European Randomized Study Of Screening For Prostate Cancer Research Articles

What explains the differences between centres in the European screening trial? A simulation study

BackgroundThe European Randomised study of Screening for Prostate Cancer (ERSPC) is a multicentre, randomised screening trial on men aged 55–69 years at baseline without known prostate cancer (PrCa) at randomisation to an intervention arm invited to screening or to a control arm. The ERSPC has shown a significant 21% reduction in PrCa mortality at 13 years of follow-up. The effect of screening appears to vary across centres, for which several explanations are possible. We set to assess if the apparent differences in PrCa mortality reduction between the centres can be explained by differences in screening protocols. MethodsWe examined the centre differences by developing a simulation model and estimated how alternative screening protocols would have affected PrCa mortality. ResultsOur results showed outcomes similar to those observed, when the results by centres were reproduced by simulating the screening regimens with PSA threshold of 3 versus 4ng/ml, or screening interval of two versus four years. The findings suggest that the differences are only marginally attributable to the different screening protocols. ConclusionThe small screening impact in Finland was not explained by the differences in the screening protocols. A possible reason for it was the contamination of and the unexpectedly low PrCa mortality in the Finnish control arm.

European Randomized Study of Screening for Prostate Cancer Risk Calculator: External Validation, Variability, and Clinical Significance

To externally validate the European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculator (RC) and to evaluate its variability between 2 consecutive prostate-specific antigen (PSA) values. We prospectively catalogued 1021 consecutive patients before prostate biopsy for suspicion of prostate cancer (PCa). The risk of PCa and significant PCa (Gleason score ≥7) from 749 patients was calculated according to ERSPC-RC (digital rectal examination-based version 3 of 4) for 2 consecutive PSA tests per patient. The calculators' predictions were analyzed using calibration plots and the area under the receiver operating characteristic curve (area under the curve). Cohen kappa coefficient was used to compare the ability and variability. Of 749 patients, PCa was detected in 251 (33.5%) and significant PCa was detected in 133 (17.8%). Calibration plots showed an acceptable parallelism and similar discrimination ability for both PSA levels with an area under the curve of 0.69 for PCa and 0.74 for significant PCa. The ERSPC showed 226 (30.2%) unnecessary biopsies with the loss of 10 significant PCa. The variability of the RC was 16% for PCa and 20% for significant PCa, and a higher variability was associated with a reduced risk of significant PCa. We can conclude that the performance of the ERSPC-RC in the present cohort shows a high similitude between the 2 PSA levels; however, the RC variability value is associated with a decreased risk of significant PCa. The use of the ERSPC in our cohort detects a high number of unnecessary biopsies. Thus, the incorporation of ERSPC-RC could help the clinical decision to carry out a prostate biopsy.

Reply by Authors

No AccessJournal of UrologyLetter to the Editor/Errata1 Jan 2017Reply by Authors View All Author Informationhttps://doi.org/10.1016/j.juro.2016.07.100AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Reply by Authors." The Journal of Urology, 197(1), p. 264 References 1 : Heterogeneity in D'Amico classification-based low-risk prostate cancer: differences in upgrading and upstaging according to active surveillance eligibility. Urol Oncol2015; 33: 329.e13. Google Scholar 2 : Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet2014; 384: 2027. Google Scholar 3 : Tumor volume in insignificant prostate cancer: increasing threshold gains increasing risk. Prostate2015; 75: 45. Google Scholar © 2017 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 197Issue 1January 2017Page: 264 Advertisement Copyright & Permissions© 2017 by American Urological Association Education and Research, Inc.MetricsAuthor Information Expand All Advertisement PDF downloadLoading ...

Let's Not Throw the Baby out With the Bathwater in Prostate Cancer Screening

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 current state of prostate-specific antigen testing.

Since prostate-specific antigen (PSA) testing was approved in 1994, the incidence of metastasis and mortality from prostate cancer have significantly decreased. However, PSA screening for prostate cancer has limitations and few large randomized controlled trials have been conducted to determine the mortality benefit of PSA screening. Two studies that have been conducted are the Prostate, Lung, Colorectal, and Ovarian (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC). These were the two main studies the US Preventive Services Task Force (USPSTF) used in its recommendation against prostate cancer screening in 2012. However, new evidence has demonstrated that the PLCO trial had significant limitations and the results of the ERSPC trial were more significant than previously thought. This article describes the strengths and weaknesses of the USPSTF's recommendation, along with current guidelines for prostate cancer screening.

Design-corrected variation by centre in mortality reduction in the ERSPC randomised prostate cancer screening trial.

Objectives To calculate design-corrected estimates of the effect of screening on prostate cancer mortality by centre in the European Randomised Study of Screening for Prostate Cancer (ERSPC). Setting The ERSPC has shown a 21% reduction in prostate cancer mortality in men invited to screening with follow-up truncated at 13 years. Centres either used pre-consent randomisation (effectiveness design) or post-consent randomisation (efficacy design). Methods In six centres (three effectiveness design, three efficacy design) with follow-up until the end of 2010, or maximum 13 years, the effect of screening was estimated as both effectiveness (mortality reduction in the target population) and efficacy (reduction in those actually screened). Results The overall crude prostate cancer mortality risk ratio in the intervention arm vs control arm for the six centres was 0.79 ranging from a 14% increase to a 38% reduction. The risk ratio was 0.85 in centres with effectiveness design and 0.73 in those with efficacy design. After correcting for design, overall efficacy was 27%, 24% in pre-consent and 29% in post-consent centres, ranging between a 12% increase and a 52% reduction. Conclusion The estimated overall effect of screening in attenders (efficacy) was a 27% reduction in prostate cancer mortality at 13 years' follow-up. The variation in efficacy between centres was greater than the range in risk ratio without correction for design. The centre-specific variation in the mortality reduction could not be accounted for by the randomisation method.

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

BackgroundThe validity of prediction models needs external validation to assess their value beyond the original development setting. ObjectiveTo report the diagnostic accuracy of the European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculator (RC)3 and RC4 in a contemporary Dutch clinical cohort. Design, setting, and participantsWe retrospectively identified all men who underwent prostate biopsy (PBx) in the Jeroen Bosch Hospital, The Netherlands, between 2007 and 2016. Patients were included if they met ERSPC RC requirements of age (50–80 yr), prostate-specific antigen (PSA) (0.4–50 ng/ml), and prostate volume (10–150ml). The probability of a positive biopsy for prostate cancer (PCa) and significant PCa (Gleason score ≥7 and/or higher than T2b) were calculated and compared with PBx pathology results. Outcome measurements and statistical analysisEvaluation was performed by calibration, discrimination, and clinical usefulness using calibration plots, area under the receiver operating characteristic curves (AUCs), and decision curve analyses (DCAs), respectively. Results and limitationsA total of 2270 PBx sessions were eligible for final analysis. Discriminative ability of RC3 (AUC) was 0.78 and 0.90 for any PCa and significant PCa, respectively. For RC4 the calculated AUCs were 0.62 (any PCa) and 0.76 (significant PCa). The calibration plots of RC3 showed good results for both any PCa risk and significant PCa risk. In the repeat PBx group, RC4 tended to underestimate outcomes for PCa and showed moderate calibration for significant PCa. DCA showed an overall net benefit compared with PSA and digital rectal examination (DRE) alone. Limitations of this study are its retrospective single-institution design, retrospectively assessed DRE outcomes, no time restrictions between the first and repeat biopsy sessions, and no anterior sampling in the repeat PBx protocol. ConclusionsThe ERSPC RCs performed well in a contemporary clinical setting. Most pronounced in the biopsy-naive group, both RCs should be favoured over a PSA plus DRE–based stratification in the decision whether or not to perform PBx. Patient summaryWe looked at the ability of the existing European Randomized Study of Screening for Prostate Cancer risk calculator (RC), using different clinical data to predict the presence of prostate cancer in Dutch men. The RC performed well and should be favoured in the decision of whether or not to perform prostate biopsies over the conventional diagnostic pathway.

Correlation between stage shift and differences in mortality in the European Randomised study of Screening for Prostate Cancer (ERSPC).

Correlation between stage shift and differences in mortality in the European Randomised study of Screening for Prostate Cancer (ERSPC).

Discoveries and application of prostate-specific antigen, and some proposals to optimize prostate cancer screening.

The discoveries and application of prostate-specific antigen (PSA) have been much appreciated because PSA-based screening has saved millions of lives of prostate cancer (PCa) patients. Historically speaking, Flocks et al first identified antigenic properties in prostate tissue in 1960. Then, Barnes et al detected immunologic characteristics in prostatic fluid in 1963. Hara et al characterized γ-semino-protein in semen in 1966, and it has been proven to be identical to PSA. Subsequently, Ablin et al independently reported the presence of precipitation antigens in the prostate in 1970. Wang et al purified the PSA in 1979, and Kuriyama et al first applied an enzyme-linked immunosorbent assay for PSA in 1980. However, the positive predictive value with a cutoff figure of 4.0 ng/mL appeared substantially low (∼30%). There are overdiagnoses and overtreatments for latent/low-risk PCa. Controversies exist in the PCa mortality-reducing effects of PSA screening between the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. For optimizing PCa screening, PSA-related items may require the following: 1) adjustment of the cutoff values according to age, as well as setting limits to age and screening intervals; 2) improving test performance using doubling time, density, and ratio of free: total PSA; and 3) fostering active surveillance for low-risk PCa with monitoring by PSA value. Other items needing consideration may include the following: 1) examinations of cell proliferation and cell cycle markers in biopsy specimens; 2) independent quantification of Gleason grading; 3) developing ethnicity-specific staging nomograms based on tumor stage, PSA value, and Gleason score; 4) delineation of the natural history; 5) revisiting the significance of the androgen/testosterone hypothesis; and 6) devoting special attention to individuals with a certain genetic predisposition. Finally, considering the uncertainty that exists in medicine, risk communication on PSA-based screening is indeed due.

Screening Coverage Needed to Reduce Mortality from Prostate Cancer: A Living Systematic Review.

IntroductionScreening for prostate cancer remains controversial because of conflicting results from the two major trials: The Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) screening trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC).ObjectiveMeta-analyze and meta-regress the available PSA screening trials.MethodsWe performed a living systematic review and meta-regression of the reduction in prostate cancer mortality as a function of the duration of screening provided in each trial. We searched PubMed, Web of Science, the Cochrane Registry, and references lists from previous meta-analyses to identify randomized trials of PSA screening. We followed PRISMA guidelines and qualified strength of evidence with a GRADE Profile.ResultsWe found 6 trials, but excluded one that also screened with trans-rectal ultrasound. We considered each ERSPC center as a separate trial. When pooling together all 11 trials we found no significant benefit from screening; however, the heterogeneity was 28.2% (95% CI: 0% to 65%). Heterogeneity was explained by variations in the duration of serial screening (I2 0%; 95% CI: 0% to 52%). When we analyzed the subgroup of trials that added more than 3 years of screening (range 3.2 to 3.8) we found a significant benefit for screening with risk ratio 0.78 (95% CI 0.65–0.94; I2 = 0%; 95% CI: 0% to 69%) and a number needed to invite for screening of 1000. We downgraded the quality of evidence to moderate due to our retrospective identification of subgroups and limited data on control group screening.ConclusionsAdequate duration of screening reduces mortality from prostate cancer. The benefit, while small, compares favorably with screening for other cancers. Our projections are limited by the moderate quality of evidence.

MP39-15 SCREENING FOR PROSTATE CANCER: RESULTS FROM THE SWISS SECTION OF THE ERSPC (AARAU)

You have accessJournal of UrologyProstate Cancer: Detection & Screening V1 Apr 2016MP39-15 SCREENING FOR PROSTATE CANCER: RESULTS FROM THE SWISS SECTION OF THE ERSPC (AARAU) Maciej Kwiatkowski, Lukas Prause, Stephen F Wyler, Tilmann Moeltgen, Andreas Huber, Rainer Grobholz, Lukas Manka, and Franz Recker Maciej KwiatkowskiMaciej Kwiatkowski More articles by this author , Lukas PrauseLukas Prause More articles by this author , Stephen F WylerStephen F Wyler More articles by this author , Tilmann MoeltgenTilmann Moeltgen More articles by this author , Andreas HuberAndreas Huber More articles by this author , Rainer GrobholzRainer Grobholz More articles by this author , Lukas MankaLukas Manka More articles by this author , and Franz ReckerFranz Recker More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.140AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In year 1998 Switzerland (Aarau) started participation in the European Randomized Study of Screening for Prostate Cancer (ERSPC) study. The important reason to join this multicenter trial was the epidemiological data showing Switzerland as having one of the highest rates of morbidity and mortality of prostate cancer (PCa) worldwide. This study aims to investigate the influence of the PSA based screening on the PCa specific mortality. The study setting is the prospective randomized population based screening trial with the primary hypothesis that screening can significantly reduce PCa specific mortality by at least 25%. We present the results of the Aarau section of the ERSPC. METHODS From 1998 to 2003, 10311 men, participants of the Swiss section (Aarau) of the ERSPC, were randomised into the active screening (Gr.1, eligible n=5130) and control (Gr.2, n=5121) groups. In the intervention group PSA-screening was undertaken every 4 years with a value of ≥ 3.0 ng/ml as indication for prostate biopsy (3 screening rounds). The data for this study are complete until December 2012. Primary endpoint was PCa death or death from any causes. Causes of death were monitored by the Swiss Office of Statistics and reviewed by an independent reviewer panel. The PCa specific mortality was analysed and the group differences tested for their statistical significance using Poisson regression and Nelson-Aalen cumulative hazard rate. RESULTS Overall median follow up was 12.2 years (IQR 10.6-13.3) years. Mean age at study entrance was 60.5 (Gr.1) and 60.7 (Gr.2), respectively. 4932 men in Gr.1 were screened in the first round of screening (compliance 96.1%). PCa incidence was 630 (12.3%) in Gr. 1 vs. 365 (7.1%). 13% of all men randomized died until December 2012. PCa mortality in ″intention to screen″ was 18 (0.3 rate per 1000 person-years) in the Gr. 1 vs. 25 (0.42 rate per 1000 person-years) resulting in the RR of 0.72 (CI 95%; 0.39 - 1.31; p=0.28) thus the statistically not significant risk reduction of 28%. The resulting PCa mortality rate was 2.7% in the intervention and 3.8% in the control group respectively. CONCLUSIONS The swiss data support the significant mortality reduction of the ERSPC. Due to the smaller number of participants a statistical significance cannot result as expected. Mortality reduction after 12 years is in line with the natural course of disease but the follow-up might still be too short. Only the analysis of all data of the ERSPC could confirm the study hypothesis with adequate power. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e547 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Maciej Kwiatkowski More articles by this author Lukas Prause More articles by this author Stephen F Wyler More articles by this author Tilmann Moeltgen More articles by this author Andreas Huber More articles by this author Rainer Grobholz More articles by this author Lukas Manka More articles by this author Franz Recker More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Editorial Comment

Due to the relatively modest survival benefit associated with the early detection of prostate cancer (PCa), prostate-specific antigen (PSA)-based screening has become controversial, with concerns regarding both overdiagnosis and overtreatment. 1 Kim E.H. Andriole G.L. Prostate-specific antigen-based screening: controversy and guidelines. BMC Med. 2015; 13: 61 Crossref PubMed Scopus (76) Google Scholar The authors of this manuscript attempt to consolidate the numerous disparate PSA screening recommendations into a unified guideline based on expert opinion informed by the best available data. 2 Vickers A.J. Eastham J.A. Scardino P.T. Lilja H. The Memorial Sloan Kettering Cancer Center recommendations for prostate cancer screening. Urology. 2016; https://doi.org/10.1016/j.urology.2015.12.054 Abstract Full Text Full Text PDF Scopus (49) Google Scholar The Memorial Sloan Kettering Cancer Center (MSKCC) recommendation for PCa screening begins at 45 years of age and provides a PSA-based risk-stratified algorithm: consider biopsy for those with PSA >3 ng/mL, routine screening for those with PSA between 1 and 3 ng/mL, and infrequent screening for those with PSA <1 ng/mL. Recommendations to begin testing at an earlier age and risk stratification according to PSA level were based in part on the Malmö Preventative Project study, 3 Lilja H. Cronin A.M. Dahlin A. et al. Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50. Cancer. 2011; 117: 1210-1219 Crossref PubMed Scopus (116) Google Scholar whereas the threshold to consider biopsy and the screening interval of 2 to 4 years were based on the results of the European Randomized Screening for Prostate Cancer and the United States prostate, lung, colorectal, and ovarian cancer screening trials. 4 Schroder F.H. Hugosson J. Roobol M.J. et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years follow-up. Lancet. 2014; 384: 6-12 Abstract Full Text Full Text PDF PubMed Scopus (1052) Google Scholar , 5 Andriole G.L. Crawford E.D. Grubb R.L. et al. Prostate cancer screening in the randomized prostate, lung, colorectal, and ovarian cancer screening trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012; 104: 1-8 Crossref Scopus (826) Google Scholar

Long-term prostate-specific antigen contamination in the Spanish arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC)

ObjectivesRecently, the European Randomized Study of Screening for Prostate Cancer achieved a reduction in prostate cancer mortality by measuring serum prostate-specific antigen (PSA) levels. These results were not reproduced in the Spanish arm of European Randomized Study of Screening for Prostate Cancer. PSA contamination (opportunistic measurements outside the study) could decrease the study's contrasting power if performed in the control arm. We have calculated the long-term rate of PSA contamination and its effect on performing prostate biopsy and detecting cancer. Material and methodsA total of 4276 men were randomized (2415 to the screening arm, 1861 to the control arm) in the Spanish section of the European Randomized Study of Screening for Prostate Cancer. PSA measurements were not scheduled in the control arm. Sextant prostate biopsy was indicated if PSA levels were ≥3ng/ml. All PSA readings performed outside the study were labeled as “PSA contamination”. We calculated the rates of PSA contamination, biopsy implementation and cancer detection. ResultsThe median age and follow-up time were 57 and 15.1 years, respectively. A total of 2511 men underwent at least one PSA reading outside the study. PSA contamination at 5, 10 and 15 years was 22.0%, 47.1% and 66.3% in the screening arm, respectively, and 20.8%, 43.2% and 58.6% in the control arm, respectively (p<0.0001). The biopsy rate at 5, 10 and 15 years was 19.3%, 22.6% and 24.1% (screening), respectively, and 1.0%, 3.6% and 7.1% (control), respectively (p<0.0001). The PC detection rate was 6.7% (screening) and 4.3% (control; p=0.0006). ConclusionsAlthough the cumulative PSA contamination was pronounced in the 2 study arms, the rate of prostate biopsies was low in the control arm. We therefore believe that the effect of PSA contamination on the study's statistical power should be limited.

A positive family history as a risk factor for prostate cancer in a population-based study with organised prostate-specific antigen screening: results of the Swiss European Randomised Study of Screening for Prostate Cancer (ERSPC, Aarau).

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.

Abstract 4681: Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish arm of the European randomised study of screening for prostate cancer (ERSPC)

Abstract Background The US Preventive Services Task Force (USPSTF) recommends against serum prostate specific antigen (PSA) based screening for prostate cancer, on the grounds that the expected harms of screening (mainly overdiagnosis and subsequent overtreatment) outweigh the potential benefits (mainly reduction in cancer-specific mortality). This study aims to estimate the mean sojourn time (MST) and sensitivity and then use these estimates to derive the probability of overdiagnosis by polygenic risk group. Methods We calculated the polygenic risk score based on genotypes of 66 known prostate cancer susceptibility variants for 4,967 men from the Finnish arm of the European randomised study of screening for prostate cancer (ERSPC). We stratified the 80,179 Finnish trial participants into two risk groups below and above 50th percentile risk. Using a maximum likelihood method based on interval cancers, we estimated the MST and episode sensitivity. We calculated the expected number of non-overdiagnosed screen-detected cancers over three rounds of screening. We estimated the proportion of screen-detected cancers that are likely to be overdiagnosed from the difference between the observed and expected number of screen-detected cancers. We derived overall and separate estimates of overdiagnosis by polygenic risk group. Result Men in the above average genetic risk group accounted for 74 percent of the prostate cancers cases. The episode sensitivity was 0.55 (95% CI 0.45 to 0.65) and MST 6.3 (95% CI 4.2 to 8.3) years. The overall overdiagnosis was 42% (95% CI 37 to 52) with 58% (95% CI 54 to 65) in the lower risk group and 37% (95% CI 31 to 47) in the higher risk group. Targeting screening to men in the higher polygenic risk group would reduce screening episodes by half while detecting 80% of the non-overdiagnosed cancers and preventing 38% of the overdiagnosed cancers at a cost of missing 20% of the non-overdiagnosed cancers. Conclusion Polygenic risk-stratified screening for prostate cancer is a promising approach to decrease overdiagnosis. Further research is needed to study the effect of targeted screening on cancer-specific mortality. Citation Format: Nora Pashayan, Paul D.P. Pharoah, Johanna Schleutker, Kirsi Talala, Teuvo LJ Tammela, Liisa Määttänen, Patricia Harrington, Jonathan Tyrer, Rosalind Eeles, Stephen W. Duffy, Anssi Auvinen. Reducing overdiagnosis by polygenic risk-stratified screening: findings from the Finnish arm of the European randomised study of screening for prostate cancer (ERSPC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4681. doi:10.1158/1538-7445.AM2015-4681

Prostate cancer: net survival and cause-specific survival rates after multiple imputation.

BackgroundEstimations of survival rates are diverse and the choice of the appropriate method depends on the context. Given the increasing interest in multiple imputation methods, we explored the interest of a multiple imputation approach in the estimation of cause-specific survival, when a subset of causes of death was observed.MethodsBy using European Randomized Study of Screening for Prostate Cancer (ERSPC), 20 multiply imputed datasets were created and analyzed with a Multivariate Imputation by Chained Equation (MICE) algorithm. Then, cause-specific survival was estimated on each dataset with two methods: Kaplan-Meier and competing risks. The two pooled cause-specific survival and confidence intervals were obtained using Rubin’s rules after complementary log-log transformation. Net survival was estimated using Pohar-Perme’s estimator and was compared to pooled cause-specific survival. Finally, a sensitivity analysis was performed to test the robustness of our constructed multiple imputation model.ResultsCause-specific survival performed better than net survival, since this latter exceeded 100 % for almost the first 2 years of follow-up and after 9 years whereas the cause-specific survival decreased slowly and than stabilized at around 94 % at 9 years. Sensibility study results were satisfactory.ConclusionsOn our basis of prostate cancer data, the results obtained by cause-specific survival after multiple imputation appeared to be better and more realistic than those obtained using net survival.Electronic supplementary materialThe online version of this article (doi:10.1186/s12874-015-0048-4) contains supplementary material, which is available to authorized users.

Rule-based versus probabilistic selection for active surveillance using three definitions of insignificant prostate cancer.

PurposeTo study whether probabilistic selection by the use of a nomogram could improve patient selection for active surveillance (AS) compared to the various sets of rule-based AS inclusion criteria currently used.MethodsWe studied Dutch and Swedish patients participating in the European Randomized study of Screening for Prostate Cancer (ERSPC). We explored which men who were initially diagnosed with cT1-2, Gleason 6 (Gleason pattern ≤3 + 3) had histopathological indolent PCa at RP [defined as pT2, Gleason pattern ≤3 and tumour volume (TV) ≤0.5 or TV ≤ 1.3 ml, and TV no part of criteria (NoTV)]. Rule-based selection was according to the Prostate cancer Research International: Active Surveillance (PRIAS), Klotz, and Johns Hopkins criteria. An existing nomogram to define probability-based selection for AS was refitted for the TV1.3 and NoTV indolent PCa definitions.Results619 of 864 men undergoing RP had cT1-2, Gleason 6 disease at diagnosis and were analysed. Median follow-up was 8.9 years. 229 (37 %), 356 (58 %), and 410 (66 %) fulfilled the TV0.5, TV1.3, and NoTV indolent PCa criteria at RP. Discriminating between indolent and significant disease according to area under the curve (AUC) was: TV0.5: 0.658 (PRIAS), 0.523 (Klotz), 0.642 (Hopkins), 0.685 (nomogram). TV1.3: 0.630 (PRIAS), 0.550 (Klotz), 0.615 (Hopkins), 0.646 (nomogram). NoTV: 0.603 (PRIAS), 0.530 (Klotz), 0.589 (Hopkins), 0.608 (nomogram).ConclusionsThe performance of a nomogram, the Johns Hopkins, and PRIAS rule-based criteria are comparable. Because the nomogram allows individual trade-offs, it could be a good alternative to rigid rule-based criteria.Electronic supplementary materialThe online version of this article (doi:10.1007/s00345-015-1628-y) contains supplementary material, which is available to authorized users.

Comparison of Two Prostate Cancer Risk Calculators that Include the Prostate Health Index

BackgroundRisk prediction models for prostate cancer (PCa) have become important tools in reducing unnecessary prostate biopsies. The Prostate Health Index (PHI) may increase the predictive accuracy of such models. ObjectivesTo compare two PCa risk calculators (RCs) that include PHI. Design, setting, and participantsWe evaluated the predictive performance of a previously developed PHI-based nomogram and updated versions of the European Randomized Study of Screening for Prostate Cancer (ERSPC) RCs based on digital rectal examination (DRE): RC3 (no prior biopsy) and RC4 (prior biopsy). For the ERSPC updates, the original RCs were recalibrated and PHI was added as a predictor. The PHI-updated ERSPC RCs were compared with the Lughezzani nomogram in 1185 men from four European sites. Outcomes were biopsy-detectable PC and potentially advanced or aggressive PCa, defined as clinical stage >T2b and/or a Gleason score ≥7 (clinically relevant PCa). Results and limitationsThe PHI-updated ERSPC models had a combined area under the curve for the receiver operating characteristic (AUC) of 0.72 for all PCa and 0.68 for clinically relevant PCa. For the Lughezzani PHI-based nomogram, AUCs were 0.75 for all PCa and 0.69 for clinically relevant PCa. For men without a prior biopsy, PHI-updated RC3 resulted in AUCs of 0.73 for PCa and 0.66 for clinically relevant PCa. Decision curves confirmed these patterns, although the number of clinically relevant cancers was low. ConclusionDifferences between RCs that include PHI are small. Addition of PHI to an RC leads to further reductions in the rate of unnecessary biopsies when compared to a strategy based on prostate-specific antigen measurement. Patient summaryRisk prediction models for prostate cancer have become important tools in reducing unnecessary prostate biopsies. We compared two risk prediction models for prostate cancer that include the Prostate Health Index. We found that these models are equivalent to each other, and both perform better than the prostate-specific antigen test alone in predicting cancer.

Predicting prostate cancer: analysing the clinical efficacy of prostate cancer risk calculators in a referral population.

The decision to proceed to biopsy for the diagnosis of prostate cancer in clinical practice is a difficult one. Prostate cancer risk calculators allow for a systematic approach to the use of patient information to predict a patient's likelihood of prostate cancer. In this paper, we validate the two leading prostate cancer risk calculators, the prostate cancer prevention trial (PCPT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC) in an Irish population. Data were collected for 337 men referred to one tertiary referral center in Ireland. Calibration analysis, ROC analysis and decision curve analysis were undertaken to ascertain the performance of the PCPT and the ERSPC risk calculators in this cohort. Of 337 consecutive biopsies, cancer was subsequently diagnosed in 146 men (43 %), 98 (67 %) of which were high grade. The AUC for the PCPT and ERSPC risk calculators were 0.68 and 0.66, respectively for the prediction of prostate cancer. Each calculator was sufficiently calibrated in this cohort. Decision curve analysis demonstrated a net benefit via the use of the PCPT and ERSPC risk calculators in the diagnosis of prostate cancer. The PCPT and ERSPC risk calculators achieve a statistically significant prediction of prostate cancer in this Irish population. This study provides external validation for these calculators, and therefore these tools can be used to aid in clinical decision making.

PD46-06 PSA BASED SCREENING FOR PROSTATE CANCER: STARTING TOO LATE AND NON-COMPLIANCE, LIMITING THE NUMBER OF SCREENING VISITS, NEGATIVELY AFFECT PC MORTALITY REDUCTION.

You have accessJournal of UrologyProstate Cancer: Detection and Screening V1 Apr 2015PD46-06 PSA BASED SCREENING FOR PROSTATE CANCER: STARTING TOO LATE AND NON-COMPLIANCE, LIMITING THE NUMBER OF SCREENING VISITS, NEGATIVELY AFFECT PC MORTALITY REDUCTION. Monique Roobol and ERSPC study group Rotterdam Monique RoobolMonique Roobol More articles by this author and ERSPC study group RotterdamERSPC study group Rotterdam More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2737AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The published 3rd update of ERSPC (European Randomized study of Screening for Prostate Cancer) showed an increase in absolute PC mortality reduction (AR: from 1.07 to 1.28 per 1000 men) but no increase in the relative PC mortality reduction (RR) in favor of screening (stable RR of 20%). I.e. more events occur over time but at a similar relative increase. ERSPC Rotterdam (ERSPC-R) continues screening (scr) up to 75 years and has most biopsy referrals. METHODS ERSPC_R randomized 42,376 men aged 55-74 yr, to either scr (S, N=21,210) or control arm (N=21,166) in the period 1993-1999. Scr interval is 4 yr with PSA >= 3.0 ng/ml triggering biopsy. We compare the published 2010 data (follow-up (FU) 12.8 yr; the 2010_data) with the 2012 data (FU of 14.5 yr; the 2012_data, 97% complete) focusing at newly emerged PC deaths; specifically in interval PC ( I-PC detected in men in S-arm outside the scr protocol) and S-detected PC cases. RESULTS The increase in PC deaths in S-arm and C-arm is comparable, 18.4% (2010_data) and 17.5% (2012_data), the RR of PC mortality reduction remained stable: 20% and 20.6% res. Similar data in age group 55-69 yr show a 19.3% and 16.1% increase in PC deaths in S- and C-arm res. and RR decreasing from 31.6% to 28.9%. AR changed from 2.6 to 2.8 PC deaths per 1000 men. The table (PC deaths) shows that 40% of PC deaths in the S-arm occur in I-PC. New PC deaths in the S-arm mainly occurred in 2nd round S-detected PC and I-PC emerging in the 3rd and 4th interval. Fatal S-detected PC at 2nd round consisted for 50% of men > 60 yr at 1st screen and for 33% of men with a PSA between 3 and 4 and no biopsy at 1st screen. 3rd and 4th period I-PC deaths (N=39 in total age group) mainly emerged in men > 70 yr at randomization, hence screened only once (N=14) and in men that did not attend next screening ( i.e often screened once) mostly due to previous negative biopsies (N=14). 11 I-PC were in men fully screened. CONCLUSIONS ERSPC-R 2012_data confirm the stable RR. The increase in PC deaths in the S-arm is mainly due to starting too late and non-compliance with the S-algorithm (limiting the number of screens). A more tailored S-algorithm potentially reducing non-compliance and starting at younger age may increase the effect of PC screening on PC specific mortality. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e958 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Monique Roobol More articles by this author ERSPC study group Rotterdam More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...