10 prostate cancer and septuagenarians with prostate cancer who had an abnormal DRE result have a 74% frequency of GSS 7-10 prostate cancer. As 50% of biopsy specimens underestimate the pathologic grade, we estimate that the actual frequency of GSS 7-10 prostate cancer is approximately 80% to 85% with a positive DRE result. Based on these ­f indings and other published studies, we strongly believe that prostate cancer screening should be made available to men 70 years and older. The authors declare no real or apparent conflicts of interest. References 1. 2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29. Prostate Cancer. American Cancer Society website. http://www.cancer.org/cancer/prostatecancer/overviewguide/prostate-cancer-overview-key-statistics. Accessed November 17, 2016. 186 • Vol. 18 No. 4 • 2016 • Reviews in Urology 05_4004170006_RIU0732.indd 186 12/12/16 11:55 am Frequency of Gleason Score 7-10 in Elderly Prostate Cancer Patients 3. 4. 5. 6. 7. 8. 9. 10. Efstathiou JA, Chen MH, Catalona WJ, et al. 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Men older than 70 years have higher risk prostate cancer and poorer survival in the early and late prostate specific antigen eras. J Urol. 2009;182:2242-2248. Loeb S, Hernandez DJ, Mangold LA, et al. Progression after radical prostatectomy for men in their thirties compared to older men. BJU Int. 2008;101: 1503-1506. Vellekoop A, Loeb S, Folkvaljon Y, Stattin P. ­Population based study of predictors of adverse ­pathology among candidates for active surveillance with Gleason 6 ­prostate cancer. J Urol. 2014;191: 350-357. Dinh KT, Mahal BA, Ziehr DR, et al. Incidence and predictors of upgrading and up staging among 10,000 contemporary patients with low risk prostate cancer. J Urol. 2015;194:343-349. Muralidhar V, Ziehr DR, Mahal BA, et al. Association between older age and increasing Gleason score. Clin Genitourin Cancer. 2015;13:525-530.e1-3. Actuarial Life Table. Social Security Administration website. https://www.ssa.gov/oact/STATS/table4c6. html. Accessed November 17, 2016. DeSantis CE, Siegel RL, Sauer AG, et al. Cancer ­statistics for African Americans, 2016: progress and opportunities in reducing racial disparities. CA ­Cancer J Clin. 2016;66:290-308. Main Points • Men with prostate cancer 70 to 80 years old have a 61% frequency of Gleason sum score 7-10 disease. • Men with prostate cancer 70 to 80 years old with an abnormal digital rectal examination result have a 74% frequency of Gleason sum score 7-10 disease. • Because biopsy specimens have been shown to underestimate Gleason grade at a rate of 50%, we estimate that the true frequency of Gleason sum score 7-10 prostate cancer is approximately 80% to 85% in men 70 to 80 years old. Vol. 18 No. 4 • 2016 • Reviews in Urology • 187 05_4004170006_RIU0732.indd 187 12/12/16 11:55 am