A Trend Toward Aggressive Prostate Cancer

Original Research

Original Research A Trend Toward Aggressive Prostate Cancer Navin Shah, MD,1 Vladimir Ioffe, MD2 Urology Associates, Greenbelt, MD; 221st Century Oncology, Greenbelt, MD 1Mid-Atlantic To compare prostate biopsy (Pbx) characteristics before and after the 2012 United States Preventive Services Task Force (USPSTF) prostate cancer (PCa) screening guidelines, we completed a retrospective comparative analysis of 1703 sequential patients that had a Pbx in 2010 to 2012 (3 years) with 383 patients biopsied in 2018 and 310 patients biopsied in 2019. Data was collected on patient age, race, serum prostate specific antigen (PSA) level, digital rectal examination (DRE) results, total number of biopsies performed, and Gleason sum score (GSS). Data were analyzed to determine whether the 2012 USPSTF screening recommendations against PCa screening may have affected PCa characteristics. Three study groups were defined as Group A, Group B, and Group C. Group A represents Pbx prior to the 2012 USPSTF screening guidelines (2010-2012), Group B represents Pbx in 2018, and Group C represents Pbx in 2019. The patient population consisted of 73% Black men, 16% White men, and 11% men of other races. The number of patients that had a biopsy in Groups A through C, respectively, were 567 patients/year, 383 patients/year, and 310 patients/year. The annual positive Pbx rate for Group A through C was 134/year, 175/year, and 201/year, respectively. High-grade PCa (GSS 7-10) in Groups A through C was 51.5%, 60.5%, and 60.0%. The proportion of patients with a serum PSA level 10 ng/mL or greater in Groups A through C was 25.4%, 29.3%, and 33%. For patients age 70 to 80 years, there was an increasing trend for serum PSA levels 10 ng/mL and higher: 31%, 38%, and 39%, respectively. In this age group, high-grade tumors (GSS 7-10) occurred in 61%, 65%, and 68%, respectively. In 2019, Grade Group 3, 4, and 5 was present in 37.7% of 70- to 80-yearold men and 34.6% of Black men. More than 50% positive biopsy cores were present in 46.3% of 70- to 80-year old men and 36.6% of Black men. Our data through 2019 continued to show that after the 2012 USPSTF recommendations against PCa screening, PCa screening has decreased. We found decreased Pbx, increased PCa diagnosis, and increased high-grade PCa (GSS 7-10). As our patient population consisted of 73% Black patients and 33% of men age 70 to 80 years, our results support aggressive PCa screening for high-risk patients, which include Black men, men with a family history of PCa, and healthy men age 70 to 80 years. [Rev Urol. 2020;22(3):102–109] © 2020 MedReviews®, LLC 102 • Vol. 22 No. 3 • 2020 • Reviews in Urology 4170020_05_RIU0875_V3_ptg01.indd 102 19/10/20 3:15 PM Trending Toward Aggressive PCa KEY WORDS Prostate cancer • Prostate-specific antigen screening • United States Preventive Services Task Force • Black men • Elderly men P rostate cancer (PCa) is the most common cancer in men and the second-leading cause of cancer death in American men. One in 9 men will be diagnosed with PCa during their lifetime. In 2019, the American Cancer Society (ACS) reported 174,650 new cases of PCa (6% higher than 2018) and 31,620 deaths due to PCa (7% higher than 2018) in the United States. For 2020, the ACS has projected a rise of new PCa cases to 191,930 and deaths due to PCa to 33,330. The incidence of PCa among all races is 123.2 (per 100,000 population); it is the highest, 198.4, in Black men and 114.8 in White men. Black men have 60% more new cases of PCa and more advanced stages of PCa compared with White men. The incidence of PCa is the highest in men age 65 years and older (66%).1-3 In the 20 years prior to 2012, serum prostate-specific antigen (PSA) level and digital rectal examination (DRE)– based PCa screening reduced PCa mortality by 50%.4 There are 3 million PCa survivors in the United States.5 Treatment of localized PCa results in a 10-year survival of 98%.6 In 2012, the USPSTF recommended against PCa screening for all age groups (grade D).7,8 Survey data indicate that subsequent to 2013, 50% of primary care doctors did not offer PCa screening to their patients.9 In 2013, national PCa screening decreased by 18%.10 Unfortunately, a 72% rise in metastatic PCa compared with that in 2004 has been reported.11-13 It is estimated that if PCa screening is discontinued, 6000 additional deaths due to PCa will occur annually in the United States.14 In 2018, the USPSTF upgraded its recommendation for PCa screening to Grade C in men age 55 to 69 years only and continued to recommend against screening in men age 70 years and older.15 As the life expectancy for American men is approximately 84 years, an increasing number of healthy elderly men will be at risk for high-grade PCa.16 A 10-year study of 230,081 American veterans found that 10.5% died from PCa and 77.4% of the PCa deaths occurred in men between the ages of 70 and 89 years.17 There are approximately 24 million American men age 70 years and older. In our previous study, we showed that after the 2012 USPSTF recommendations against PCa screening, the number of PCa diagnoses and, especially, high-grade PCa increased.18 In this study, we review our 2019 Pbx data to determine if this rising trend continues. Methods and Materials In 2014, we published a retrospective analysis of 402 PCa patients diagnosed by Pbx.19 The study examined the Pbx characteristics of PCa patients from 2010 through 2012 (3 years). In 2018, we published a comparison of Pbx characteristics prior to (2010-2012) and after (20152017) the 2012 USPSTF recommendations against PCa screening.20 In 2019, we published a comparison of Pbx characteristics carried out through 2018.18 The current study analyzed an additional 310 patients who had Pbx in 2019 to determine whether the trend continues. Data was collected on patient age, race, PSA, DRE, number of biopsies, and Gleason sum score (GSS). All cases are collected from our community clinical practice from a group of 10 board-certified urologists located in Prince George’s County, Maryland, in the Washington, DC metro area. Pbx were performed on men with a serum PSA level of over 2.5 ng/mL, an abnormal DRE, or both. Most of the patients had a transrectal ultrasound-guided (TRUS) 12-core Pbx under intravenous sedation on an outpatient basis (a few patients were biopsied under local anesthesia). All patients were cleared for the procedure by their primary care physician. Patient age was stratified as age 55 years and younger, age 56 through 69 years, and age 70 through 80 years. The charts of consecutive patients from our practice were reviewed and the information was entered in a database. The data were analyzed to determine whether the 2012 USPSTF screening recommendations affected PCa characteristics. Three study groups were defined: Group A, patients diagnosed prior to the USPSTF screening recommendations (2010-2012); Group B, patients diagnosed after the USPSTF screening recommendations in 2018; and Group C, patients diagnosed in 2019. We separated the GSS into two groups, GSS 6 and GSS 7-10. We defined the GSS 7-10 group as high grade because it harbors a Gleason score 4 or higher component. Chi-squared or Fisher’s exact tests were used to compare frequencies. All analyses were conducted using the SAS software program (SAS Institute, Cary, NC). The study was approved by the Western Institutional Review Board (study number 1087891). Vol. 22 No. 3 • 2020 • Reviews in Urology • 103 4170020_05_RIU0875_V3_ptg01.indd 103 19/10/20 3:15 PM Trending Toward Aggressive PCa continued TABLE 1 Patient Characteristics Group A (n 5 402) Group B (n 5 175) Group C (n 5 201) #55 36 (9%) 15 (8.6%) 16 (8%) 56-69 226 (56%) 100 (57%) 126 (62.7%) 70-80 140 (35%) 60 (34%) 59 (29.4%) Black — 131 (75%) 147 (73%) White — 24 (13.8%) 33 (16.4%) Other — 20 (11.2%) 21 (10.4%) 45 (11.2) 13 (7.4%) 10 (5%) 4-9.9 255 (63.4%) 111 (63.4%) 123 (61%) $10 102 (25.4%) 51 (29.2%) 66 (32.8%) Characteristic Age (y) Race PSA (ng/mL) ,4 Unspecified 2 (1%) Gleason Sum Score 6 195 (48.5%) 70 (39.6%) 82 (40.8%) 7-10 207 (51.5%) 105 (60%) 119 (59.2%) Normal 151 (37.5%) 135 (77.1%) 128 (63.7%) Abnormal 251 (62.4%) 40 (22.9%) 73 (36.3%) ,50% — — 146 (72.6%) $50% — — 55 (27.4%) DRE % Positive Cores DRE, digital rectal examination; PSA, serum prostate specific antigen level. Results Patient Characteristics Patient characteristics are shown in Table 1. The age categories were divided into three groups: #55 years, 56 through 69 years, and 70 through 80 years. Patient race is indicated as Black, White, or Other. The study was conducted in the Washington, DC metro area, Prince George’s County (PGC), Maryland. According to the 2015 American Community Survey, PGC had a population of 62% Black, 14% White, and 25% other races. Our 104 • Vol. 22 No. 3 • 2020 • Reviews in Urology 4170020_05_RIU0875_V3_ptg01.indd 104 19/10/20 3:15 PM Trending Toward Aggressive PCa TABLE 2 Comparison of Biopsy Statistics Group A (2010-2012) Group B (2018) Group C (2019) Total 1703 383 310 Annual rate 567 383 (32%i) 310 (45%i) Total positive 402 (23.6%) 175 (45.7%) 201 (64.8%) 134/y 175/y (31%) 201/y (50%) Biopsy Annual positive rate study had a Black representation of 73%, White 16%, and Other 11%. Note we were not able to extract the race from the data set for group A but because the study consisted of patients in the same county and in the same urology practice, we assume that the demographics are consistent between study groups. We show the breakdown by serum PSA level of <4 ng/mL, 4 to 9.9 ng/mL, and ≥10 ng/mL. The GSS are shown as 6 and 7-10. The GSS was grouped as 7-10 to indicate high-grade tumors that have a Gleason grade 4 component. DRE is grouped as either normal or abnormal. The percentage of positive cores, <50% and ≥50%, is shown for Group C. Prostate Biopsy In the pre-USPSTF period (Group A), 1703 total Pbx were performed over 3 years. The PBx rate was 567 biopsies/year. There were 402 positive prostate biopsies over 3 years (23.6%). The annual positive biopsy rate was 134 positive biopsies/year. In the post-USPSTF period (Group B), there were 383 total Pbx, an annual rate of 383 biopsies/year. Pbx decreased in Group B by 32%. In Group C, there were 310 total Pbx, an annual rate of 310 biopsies/year. The Pbx was decreased by 45% compared with Group A and decreased 19% compared with Group B. In Group C, there were 201 positive Pbx (64.8%) compared with 45.7% in Group B. In Group B, there was nearly a twofold increase in positive Pbx compared with Group A and in Group C there was approximately a threefold increase in positive Pbx compared with Group A (Table 2). Prostate-specific Antigen Serum PSA levels in Group A were <4 ng/mL in 11%, 4 to 9.9 ng/mL in 63%, and ≥10 ng/mL in 25%. In Group B, the serum PSA levels were <4 ng/mL in 7%, 4 to 9.9 ng/mL in 63%, and ≥10 ng/mL in 29%. In Group B, there were more patients with a serum PSA level ≥10 ng/mL in all age groups compared with Group A. In group C, the serum PSA levels were <4 ng/mL in 5%, 4 to 9.9 ng/mL in 63%, and ≥10 ng/ mL in 32% (Table 3). Gleason Sum Score In Group A, 195 patients (49%) had GSS 6; Group B had 70 patients (40%) and Group C had 82 patients (41%) with GSS 6. In Group A, 207 patients (52%) had GSS 7-10; Group B had 105 patients (60%) and Group C had 119 patients (59%) with GSS 7-10. GSS 7-10 was higher in group B by 8.5% compared with Group A and the increased trend continued for group C. In patients age 70 to 80 years, high-grade (GSS 7-10) disease was 4% higher in Group B and 8% higher in Group C versus Group A (Table 4). Discussion This study reviewed our community-based urologic practice and found that the Pbx rate decreased by 32% in the post-2012 USPSTF period (2018, Group B) and continued to decrease through 2019 (Group C) by 45%. Additionally, the PCa detection rate increased by 31% in 2018 and by 50% in 2019. We confirmed a continuing rising trend of 8% to 9% for high-grade PCa (GSS 7-10) in the post-USPSTF period. Despite a 32% to 45% reduction in the number of biopsies post-USPSTF guidelines, there was a threefold relative increase in the total number of positive biopsies. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) on which the USPSTF based their 2012 recommendation against PCa screening was found to be 90% contaminated and hence should not form the basis of national guidelines.21,22 Unfortunately, following the 2012 USPSTF guidelines Vol. 22 No. 3 • 2020 • Reviews in Urology • 105 4170020_05_RIU0875_V3_ptg01.indd 105 19/10/20 3:15 PM Trending Toward Aggressive PCa continued TABLE 3 Comparison of Serum PSA Levels by Age in Patients With a Positive Pbx Age (y) P Value N PSA ,4 ng/mL PSA 4-9.9 ng/mL PSA $10 ng/mL #55 36 5 (13.9%) 25 (69.4%) 6 (16.6%) 56-69 226 23 (10.2%) 150 (66.4%) 53 (23.5%) 70-80 140 17 (12.1%) 80 (57.1%) 43 (30.7%) Total 402 45 (11.2%) 255 (63.4%) 102 (25.4%) #55 15 1 (6.7%) 11 (73.3%) 3 (20%) 0.7978 56-69 100 8 (8%) 67 (67%) 25 (25%) 0.8109 70-80 60 4 (7%) 33 (55%) 23 (38%) 0.3730 Total 175 13 (7.4%) 111 (63.4%) 51 (29.2%) #55 16 2 (12.5%) 11 (6.9%) 3 (18.8%) 1.000 56-69 124 5 (4%) 81 (65%) 38 (30.1%) 0.0677 70-80 61 3 (4.9%) 34 (55.7%) 24 (39.3%) 0.2026 Total 201 10 (5.0%) 126 (62.7%) 65 (32.3%) Group A Group B Group C Pbx, prostate biopsy; PSA, serum prostate-specific antigen level. against PCa screening, there was a 64% decrease in DRE and a 39% decrease in PSA testing.23 Other large studies have replicated our results and have shown that after the 2012 USPSTF guidelines, Pbx have decreased and positive Pbx have increased and are associated with increased rates of high-grade GSS and more advanced PCa disease presentations.24-30 Jemal and colleagues found the incidence for regional and distant stage disease increased for men ages 50 through 74 years and ≥75 years by 5.2% per year from 2010 through 2016 based on an analysis of the US Cancer Statistics Public Use Research Database.31 The benefit of PCa screening was recently reconfirmed by Alpert, in which a review of 400,887 patients under age 80 years showed that annual PSA-based screening reduced prostate cancer deaths by 64% and all-cause mortality by 24%.32 Our study is unique because 73% of the study population was Black, a documented high-risk group. The 2012 USPSTF guidelines were based on studies in which high-risk populations were underrepresented (only 4% were Black in the PLCO study).33-35 In some of the studies not based in the United States that were considered by USPSTF, there is also minimal representation of Black men and men age 70 to 80 years. In the United States, Blacks constitute 12% to 15% of the population and approximately 30% in large cities. PCa studies outside the United States enroll approximately 1% Black men and therefore their results should not be extrapolated to the United States for PCa screening and treatment. A recent study showed that GSS 6 is more aggressive in Black men compared with men of other races and is associated with 100% increase in 106 • Vol. 22 No. 3 • 2020 • Reviews in Urology 4170020_05_RIU0875_V3_ptg01.indd 106 19/10/20 3:15 PM Trending Toward Aggressive PCa TABLE 4 Comparison of GSS by Age Age (y) P Value n GSS 6 GSS 7-10 #55 36 18 (50.0%) 18 (50.0%) 56-69 226 122 (54%) 104 (46.0%) 70-80 140 55 (39.3%) 85 (60.7%) Total 402 195 (48.5%) 207 (51.5%) #55 15 10 (66.7%) 5 (33.3%) 0.2758 56-69 100 39 (39%) 61 (61%) 0.0126 70-80 60 21 (35%) 39 (65%) 0.5672 Total 175 70 (39.5%) 105 (60.0%) #55 16 5 (31.2%) 11 (68.8%) 0.2089 56-69 125 58 (46.4%) 67 (53.6%) 0.1735 70-80 60 19 (31.6%) 41 (68.3%) 0.3064 Total 201 82 (40.8%) 119 (59.2%) Group A Group B Group C GSS, Gleason Sum Score. Main Points • This study shows that the annual prostate biopsy rate decreased by 32% to 45% after the 2012 US Preventive Services Task Force (USPSTF) prostate cancer (PCa) screening guidelines but the annual PCa detection rate increased by up to 50%. • High-grade GSS 7-10 PCa increased by 8% to 9% after the 2012 USPSTF guidelines. • Despite a 45% reduction in the total number of biopsies there was a threefold increase in the total number of positive biopsies by 2019. • As patient population in this study included 73% Black men and 33% men age 70 to 80 years, these findings suggest that the USPSTF should immediately endorse PCa screening in high-risk populations to decrease the rising trend of PCa morbidity, mortality, and the high cost to treat advanced PCa. • The authors strongly recommend that PSA- and DRE-based annual PCa screening should be made available, especially to Black men, men with a family history of PCa, and healthy men age 70 to 80 years. Vol. 22 No. 3 • 2020 • Reviews in Urology • 107 4170020_05_RIU0875_V3_ptg01.indd 107 19/10/20 3:15 PM Trending Toward Aggressive PCa continued prostate cancer death.36 High-risk populations, especially Black men and healthy men age 70 to 80 years are disproportionately adversely affected by the current USPSTF guidelines. Our data of TRUS Pbx showed 68% of men age 70 to 80 years had high-grade GSS 7-10. In our prior study of 5100 American men age 70 to 80 years with average risk PCa (84% with PSA <10 ng/mL), 61% had high-grade GSS 7-10.37 As surgical series have found that 50% of GSS 6 patients on biopsy are upgraded to GSS 7-10 at the time of prostatectomy, it is likely that 80% of our patients age 70 to 80 years had GSS 7-10.38,39 TRUS Pbx was recently improved by MRI fusion to produce higher rates of clinically significant cancer detection.40 To determine whether patients age 70 to 80 years had an increased rate of ≥50% positive biopsy cores, we reviewed our 552 positive biopsies (total of 1194 Pbx from 2015 to 2017) and 175 positive biopsies (total of 383 Pbx in 2018). From 2015 through 2017, 28% of patients had ≥50% positive biopsy cores whereas in 2018 and 2019 it was 35% and 32%, respectively. The published US literature shows that men age 70 years and older have more prevalence of PCa, more locally advanced PCa, more metastatic PCa, and more deaths due to PCa.41-43 Our study shows that limiting screening for high-risk men over age 70 years is definitely harmful. Since 2013, more locally advanced PCa, metastatic PCa, and PCaspecific deaths have been documented. The 5-year survival rate in metastatic PCa is 28% and the cost of treating metastatic PCa is well over $200,000.44 More importantly, patients with metastatic PCa have more pain, a much lower quality of life, and almost certain death. The Center for Medicare and Medicaid Services (CMS) spent $11.8 billion in 2010 and $15.3 billion in 2018 for PCa.45 The annual cost of the screening PSA test for PCa is $25. The 2018 USPSTF guidelines upgraded PCa screening in men age 55 to 69 years from a D Grade to a C Grade but still excludes men age 70 years and older. We believe the aforementioned reports strongly indicate that PCa screening should also be made available to detect early PCa in healthy men age 70 to 80 years.46 Based on our data and others, the USPSTF should urgently endorse PCa screening for men, especially in high-risk populations including Black men, men with a family history of PCa, and healthy men age 70 to 80 years.47 Men with a family history of PCa have twice the incidence of PCa compared with men without a family history.48 Over the last several years new tools to facilitate PCa detection and risk stratification have entered clinical practice. These include imaging technology such as the multi-parametric prostate MRI (mpMRI),49 novel genetic and molecular tests,50 and chemical assays.51 These new diagnostic and risk stratification tools give clinicians the ability to counsel patients regarding which prostate cancers are indolent and appropriate for active surveillance and which are aggressive and need treatment. These technological innovations have significantly reduced PCa overdiagnosis and overtreatment in clinical practice. Conclusions This study shows that the annual Pbx rate decreased by 32% to 45% after the 2012 USPSTF PCa screening guidelines but the annual PCa detection rate increased by up to 50%. High-grade GSS 7-10 PCa increased by 8% to 9% after the 2012 USPSTF guidelines. Despite a 45% reduction in the total number of biopsies there was a threefold increase in the total number of positive biopsies by 2019. As our patient population included 73% Black men and 33% men age 70 to 80 years, these findings suggest that the USPSTF should immediately endorse PCa screening in high-risk populations to decrease the rising trend of PCa morbidity, mortality, and the high cost to treat advanced PCa. We strongly recommend that PSA- and DRE-based annual PCa screening should be made available, especially to Black men, men with a family history of PCa, and healthy men age 70 to 80 years. Medicare covers annual PCa screening for men 65 years and older; Medicaid covers annual PCa screening for men 50 years and older. The authors report no real or apparent conflict of interest; no outside funding was used. The authors express their gratitude to Sharon Salenius for her thoughtful review of our manuscript and data analysis. They also thank pathologist Thomas Huebner, MD, for data compilation. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7-30. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7-30. Etzioni R, Gulati R. Recent trends in PSA testing and prostate cancer incidence: a look at context. JAMA Oncol. 2016;2:955-956. American Cancer Society. Cancer Facts & Figures 2020. Atlanta: American Cancer Society; 2020. Johns Hopkins Medicine. 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