Rethinking Gleason pattern quantification in predicting metastasis: results of 20 years of follow-up in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer.

Prostate cancer screening in Europe

To screen or not to screen

In 2012, the United States Preventive Services Task Force recommended against prostate-specific antigen (PSA) –based screening for prostate cancer (grade D recommendation) primarily on the basis of the results of two large randomized clinical trials: the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). In the article accompanying this editorial, Shoag et al present their analysis of questionnaire data sent to a subset of participants in the prostate component of the PLCO study. They again illustrate the high contamination rate in the control arm of the study and call into question the internal validity of PLCO and, ultimately, whether the negative study finding can be used to inform the discussion around the effectiveness of PSA-based screening. The United States Preventive Services Task Force is currently in the process of updating their recommendation concerning PSA-based screening. Given the data presented by Shoag et al, the panel will have to seriously reconsider the validity of the PLCO trial in their deliberations. However, even if they were to completely discount PLCO, it is not entirely clear that the magnitude of benefit currently seen in the ERSPC trial will be enough to support a change in the recommendation. The latest report from ERSPC indicates that, with 13-year follow-up, 27 cases of prostate cancer need to be detected (NND) to prevent one prostate cancer–related death (NND). Although modeling studies extrapolating follow-up in ERSPC out to 25 years or more indicate that NND ultimately may be less than 10, these simulation studies are dependent on myriad assumptions, which may or may not prove to be true. To this end, the task force may choose to only consider the actual randomized clinical trial evidence collected from ERSPC to date, which currently indicates a small to moderate benefit at best. The documented (albeit small) benefit of PSA screening identified in ERSPC must then be weighed against the potential harms of screening. For example, an elevated PSA test often leads to a prostate biopsy. In a recent study of 1,147 men undergoing prostate biopsy in the Prostate Testing for Cancer and Treatment study, 31.8% reported grade 2 adverse events (defined as symptoms causing moderate/major problems or requiring contact with the health care system) and 1.4% required hospital admission within 30 days. Although no deaths were noted in the cohort, these adverse events undoubtedly resulted in discomfort and anxiety, with at least a temporary negative impact on overall health. Furthermore, in patients in whom prostate cancer is diagnosed and treated, both surgery and radiation are associated with a considerable risk of sexual, urinary, or bowel problems. This may be acceptable in patients with higher-risk disease, who are likely to experience a survival benefit from aggressive treatment. Given the widely recognized risk of overdiagnosis associated with population-based annual PSA screening, patients diagnosed with low-risk clinically indolent disease who elect aggressive therapy are unlikely to garner any survival advantage and are, therefore, at considerable risk of overtreatment. Recent data demonstrating increased use of active surveillance in American men diagnosed with low-risk disease is reassuring, however, as we attempt to optimize the balance of predicted benefit associated with prostate cancer treatment and the predicted morbidity of therapy. Increasing penetration of active surveillance will likely mitigate some of the risk of overtreatment, but, given ongoing challenges associated with accurately classifying indolent and clinically relevant disease, it certainly does not eliminate it. If one weighs the benefits of population-based screening seen in ERSPC (completely dismissing PLCO) against the potential harms noted in these and other studies, it is not completely unreasonable to conclude that the benefits of population-wide annual PSA screening do not outweigh the harms. Does this mean that we should abandon PSA-based screening altogether? Given the benefit seen in ERSPC, the answer is clearly no. Rather, we should focus on identifying better screening strategies that optimize the risk-benefit ratio by personalizing the approach to the target population’s underlying risk of disease. Consider that the ERSPC consisted of eight unique sites that used eight similar but distinct protocols for prostate cancer screening that varied by age of initiation, screening interval, and threshold for diagnostic biopsy. Of these eight sites, only two (Sweden and the Netherlands) noted a statistically significant difference in prostate cancer–specific survival, although the magnitude of observed differences and the size of these cohorts were sufficient to drive the results of the parent study. The observed heterogeneity in outcomes between ERSPC sites is likely the result of variation in the intensity and delivery of the intervention (PSA screening) superimposed on differences in underlying risk of disease between

THE PERCENT OF CORES POSITIVE FOR CANCER IN PROSTATE NEEDLE BIOPSY SPECIMENS IS STRONGLY PREDICTIVE OF TUMOR STAGE AND VOLUME AT RADICAL PROSTATECTOMY

7 Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) applies a prostate- specific antigen (PSA) cut-off >3.0 ng/mL as an indication for biopsy. We analyzed the incidence and disease-specific mortality for prostate cancer (PC) within ERSPC Rotterdam for men with an initial PSA <3.0 ng/ml in a 15-year follow-up period. Methods: From 1993-1999, a total of 42,376 men identified from population registries in the Rotterdam region (55-74 yrs) were randomized to a screening or control arm. During the first screening round 19,950 men were screened, with biopsies being initially recommended in case of abnormal DRE or PSA >4.0 ng/mL. From 1997 on, solely PSA >3.0 ng/mL was used. The screening interval was 4 yrs. A total of 15,758 men (79%) had an initial PSA <3.0 ng/mL. Follow-up was complete until January 2009. Results: From 1993-2008, 915 PC cases were diagnosed in 15,758 men (5.8%, median age 62.3 yrs) with an initial PSA <3.0 ng/mL (733 screen detected and 182 interval detected). Median follow-up was 11 yrs. PC incidence increased significantly with higher initial PSA levels (Table). Aggressive PC (clinical stage >T2c, Gleason score >8, PSA >20 ng/mL, positive lymph nodes or metastases at diagnosis) was detected in 65/733 screen detected PC (8.9%) and 102/182 interval detected PC (56.0%). PC death occurred in 23 cases (5 screen detected and 18 interval detected) in the total population (0.15%), with increasing risk in men with higher initial PSA values. Conclusions: The risk of (aggressive) PC and PC mortality in a screening population with initial PSA <3.0 ng/mL increases significantly with higher PSA levels. The risk of dying of PC is minor in men with initial PSA <1.0 ng/mL. Interval detected PC is more aggressive and has a substantial influence on PC specific mortality. [Table: see text] [Table: see text]

PSA velocity may not be of value in prostate cancer detection

Study Type--Therapy (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Radical prostatectomy was previously shown to improve long-term outcomes among men with clinically-detected prostate cancer. Our data suggests that radical prostatectomy is also associated with improved outcomes in men with screen-detected prostate cancer. • To examine the long-term outcomes of radical prostatectomy (RP) among men diagnosed with prostate cancer from the screening and control arms of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). • Among 42,376 men randomised during the period of the first round of the trial (1993-1999), 1151 and 210 in the screening and control arms were diagnosed with prostate cancer, respectively. • Of these men, 420 (36.5%) screen-detected and 54 (25.7%) controls underwent RP with long-term follow-up data (median follow-up 9.9 years). • Progression-free (PFS), metastasis-free (MFS) and cancer-specific survival (CSS) rates were examined, and multivariable Cox proportional hazards models were used to determine whether screen-detected (vs control) was associated with RP outcomes after adjusting for standard predictors. • RP cases from the screening and control arms had statistically similar clinical stage and biopsy Gleason score, although screen-detected cases had significantly lower prostate-specific antigen (PSA) levels at diagnosis. • Men from the screening arm had a significantly higher PFS (P = 0.003), MFS (P < 0.001) and CSS (P = 0.048). • In multivariable models adjusting for age, PSA level, clinical stage, and biopsy Gleason score, the screening group had a significantly lower risk of biochemical recurrence (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.23-0.83, P = 0.011) and metastasis (HR 0.18, 95% CI 0.06-0.59, P = 0.005). • Additionally adjusting for tumour volume and other RP pathology features, there was no longer a significant difference in biochemical recurrence between the screening and control arms. • Limitations of the present study include lead-time bias and non-randomised treatment selection. • After RP, screen-detected cases had significantly improved PFS, MFS and CSS compared with controls within the available follow-up time. • The screening arm remained significantly associated with lower rates of biochemical recurrence and metastasis after adjusting for other preoperative variables. • However, considering also RP pathology, the improved outcomes in the screening group appeared to be mediated by a significantly lower tumour volume.

To assess the value of a positive family history (FH) as a risk factor for prostate cancer incidence and grade among men undergoing organised prostate-specific antigen (PSA) screening in a population-based study. The study cohort comprised all attendees of the Swiss arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) with systematic PSA level tests every 4 years. Men reporting first-degree relative(s) diagnosed with prostate cancer were considered to have a positive FH. Biopsy was exclusively PSA triggered at a PSA level threshold of 3 ng/mL. The primary endpoint was prostate cancer diagnosis. Kaplan-Meier and Cox regression analyses were used. Of 4 932 attendees with a median (interquartile range, IQR) age of 60.9 (57.6-65.1) years, 334 (6.8%) reported a positive FH. The median (IQR) follow-up duration was 11.6 (10.3-13.3) years. Cumulative prostate cancer incidence was 60/334 (18%, positive FH) and 550/4 598 (12%, negative FH) [odds ratio 1.6, 95% confidence interval (CI) 1.2-2.2, P = 0.001). In both groups, most prostate cancer diagnosed was low grade. There were no significant differences in PSA level at diagnosis, biopsy Gleason score or Gleason score on pathological specimen among men who underwent radical prostatectomy between both groups. On multivariable analysis, age (hazard ratio [HR] 1.04, 95% CI 1.02-1.06), baseline PSA level (HR 1.13, 95% CI 1.12-1.14), and FH (HR 1.6, 95% CI 1.24-2.14) were independent predictors for overall prostate cancer incidence (all P < 0.001). Only baseline PSA level (HR 1.14, 95% CI 1.12-1.16, P < 0.001) was an independent predictor of Gleason score ≥7 prostate cancer on prostate biopsy. The proportion of interval prostate cancer diagnosed in-between the screening rounds was not significantly different. Irrespective of the FH status, the current PSA-based screening setting detects the majority of aggressive prostate cancers and missed only a minority of interval cancers with a 4-year screening algorithm. Our results suggest that men with a positive FH are at increased risk of low-grade but not aggressive prostate cancer.

Prostate cancer heterogeneity and multifocality might result in different Gleason scores (GS) at individual biopsy cores. According to World Health Organisation/International Society of Urologic Pathology (WHO/ISUP) guidelines, the GS in each biopsy core should be recorded with optional reporting of overall GS for the entire case. We aimed to compare the clinicopathological characteristics and outcome of men with overall biopsy GS 3+4=7 with highest GS 3+4=7 (HI=OV) to those with highest GS>3+4=7 (HI>OV). Prostate cancer biopsies from the European Randomised Study of Screening for Prostate Cancer (ERSPC) were revised according to WHO/ISUP 2014 guidelines (n=1031). In total, 370 patients had overall GS 3+4=7, 60 of whom (16%) had had at least one biopsy core with GS 4+3=7 or 4+4=8. Men with higher GS than 3+4 (HI>OV) in any of the cores had higher age, prostate-specific antigen (PSA) level, number of positive biopsies, percentage tumour involvement, percentage Gleason grade 4 and cribriform or intraductal growth (all P<0.05) than those with GS 3+4=7 at highest (HI=OV). In multivariable Cox regression analysis, including PSA, percentage positive biopsies and percentage tumour involvement, biochemical recurrence-free survival after radical prostatectomy (P=0.52) or radiotherapy (P=0.35) was not statistically different between both groups. Among patients with overall GS 3+4=7, those with highest GS>3+4=7 had worse clinicopathological features, but clinical outcome was not statistically significant. Therefore, the use of overall GS instead of highest GS for clinical decision-making is justified, potentially preventing overtreatment in prostate cancer patients.

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Relationship Among Initial Serum Prostate Specific Antigen, Prostate Specific Antigen Progression and Prostate Cancer Detection at Repeat Screening Visits

Mass Screening for Prostate Cancer in Korea: A Population Based Study

• To describe metastasis-free survival (MFS) and overall survival (OS) among men with prostate-specific antigen (PSA)-recurrent prostate cancer after radical prostatectomy who did not receive additional therapy until metastasis, using a multicentre database capturing a wide ethnic mix. • A retrospective analysis of the Center for Prostate Disease Research National Database (comprised of five US military hospitals and one civilian centre) was performed for patients with PSA relapse (≥ 0.2 ng/mL) after radical prostatectomy who had no additional therapy until the time of radiographic metastatic disease. • We investigated factors influencing metastasis and all-cause mortality using univariate and multivariate Cox regression analysis. • There were a total of 346 men who underwent radical prostatectomy between May 1983 and November 2008 and fulfilled the entry criteria. All patients had information on survival and 190 men had information on metastasis. Among patients with survival data (n= 346), 10-year OS was 79% after a median follow-up of 8.6 years from biochemical recurrence. • Among men with metastasis data (n= 190), 10-year MFS was 46% after a median follow-up of 7.5 years. • In Cox regressions, four clinical factors (Gleason score, pathological stage, time to PSA relapse and PSA doubling time), as well as age, were predictive of OS and/or MFS in univariate analysis, although only PSA doubling time (≥ 9 vs 3-8.9 vs <3 months) remained independently predictive of these outcomes in multivariate analysis (P < 0.001). • This multicentre multi-ethnic dataset shows that OS and MFS can be extensive for men with PSA-recurrent prostate cancer, even in the absence of further therapy before metastasis. • This unique patient cohort, the second largest of its type after the Johns Hopkins cohort, confirms that PSA doubling time is the strongest determinant of OS and MFS in men with PSA-recurrent disease. • Longer follow-up and more events will be required to determine whether other variables may also contribute to these outcomes.

Study Type--Diagnosis (validating cohort) Level of Evidence 1b. What's known on the subject? and What does the study add? The European Randomized study of Screening for Prostate Cancer (ERSPC) showed a reduction in prostate cancer mortality of 21% for PSA-based screening at a median follow-up of 11 years. In the ERSPC, men are screened at 4-year intervals. A prostate biopsy is recommended for men with a PSA level ≥ 3.0 ng/mL. The study shows that the positive predictive value (PPV) of a prostate biopsy indicated by PSA-based screening remains equal throughout consecutive screening rounds in men without a previous biopsy. In men who have previously had a benign biopsy, the PPV drops considerably, but 20% of the cancers detected still show aggressive characteristics. • To assess the positive predictive value (PPV) of prostate biopsy, indicated by a prostate-specific antigen (PSA) threshold of ≥ 3.0 ng/mL, over time, in the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC). • In the Rotterdam section of the ERSPC, a total of 42,376 participants, aged 55-74 years, identified from population registries were randomly assigned to a screening or control arm. • For the ERSPC men undergo PSA screening at 4-year intervals. A total of three screening rounds were evaluated; therefore, only men aged 55-69 years at the first screening were eligible for the present study. • PPVs for men without previous biopsy remained equal throughout the three subsequent screenings (25.5, 22.3 and 24.8% respectively). • Conversely, PPVs for men with a previous negative biopsy dropped significantly (12.0 and 15.2% at the second and third screening, respectively). • Additionally, in men with and without previous biopsy, the percentage of aggressive prostate cancers (clinical stage >T2b, Gleason score ≥ 7) decreased after the first round of screening from 44.4 to 23.8% in the second (P < 0.001) and 18.6% in the third round (P < 0.001). • Repeat biopsies accounted for 24.6% of all biopsies, but yielded only 8.6% of all aggressive cancers. • In consecutive screening rounds the PPV of PSA-based screening remains equal in previously unbiopsied men. • In men with a previous negative biopsy the PPV drops considerably, but 20% of cancers detected still show aggressive characteristics. • Individualized screening algorithms should incorporate previous biopsy status in the decision to perform a repeat biopsy with the aim of further reducing unnecessary biopsies.

Prediction of Prostate Cancer: External Validation of the ERSPC Risk Calculator in a Contemporary Dutch Clinical Cohort