Search

Background and Objective: While prostate cancer (PCa) incidence and mortality rates continue to rise, early detection of PCa remains highly controversial, and the research landscape is rapidly evolving. Existing systematic reviews (SRs) and meta-analyses (MAs) provide valuable insights, but often focus on single aspects of early detection, hindering a comprehensive understanding of the topic. We aim to fill this gap by providing a comprehensive SR of contemporary SRs covering different aspects of early detection of PCa in the European Union (EU) and the UK., Methods: On June 1, 2023, we searched four databases (Medline ALL via Ovid, Embase, Web of Science, and Cochrane Central Register of Controlled Trials) and Google Scholar. To avoid repetition of previous studies, only SRs (qualitative, quantitative, and/or MAs) were considered eligible. In the data, common themes were identified to present the evidence systematically., Key Findings and Limitations: We identified 1358 citations, resulting in 26 SRs eligible for inclusion. Six themes were identified: (1) invitation: men at general risk should be invited at >50 yr of age, and testing should be discontinued at >70 yr or with <10 yr of life expectancy; (2) decision-making: most health authorities discourage population-based screening and instead recommend a shared decision-making (SDM) approach, but implementation of SDM in clinical practice varies widely; decision aids help men make more informed and value-consistent screening decisions and decrease men's intention to attempt screening, but these do not affect screening uptake; (3) acceptance: facilitators for men considering screening include social prompting by partners and clinician recommendations, while barriers include a lack of knowledge, low-risk perception, and masculinity attributes; (4) screening test and algorithm: prostate-specific antigen-based screening reduces PCa-specific mortality and metastatic disease in men aged 55-69 yr at randomisation if screened at least twice; (5) harms and benefits: these benefits come at the cost of unnecessary biopsies, overdiagnosis, and subsequent overtreatment; and (6) future of screening: risk-adapted screening including (prebiopsy) risk calculators, magnetic resonance imaging, and blood- and urine-based biomarkers could reduce these harms. To enable a comprehensive overview, we focused on SRs. These do not include the most recent prospective studies, which were therefore incorporated in the discussion., Conclusions and Clinical Implications: By identifying consistent and conflicting evidence, this review highlights the evidence-based foundations that can be built upon, as well as areas requiring further research and improvement to reduce the burden of PCa in the EU and UK., Patient Summary: This review of 26 reviews covers various aspects of prostate cancer screening such as invitation, decision-making, screening tests, harms, and benefits. This review provides insights into existing evidence, highlighting the areas of consensus and discrepancies, to guide future research and improve prostate cancer screening strategies in Europe., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: In Europe, prostate cancer (PCa) is the most common cancer in men. Screening may therefore be crucial to lower health care costs, morbidity, and mortality. This systematic review aimed to provide a contemporary overview of the costs and benefits of PCa screening programmes., Methods: A peer-reviewed literature search was conducted, using the PICO method. A detailed search strategy was developed in four databases based on the following key search terms: "PCa", "screening", and "cost effectiveness". Any type of economic evaluation was included. The search strategy was restricted to European countries, but no restrictions were set on the year of publication., Key Findings and Limitations: A total of 7484 studies were identified initially. Of these, 19 studies described the cost effectiveness of PCa screening in Europe. Among the studies using an initially healthy study population, most focussed on risk- and/or age- and/or magnetic resonance imaging (MRI)-based screening in addition to prostate-specific antigen (PSA) testing and compared this with no screening. Incremental cost ratios (ICERs) varied from €5872 per quality-adjusted life year (QALY) to €372 948/QALY, with a median of €56 487/QALY. Risk-based screening followed by MRI testing seemed to be a more cost-effective strategy than no screening., Conclusions and Clinical Implications: This systematic review indicates that screening programmes incorporating a risk-based approach and MRI have the potential to be cost effective., Patient Summary: In this review, we looked at the cost effectiveness of prostate cancer screening in Europe. We found that a risk-based approach and incorporation of magnetic resonance imaging has the potential to be cost effective. However, there remains a knowledge gap regarding cost effectiveness of prostate cancer screening. Therefore, determinants of cost effectiveness require further investigation., (Copyright © 2024. Published by Elsevier B.V.)

Background: Conservative management is an option for prostate cancer (PCa) patients either with the objective of delaying or even avoiding curative therapy, or to wait until palliative treatment is needed. PIONEER, funded by the European Commission Innovative Medicines Initiative, aims at improving PCa care across Europe through the application of big data analytics., Objective: To describe the clinical characteristics and long-term outcomes of PCa patients on conservative management by using an international large network of real-world data., Design, Setting, and Participants: From an initial cohort of >100 000 000 adult individuals included in eight databases evaluated during a virtual study-a-thon hosted by PIONEER, we identified newly diagnosed PCa cases (n = 527 311). Among those, we selected patients who did not receive curative or palliative treatment within 6 mo from diagnosis (n = 123 146)., Outcome Measurements and Statistical Analysis: Patient and disease characteristics were reported. The number of patients who experienced the main study outcomes was quantified for each stratum and the overall cohort. Kaplan-Meier analyses were used to estimate the distribution of time to event data., Results and Limitations: The most common comorbidities were hypertension (35-73%), obesity (9.2-54%), and type 2 diabetes (11-28%). The rate of PCa-related symptomatic progression ranged between 2.6% and 6.2%. Hospitalization (12-25%) and emergency department visits (10-14%) were common events during the 1st year of follow-up. The probability of being free from both palliative and curative treatments decreased during follow-up. Limitations include a lack of information on patients and disease characteristics and on treatment intent., Conclusions: Our results allow us to better understand the current landscape of patients with PCa managed with conservative treatment. PIONEER offers a unique opportunity to characterize the baseline features and outcomes of PCa patients managed conservatively using real-world data., Patient Summary: Up to 25% of men with prostate cancer (PCa) managed conservatively experienced hospitalization and emergency department visits within the 1st year after diagnosis; 6% experienced PCa-related symptoms. The probability of receiving therapies for PCa decreased according to time elapsed after the diagnosis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The optimal timing for discontinuing screening of prostate cancer (PCa) in elderly men is currently not known and remains debated., Objective: To assess prostate cancer-specific mortality (PCSM) in elderly men who previously underwent prostate-specific antigen (PSA)-based screening and to identify those who may benefit from continued screening., Design, Setting, and Participants: A total of 7052 men, who participated in the screening arm of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer and were aged 70-74 yr at their last screening visit after undergoing a maximum of three screening rounds without being diagnosed with PCa, were included., Outcome Measurements and Statistical Analysis: The cumulative incidence of PCSM by the age of 85 yr was assessed. Additionally, a competing risk regression was performed to assess the potential predictors of PCSM., Results and Limitations: The median follow-up was 16 yr. The cumulative incidence of PCSM by the age of 85 yr was 0.54% (95% confidence interval [CI]: 0.40-0.70) in all men, 0.11% (95% CI: 0.05-0.27) in men with PSA <2 ng/ml, 0.85% (95% CI: 0.47-1.5) in men with PSA 2-3 ng/ml, and 6.8% (95% CI: 3.1-15) in men with PSA ≥6.5 ng/ml and no previous benign biopsy. PSA (subdistribution hazard ratio [sHR]: 2.0; 95% CI: 1.7-2.3), previous benign prostate biopsy (sHR: 0.41; 95% CI: 0.23-0.72), and hypertension (sHR: 0.48; 95% CI: 0.25-0.91) were significantly associated with PCSM., Conclusions: Men aged 70-74 yr who have previously undergone PSA-based screening without receiving a PCa diagnosis have a very low risk of dying from PCa by the age of 85 yr. These data suggest that screening may be discontinued in men with PSA <3.0 ng/ml or previous benign prostate biopsies. Those with higher PSA levels and no prior biopsies may consider continued screening if life expectancy exceeds 10 yr., Patient Summary: This study shows that men who participated in a prostate cancer screening trial have a very low risk of dying from prostate cancer if they have not been diagnosed with prostate cancer by the age of 74 yr., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age., Objective: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2-4 yr)., Design, Setting, and Participants: We evaluated 25589 men aged 55-59 yr, 16898 men aged 60-64 yr, and 12936 men aged 65-69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2-4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU)., Outcome Measurements and Statistical Analysis: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60-61 yr., Results and Limitations: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2-1.5% for men with PSA <1.0 ng/ml to 13.3-13.8% for men with PSA ≥3.0 ng/ml. The association between baseline PSA and PCSM differed marginally among the three age groups. A Lorenz curve for men aged 60-61 yr showed that 92% of lethal PCa cases occurred among those with PSA above the median (1.21 ng/ml). In addition, for men initially screened at age 60-61 yr with baseline PSA <2 ng/ml, further continuation of screening is unlikely to be beneficial after the age of 68-70 yr if PSA is still <2 ng/ml. No case of PCSM emerged in the subsequent 8 yr (up to age 76-78 yr). A limitation is that these results may not be generalizable to an opportunistic screening setting or to contemporary clinical practice., Conclusions: In all age groups, baseline PSA can guide decisions on the repeat screening interval. Baseline PSA of <1.0 ng/ml for men aged 55-69 yr is a strong indicator to delay or stop further screening., Patient Summary: In prostate cancer screening, the patient's baseline PSA (prostate-specific antigen) level can be used to guide decisions on when to repeat screening. The PSA test when used according to current knowledge is valuable in helping to reduce the burden of prostate cancer., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Considering the long natural history of prostate cancer (PCa), long-term results of the European Randomised Study of Screening for PCa (ERSPC) are crucial., Objective: To provide an update on the effect of prostate-specific antigen (PSA)-based screening on PCa-specific mortality (PCSM), metastatic disease, and overdiagnosis in the Dutch arm of the ERSPC., Design, Setting, and Participants: Between 1993 and 2000, a total of 42376 men, aged 55-74 yr, were randomised to a screening or a control arm. The main analysis was performed with men aged 55-69 yr (n = 34831). Men in the screening arm were offered PSA-based screening with an interval of 4 yr., Outcome Measurements and Statistical Analysis: Intention-to-screen analyses with Poisson regression were used to calculate rate ratios (RRs) of PCSM and metastatic PCa., Results and Limitations: After a median follow-up of 21 yr, the RR of PCSM was 0.73 (95% confidence interval [CI]: 0.61-0.88) favouring screening. The numbers of men needed to invite (NNI) and needed to diagnose (NND) to prevent one PCa death were 246 and 14, respectively. For metastatic PCa, the RR was 0.67 (95% CI: 0.58-0.78) favouring screening. The NNI and NND to prevent one metastasis were 121 and 7, respectively. No statistical difference in PCSM (RR of 1.18 [95% CI: 0.87-1.62]) was observed in men aged ≥70 yr at the time of randomisation. In the screening arm, higher rates of PCSM and metastatic disease were observed in men who were screened only once and in a selected group of men above the screening age cut-off of 74 yr., Conclusions: The current analysis illustrates that with a follow-up of 21 yr, both absolute metastasis and mortality reduction continue to increase, resulting in a more favourable harm-benefit ratio than demonstrated previously. These data do not support starting screening at the age of 70-74 yr and show that repeated screening is essential., Patient Summary: Prostate-specific antigen-based prostate cancer screening reduces metastasis and mortality. Longer follow-up shows fewer invitations and diagnoses needed to prevent one death, a positive note towards the issue of overdiagnosis., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Evidence-practice gaps exist in urology. We previously surveyed European Association of Urology (EAU) guidelines for strong recommendations underpinned by high-certainty evidence that impact patient experience for which practice variations were suspected. The recommendation "Do not offer neoadjuvant androgen deprivation therapy (ADT) before surgery for patients with prostate cancer" was prioritised for further investigation. ADT before surgery is neither clinically effective nor cost effective and has serious side effects. The first step in improving implementation problems is to understand their extent. A clear picture of practice regarding ADT before surgery across Europe is not available., Objective: To assess current ADT use before prostate cancer surgery in Europe., Design, Setting, and Participants: This was an observational cross-sectional study. We retrospectively audited recent ADT practices in a multicentre international setting. We used nonprobability purposive sampling, aiming for breadth in terms of low- versus high-volume, academic, versus community and public versus private centres., Outcome Measurements and Statistical Analysis: Our primary outcome was adherence to the ADT recommendation. Descriptive statistics and a multilevel model were used to investigate differences between countries across different factors (volume, centre type, and funding type). Subgroup analyses were performed for patients with low, intermediate, and high risk, and for those with locally advanced prostate cancer. We also collected reasons for nonadherence., Results and Limitations: We included 6598 patients with prostate cancer from 187 hospitals in 31 countries from January 1, 2017 to May 1, 2020. Overall, nonadherence was 2%, (range 0-32%). Most of the variability was found in the high-risk subgroup, for which nonadherence was 4% (range 0-43%). Reasons for nonadherence included attempts to improve oncological outcomes or preoperative tumour parameters; attempts to control the cancer because of long waiting lists; and patient preference (changing one's mind from radiotherapy to surgery after neoadjuvant ADT had commenced or feeling that the side effects were intolerable). Although we purposively sampled for variety within countries (public/private, academic/community, high/low-volume), a selection bias toward centres with awareness of guidelines is possible, so adherence rates may be overestimated., Conclusions: EAU guidelines recommend against ADT use before prostate cancer surgery, yet some guideline-discordant ADT use remains at the cost of patient experience and an additional payer and provider burden. Strategies towards discontinuation of inappropriate preoperative ADT use should be pursued., Patient Summary: Androgen deprivation therapy (ADT) is sometimes used in men with prostate cancer who will not benefit from it. ADT causes side effects such as weight gain and emotional changes and increases the risk of cardiovascular disease, diabetes, and osteoporosis. Guidelines strongly recommend that men opting for surgery should not receive ADT, but it is unclear how well the guidance is followed. We asked urologists across Europe how patients in their institutions were treated over the past few years. Most do not use ADT before surgery, but this still happens in some places. More research is needed to help doctors to stop using ADT in patients who will not benefit from it., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess the predictive value of biopsy-identified cribriform carcinoma and/or intraductal carcinoma (CR/IDC) within the Briganti and MSKCC nomograms predicting lymph node metastasis (LNM) in patients with primary prostate cancer (PCa)., Methods: We retrospectively included 393 PCa patients who underwent radical prostatectomy with extended pelvic lymph node dissection at 3 tertiary referral centers. We externally validated 2 prediction tools: the Briganti 2012 nomogram and the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram. Both nomograms were augmented with CR/IDC. The original model was compared with the CR/IDC-updated model using the likelihood ratio test. The performance of the prediction tools was assessed using calibration, discrimination, and clinical utility., Results: Overall, 109 (28%) men were diagnosed with LNM. Calibration plots of the Briganti and MSKCC nomograms demonstrated an underestimation of the LNM risk across clinically relevant thresholds (≤15%). The addition of CR/IDC to the Briganti nomogram increased the fit of the data (χ 2 (1) = 4.30, P = .04), but did not improve the area under the curve (AUC) (0.69, 95% CI 0.63-0.75 vs 0.69, 95% CI 0.64-0.75). Incorporation of CR/IDC in the MSKCC nomogram resulted in an increased fit on the data (χ 2 (1) = 10.04, P <.01), but did not increase the AUC (0.66, 95% CI 0.60-0.72 vs 0.68, 95% CI 0.62-0.74). The addition of CR/IDC to the Briganti and MSKCC nomograms did not improve the clinical risk prediction., Conclusion: Incorporation of CR/IDC into the 2 clinically most used pre-radical prostatectomy nomograms does not improve LNM prediction in a multinational, contemporary PCa cohort., Competing Interests: Declarations of Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context: Harmonisation of outcome reporting and definitions for clinical trials and routine patient records can enable health care systems to provide more efficient outcome-driven and patient-centred interventions. We report on the work of the PIONEER Consortium in this context for prostate cancer (PCa)., Objective: To update and integrate existing core outcome sets (COS) for PCa for the different stages of the disease, assess their applicability, and develop standardised definitions of prioritised outcomes., Evidence Acquisition: We followed a four-stage process involving: (1) systematic reviews; (2) qualitative interviews; (3) expert group meetings to agree standardised terminologies; and (4) recommendations for the most appropriate definitions of clinician-reported outcomes., Evidence Synthesis: Following four systematic reviews, a multinational interview study, and expert group consensus meetings, we defined the most clinically suitable definitions for (1) COS for localised and locally advanced PCa and (2) COS for metastatic and nonmetastatic castration-resistant PCa. No new outcomes were identified in our COS for localised and locally advanced PCa. For our COS for metastatic and nonmetastatic castration-resistant PCa, nine new core outcomes were identified., Conclusions: These are the first COS for PCa for which the definitions of prioritised outcomes have been surveyed in a systematic, transparent, and replicable way. This is also the first time that outcome definitions across all prostate cancer COS have been agreed on by a multidisciplinary expert group and recommended for use in research and clinical practice. To limit heterogeneity across research, these COS should be recommended for future effectiveness trials, systematic reviews, guidelines and clinical practice of localised and metastatic PCa., Patient Summary: Patient outcomes after treatment for prostate cancer (PCa) are difficult to compare because of variability. To allow better use of data from patients with PCa, the PIONEER Consortium has standardised and recommended outcomes (and their definitions) that should be collected as a minimum in all future studies., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Recommendations against prostate-specific antigen (PSA) testing in 2012 have increased advanced-stage diagnosis and prostate cancer-specific mortality rates., Objective: To present the position of the European Association of Urology (EAU) in 2021 and provide recommendations for the use of PSA testing as part of a risk-adapted strategy for the early detection of prostate cancer., Evidence Acquisition: The authors combined their review of relevant literature, including the EAU prostate cancer guidelines 2021 update, with their own knowledge to provide an expert opinion, representing the EAU's position in 2021., Evidence Synthesis: The EAU has developed a risk-adapted early prostate cancer detection strategy for well-informed men based on PSA testing, risk calculators, and multiparametric magnetic resonance imaging, which can differentiate significant from insignificant prostate cancer. This approach largely avoids the overdiagnosis/overtreatment of men unlikely to experience disease-related symptoms during their lifetime and facilitates an early diagnosis of men with significant cancer to receive active treatment. It also reduces advanced-stage diagnosis, thereby potentially reducing prostate cancer-specific mortality and improving quality of life. Education is required among urologists, general practitioners, radiologists, policy makers, and healthy men, including endorsement by the European Commission to adapt the European Council's screening recommendations in its 2022 plan and requests to individual countries for its incorporation into national cancer plans., Conclusions: This risk-adapted approach for the early detection of prostate cancer will reverse current unfavourable trends and ultimately save lives., Patient Summary: The European Association of Urology has developed a patient information leaflet and algorithm for the early diagnosis of prostate cancer. It can identify men who do not need magnetic resonance imaging or a biopsy and those who would not show any symptoms versus those with more aggressive disease who require further tests/treatment. We need to raise awareness of this algorithm to ensure that all well-informed men at risk of significant prostate cancer are offered a prostate-specific antigen test., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Adherence to national and international clinical practice guidelines is suboptimal throughout Europe. The European Association of Urology Guidelines Office project "IMAGINE" (IMpact Assessment of Guidelines Implementation and Education) has been developed to measure baseline adherence to urological guideline recommendations across Europe and to identify issues that drive nonadherence., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Grade groups (GGs) are an important parameter for therapeutic decision making in prostate cancer (Pca) patients. Invasive cribriform and/or intraductal carcinoma (CR/IDC) has an independent prognostic value for disease outcome, but are not included in the GG limiting their clinical use., Objective: To perform a proof-of-principle study incorporating CR/IDC in the current GG., Design, Setting, and Participants: All prostate biopsies of 1031 men with screen-detected Pca between 1993 and 2000 were reviewed for the current GG (ranging from 1 to 5) and CR/IDC. The cribriform grade (cGrade) was equal to the GG if CR/IDC was present and GG minus 1 if not. GG1 was cGrade1 if intraductal carcinoma was absent., Intervention: Biopsy review for GG and CR/IDC. A total of 406 patients had received radical prostatectomy (RP), 508 radiotherapy (RT), 108 surveillance, and eight hormonal therapy, and the treatment was unknown for one patient. Outcome measurements and statistical analysis disease-specific survival (DSS), metastasis-free survival (MFS), and biochemical recurrence-free survival (BCRFS) after 15.1 yr (interquartile range 10.9-19.7 yr) follow-up were compared using Harrell's C-statistic., Results and Limitations: The biopsy GGs were 486 GG1, 310 GG2, 104 GG3, 64 GG4, and 67 GG5; cGrade distributions were 738 cGrade1, 102 cGrade2, 91 cGrade3, 58 cGrade4, and 42 cGrade5. The cGrade had a better discriminative value than the GG for DSS (C-index 0.79; 95% confidence interval 0.74-0.83 vs 0.76; 0.71-0.82) and MFS (0.79; 0.74-0.84 vs 0.77; 0.72-0.82). The discriminative value for BCRFS after RP and RT was similar for both models. Different diagnostic, such as use of sextant biopsies, and therapeutic strategies in the 1990s are the limitations of this study., Conclusions: The cGrade is a simple Pca grade modification with better discriminative values for DSS and MFS than the GG, particularly impacting decision making in men with current GG2 Pca., Patient Summary: Microscopic grading is an important factor for decision making in prostate cancer (Pca) patients. We show that a simple grade modification better predicts Pca outcome and might improve treatment choices., (Copyright © 2019 European Association of Urology. All rights reserved.)

Context: Magnetic resonance imaging (MRI), with or without MRI-targeted biopsy (MRI pathway), is an alternative test to systematic transrectal ultrasonography-guided biopsy in men suspected of having prostate cancer. At present, evidence on which test to use is insufficient to inform detailed evidence-based decision making., Objective: To determine the diagnostic accuracy of the index tests MRI only, MRI-targeted biopsy, MRI pathway, and systematic biopsy, as compared with template-guided biopsy (reference standard), in detecting clinically significant prostate cancer, defined as International Society of Urological Pathology grade 2 or higher, in biopsy-naive men or those with a prior-negative biopsy (or mix of both)., Evidence Acquisition: We systematically searched the literature and considered for inclusion any cross-sectional study if it investigated (1) one or more index tests verified by the reference standard, and (2) paired testing of the MRI pathway with systematic biopsy. Quality and certainty of evidence were assessed by the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) and Grading of Recommendations Assessment, Development and Evaluation, respectively., Evidence Synthesis: Accuracy analyses: Using a baseline cancer prevalence of 30%, MRI pathway (sensitivity 0.72 [95% confidence interval {CI}: 0.60-0.82]; specificity 0.96 [0.94-0.98]; eight studies) may result in 216 (180-246) true positives, 28 (14-42) false positives, 672 (658-686) true negatives, and 84 (54-120) false negatives per 1000 men. Systematic biopsy (sensitivity 0.63 [0.19-0.93]; specificity 1.00 [0.91-1.00]; four studies) may result in 189 (57-279) true positives, 0 (0-63) false positives, 700 (637-700) true negatives, and 111 (21-243) false negatives per 1000 men. Agreement analyses: With a direct comparison of the MRI pathway with systematic biopsy concerning significant disease, we found pooled detection ratios of 1.05 (95% CI: 0.95-1.16; 20 studies) in biopsy-naive men and 1.44 (1.19-1.75; 10 studies) in men with a prior-negative biopsy. Concerning insignificant disease, we found detection ratios of 0.63 (95% CI: 0.54-0.74), and 0.62 (95% CI: 0.44-0.88), respectively., Conclusions: MRI pathway had the most favourable outcome in significant and insignificant prostate cancer detection compared with systematic biopsy. The certainty in our findings was reduced by study limitations., Patient Summary: We reviewed recent advances in prostate biopsy by magnetic resonance imaging (MRI) guidance and targeting for prostate cancer detection in comparison with standard diagnosis by systematic biopsies. The findings of this Cochrane review suggest that MRI pathway is better than systematic biopsies in making a correct diagnosis of clinically important prostate cancer and reducing redundant biopsies and the detection of unimportant cancers substantially. However, MRI pathway still misses some men with important prostate cancer. Therefore, further research in this area is important., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: There is uncertainty in deferred active treatment (DAT) programmes, regarding patient selection, follow-up and monitoring, reclassification, and which outcome measures should be prioritised., Objective: To develop consensus statements for all domains of DAT., Design, Setting, and Participants: A protocol-driven, three phase study was undertaken by the European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Association of Urology Section of Urological Research (ESUR)-International Society of Geriatric Oncology (SIOG) Prostate Cancer Guideline Panel in conjunction with partner organisations, including the following: (1) a systematic review to describe heterogeneity across all domains; (2) a two-round Delphi survey involving a large, international panel of stakeholders, including healthcare practitioners (HCPs) and patients; and (3) a consensus group meeting attended by stakeholder group representatives. Robust methods regarding what constituted the consensus were strictly followed., Results and Limitations: A total of 109 HCPs and 16 patients completed both survey rounds. Of 129 statements in the survey, consensus was achieved in 66 (51%); the rest of the statements were discussed and voted on in the consensus meeting by 32 HCPs and three patients, where consensus was achieved in additional 27 statements (43%). Overall, 93 statements (72%) achieved consensus in the project. Some uncertainties remained regarding clinically important thresholds for disease extent on biopsy in low-risk disease, and the role of multiparametric magnetic resonance imaging in determining disease stage and aggressiveness as a criterion for inclusion and exclusion., Conclusions: Consensus statements and the findings are expected to guide and inform routine clinical practice and research, until higher levels of evidence emerge through prospective comparative studies and clinical trials., Patient Summary: We undertook a project aimed at standardising the elements of practice in active surveillance programmes for early localised prostate cancer because currently there is great variation and uncertainty regarding how best to conduct them. The project involved large numbers of healthcare practitioners and patients using a survey and face-to-face meeting, in order to achieve agreement (ie, consensus) regarding best practice, which will provide guidance to clinicians and researchers., (Copyright © 2019. Published by Elsevier B.V.)

Background: Men with prostate cancer (PCa) on active surveillance (AS) are followed through regular prostate biopsies, a burdensome and often unnecessary intervention, not without risks. Identifying men with at a low risk of disease reclassification may help reduce the number of biopsies., Objective: To assess the external validity of two Canary Prostate Active Surveillance Study Risk Calculators (PASS-RCs), which estimate the probability of reclassification (Gleason grade ≥7 with or without >34% of biopsy cores positive for PCa) on a surveillance biopsy, using a mix of months since last biopsy, age, body mass index, prostate-specific antigen, prostate volume, number of prior negative biopsies, and percentage (or ratio) of positive cores on last biopsy., Design, Setting, and Participants: We used data up to November 2017 from the Movember Foundation's Global Action Plan (GAP3) consortium, a global collaboration between AS studies., Outcome Measurements and Statistical Analysis: External validity of the PASS-RCs for estimating reclassification on biopsy was assessed by calibration, discrimination, and decision curve analyses., Results and Limitations: Five validation cohorts (Prostate Cancer Research International: Active Surveillance, Johns Hopkins, Toronto, Memorial Sloan Kettering Cancer Center, and University of California San Francisco), comprising 5105 men on AS, were eligible for analysis. The individual cohorts comprised 429-2416 men, with a median follow-up between 36 and 84 mo, in both community and academic practices mainly from western countries. Abilities of the PASS-RCs to discriminate between men with and without reclassification on biopsy were reasonably good (area under the receiver operating characteristic curve values 0.68 and 0.65). The PASS-RCs were moderately well calibrated, and had a greater net benefit than most default strategies between a predicted 10% and 30% risk of reclassification., Conclusions: Both PASS-RCs improved the balance between detecting reclassification and performing surveillance biopsies by reducing unnecessary biopsies. Recalibration to the local setting will increase their clinical usefulness and is therefore required before implementation., Patient Summary: Unnecessary prostate biopsies while on active surveillance (AS) should be avoided as much as possible. The ability of two calculators to selectively identify men at risk of progression was tested in a large cohort of men with low-risk prostate cancer on AS. The calculators were able to prevent unnecessary biopsies in some men. Usefulness of the calculators can be increased by adjusting them to the characteristics of the population of the clinic in which the calculators will be used., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The European Randomized study of Screening for Prostate Cancer (ERSPC) has shown a 20% relative reduction in prostate cancer mortality after 16yr [rate ratio (RR) 0.80], but centers varied by attendance, screen interval, biopsy compliance, contamination in the control arm, and treatments. We used a microsimulation model, calibrated to the ERSPC individual-level data, to predict influence of study features on the results. The relative reduction in prostate cancer mortality would have been somewhat larger with improved study features: increased attendance (90% attendance in all volunteer-based and 70% in all population-based centers, resulting in RR 0.77), a 2-yr screen interval (RR 0.75), and an 80% biopsy compliance (RR 0.79). The RR would have been substantially lower with a 30% attendance (RR 0.92), 40% biopsy compliance (RR 0.90), or 100% contamination (RR 0.85). The variations in results by trial center may reflect differences in study design and performance and results of our simulations highlight the effect of quality indicators in prostate-specific antigen screening in different settings. PATIENT SUMMARY: We evaluated the effect of various features of prostate-specific antigen (PSA) screening on its effectiveness. The compliance to PSA testing and those having a biopsy after an elevated PSA substantially influence the prostate cancer mortality., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Prostate cancer (PCa) is one of the first three causes of cancer mortality in Europe. Screening in asymptomatic men (aged 55-69yr) using prostate-specific antigen (PSA) is associated with a migration toward lower staged disease and a reduction in cancer-specific mortality. By 20yr after testing, around 100 men need to be screened to prevent one PCa death. While this ratio is smaller than for breast and colon cancer, the long natural history of PCa means many men die from other causes. As such, the nonselective use of PSA testing and radical treatments can lead to overdiagnosis and overtreatment. The European Association of Urology (EAU) supports measures to encourage appropriate PCa detection through PSA testing, while reducing overdiagnosis and overtreatment. These goals may be achieved using personalized risk-stratified approaches. For diagnosis, the greatest benefit from early detection is likely to come in men assessed using baseline PSA levels at the age of 45yr to individualize screening intervals. Multiparametric magnetic resonance imaging as well as risk calculators based on family history, ethnicity, digital rectal examination, and prostate volume should be considered to triage the need for biopsy, thus reducing the risk of overdiagnosis. For treatment, the EAU advocates balancing patient's life expectancy and cancer's mortality risk when deciding an approach. Active surveillance is encouraged in well-informed patients with low-risk and some intermediate-risk cancers, as it decreases the risks of overtreatment without compromising oncological outcomes. Conversely, the EAU advocates radical treatment in suitable men with more aggressive PCa. Multimodal treatment should be considered in locally advanced or high-grade cancers. PATIENT SUMMARY: Implementation of prostate-specific antigen (PSA)-based screening should be considered at a population level. Men at risk of prostate cancer should have a baseline PSA blood test (eg, at 45yr). The level of this test, combined with family history, ethnicity, and other factors, can be used to determine subsequent follow-up. Magnetic resonance imaging scans and novel biomarkers should be used to determine which men need biopsy and how any cancers should be treated., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

For men interested in early detection of prostate cancer, the potential impact on decisional conflict of a decision aid with or without cost compensation for the prostate-specific antigen test will be investigated., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality., Objective: To determine whether PSA screening decreases PCa mortality for up to 16yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended., Design, Setting, and Participants: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182160 men, followed up until 2014 (maximum of 16yr), with a predefined core age group of 162389 men (55-69yr), selected from population registry., Outcome Measurements and Statistical Analysis: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended., Results and Limitations: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p<0.001) at 16yr. The difference in absolute PCa mortality increased from 0.14% at 13yr to 0.18% at 16yr. The number of men needed to be invited for screening to prevent one PCa death was 570 at 16yr compared with 742 at 13yr. The number needed to diagnose was reduced to 18 from 26 at 13yr. Men with PCa detected during the first round had a higher prevalence of PSA >20ng/ml (9.9% compared with 4.1% in the second round, p<0.001) and higher PCa mortality (hazard ratio=1.86, p<0.001) than those detected subsequently., Conclusions: Findings corroborate earlier results that PSA screening significantly reduces PCa mortality, showing larger absolute benefit with longer follow-up and a reduction in excess incidence. Repeated screening may be important to reduce PCa mortality on a population level., Patient Summary: In this report, we looked at the outcomes from prostate cancer in a large European population. We found that repeated screening reduces the risk of dying from prostate cancer., (Copyright © 2019. Published by Elsevier B.V.)

Background: Differential treatment between trial arms has been suggested to bias prostate cancer (PC) mortality in the European Randomized Study of Screening for Prostate Cancer (ERSPC)., Objective: To quantify the contribution of treatment differences to the observed PC mortality reduction between the screening arm (SA) and the control arm (CA)., Design, Setting, and Participants: A total of 14 136 men with PC (SA: 7310; CA: 6826) in the core age group (55-69yr) at 16yr of follow-up., Outcome Measurements and Statistical Analysis: The outcomes measurements were observed and estimated numbers of PC deaths by treatment allocation in the SA and CA, respectively. Primary treatment allocation was modeled using multinomial logistic regression adjusting for center, age, year, prostate-specific antigen, grade group, and tumor-node-metastasis stage. For each treatment, logistic regression models were fitted for risk of PC death, separately for the SA and CA, and using the same covariates as for the treatment allocation model. Treatment probabilities were multiplied by estimated PC death risks for each treatment based on one arm, and then summed and compared with the observed number of deaths., Results and Limitations: The difference between the observed and estimated treatment distributions (hormonal therapy, radical prostatectomy, radiotherapy, and active surveillance/watchful waiting) in the two arms ranged from -3.3% to 3.3%. These figures, which represent the part of the treatment differences between arms that cannot be explained by clinicopathological differences, are small compared with the observed differences between arms that ranged between 7.2% and 10.1%. The difference between the observed and estimated numbers of PC deaths among men with PC was 0.05% (95% confidence interval [CI] -0.1%, 0.2%) when applying the CA model to the SA, had the two groups received identical primary treatment, given their clinical characteristics. When instead applying the SA model to the CA, the difference was, as expected, very similar-0.01% (95% CI -0.3%, 0.2%). Consistency of the results of the models demonstrates the robustness of the modeling approach. As the observed difference between trial arms was 4.2%, our findings suggest that differential treatment explains only a trivial proportion of the main findings of ERSPC. A limitation of the study is that only data on primary treatment were available., Conclusions: Use of prostate-specific antigen remains the predominant explanation for the reduction in PC mortality seen in the ERSPC trial and is not attributable to differential treatment between trial arms., Patient Summary: This study shows that prostate cancer deaths in the European screening trial (European Randomized Study of Screening for Prostate Cancer) were prevented because men were diagnosed and treated earlier through prostate-specific antigen screening, and not because of different, or better, treatment in the screening arm compared with the control arm., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Asians have a lower incidence of prostate cancer (PC). We compared the performance of the Prostate Health Index (PHI) for 2488 men in different ethnic groups (1688 Asian and 800 European men from 9 sites) with PSA 2-20ng/ml and PHI test and transrectal ultrasound-guided biopsy results available. Of these, 1652 men had PSA 2-10ng/ml and a normal digital rectal examination and underwent initial biopsy. The proportions of PC (Gleason ≥6) and higher-grade PC (HGPC, Gleason ≥7) across different PHI ranges were compared. The performance of PSA and PHI was compared using the area under the receiver operating characteristic curve (AUC) and decision curve analyses (DCA). Among Asian men, HGPC would be diagnosed in 1.0%, 1.9%, 13%, and 30% of men using PHI thresholds of <25, 25-35, 35-55, and >55, respectively. At 90% sensitivity for HGPC (PHI >30), 56% of biopsies and 33% of Gleason 6 PC diagnoses could have been avoided. Among European men, HGPC would be diagnosed in 4.1%, 4.3%, 30%, and 34% of men using PHI thresholds of <25, 25-35, 35-55, and >55, respectively. At 90% sensitivity for HGPC (PHI >40), 40% of biopsies and 31% of Gleason 6 PC diagnoses could have been avoided. AUC and DCA confirmed the benefit of PHI over PSA. The benefit of PHI was also seen at repeat biopsy (n=397) and for PSA 10-20ng/ml (n=439). PHI is effective in cancer risk stratification for both European and Asian men. However, population-specific PHI reference ranges should be used. PATIENT SUMMARY: The Prostate Health Index (PHI) blood test helps to identify individuals at higher risk of prostate cancer among Asian and European men, and could significantly reduce unnecessary biopsies and overdiagnosis of prostate cancer. Different PHI reference ranges should be used for different ethnic groups., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Careful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa)., Objective: Using Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation., Design, Setting, and Participants: We compared data from 10296 men on AS from 21 centres across 12 countries., Outcome Measurements and Statistical Analysis: Cumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation., Results and Limitations: During 5-yr follow-up, 27.5% (95% confidence interval [CI]: 26.4-28.6%) men showed signs of disease progression, 12.8% (95% CI: 12.0-13.6%) converted to active treatment without evidence of progression, 1.7% (95% CI: 1.5-2.0%) continued to watchful waiting, and 1.7% (95% CI: 1.4-2.1%) died from other causes. Of the 7049 men who remained on AS, 2339 had follow-up for >5yr, 4561 had follow-up for <5yr, and 149 were lost to follow-up. Cumulative incidence of progression was 27.5% (95% CI: 26.4-28.6%) at 5yr and 38.2% (95% CI: 36.7-39.9%) at 10yr. A limitation is that not all centres were included due to limited information on the reason for discontinuation and limited follow-up., Conclusions: Our descriptive analyses of current AS practices worldwide showed that 43.6% of men drop out of AS during 5-yr follow-up, mainly due to signs of disease progression. Improvements in selection tools for AS are thus needed to correctly allocate men with PCa to AS, which will also reduce discontinuation due to conversion to active treatment without evidence of disease progression., Patient Summary: Our assessment of a worldwide database of men with prostate cancer (PCa) on active surveillance (AS) shows that 43.6% drop out of AS within 5yr, mainly due to signs of disease progression. Better tools are needed to select and monitor men with PCa as part of AS., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The Rotterdam European Randomized Study of Screening for Prostate Cancer risk calculators (ERSPC-RCs) help to avoid unnecessary transrectal ultrasound-guided systematic biopsies (TRUS-Bx). Multivariable risk stratification could also avoid unnecessary biopsies following multiparametric magnetic resonance imaging (mpMRI)., Objective: To construct MRI-ERSPC-RCs for the prediction of any- and high-grade (Gleason score ≥3 + 4) prostate cancer (PCa) in 12-core TRUS-Bx±MRI-targeted biopsy (MRI-TBx) by adding Prostate Imaging Reporting and Data System (PI-RADS) and age as parameters to the ERSPC-RC3 (biopsy-naïve men) and ERSPC-RC4 (previously biopsied men)., Design, Setting, and Participants: A total of 961 men received mpMRI and 12-core TRUS-Bx±MRI-TBx (in case of PI-RADS ≥3) in five institutions. Data of 504 biopsy-naïve and 457 previously biopsied men were used to adjust the ERSPC-RC3 and ERSPC-RC4., Outcome Measurements and Statistical Analysis: Logistic regression models were constructed. The areas under the curve (AUCs) of the original ERSPC-RCs and MRI-ERSPC-RCs (including PI-RADS and age) for any- and high-grade PCa were compared. Decision curve analysis was performed to assess the clinical utility of the MRI-ERSPC-RCs., Results and Limitations: MRI-ERSPC-RC3 had a significantly higher AUC for high-grade PCa compared with the ERSPC-RC3: 0.84 (95% confidence interval [CI] 0.81-0.88) versus 0.76 (95% CI 0.71-0.80, p<0.01). Similarly, MRI-ERSPC-RC4 had a higher AUC for high-grade PCa compared with the ERSPC-RC4: 0.85 (95% CI 0.81-0.89) versus 0.74 (95% CI 0.69-0.79, p<0.01). Unlike for the MRI-ERSPC-RC3, decision curve analysis showed clear net benefit of the MRI-ERSPC-RC4 at a high-grade PCa risk threshold of ≥5%. Using a ≥10% high-grade PCa risk threshold to biopsy for the MRI-ERSPC-RC4, 36% biopsies are saved, missing low- and high-grade PCa, respectively, in 15% and 4% of men who are not biopsied., Conclusions: We adjusted the ERSPC-RCs for the prediction of any- and high-grade PCa in 12-core TRUS-Bx±MRI-TBx. Although the ability of the MRI-ERSPC-RC3 for biopsy-naïve men to avoid biopsies remains questionable, application of the MRI-ERSPC-RC4 in previously biopsied men in our cohort would have avoided 36% of biopsies, missing high-grade PCa in 4% of men who would not have received a biopsy., Patient Summary: We have constructed magnetic resonance imaging-based Rotterdam European Randomized study of Screening for Prostate Cancer (MRI-ERSPC) risk calculators for prostate cancer prediction in transrectal ultrasound-guided biopsy and MRI-targeted biopsy by incorporating age and Prostate Imaging Reporting and Data System score into the original ERSPC risk calculators. The MRI-ERSPC risk calculator for previously biopsied men could be used to avoid one-third of biopsies following MRI., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Urologists regularly develop clinical risk prediction models to support clinical decisions. In contrast to traditional performance measures, decision curve analysis (DCA) can assess the utility of models for decision making. DCA plots net benefit (NB) at a range of clinically reasonable risk thresholds., Objective: To provide recommendations on interpreting and reporting DCA when evaluating prediction models., Evidence Acquisition: We informally reviewed the urological literature to determine investigators' understanding of DCA. To illustrate, we use data from 3616 patients to develop risk models for high-grade prostate cancer (n=313, 9%) to decide who should undergo a biopsy. The baseline model includes prostate-specific antigen and digital rectal examination; the extended model adds two predictors based on transrectal ultrasound (TRUS)., Evidence Synthesis: We explain risk thresholds, NB, default strategies (treat all, treat no one), and test tradeoff. To use DCA, first determine whether a model is superior to all other strategies across the range of reasonable risk thresholds. If so, that model appears to improve decisions irrespective of threshold. Second, consider if there are important extra costs to using the model. If so, obtain the test tradeoff to check whether the increase in NB versus the best other strategy is worth the additional cost. In our case study, addition of TRUS improved NB by 0.0114, equivalent to 1.1 more detected high-grade prostate cancers per 100 patients. Hence, adding TRUS would be worthwhile if we accept subjecting 88 patients to TRUS to find one additional high-grade prostate cancer or, alternatively, subjecting 10 patients to TRUS to avoid one unnecessary biopsy., Conclusions: The proposed guidelines can help researchers understand DCA and improve application and reporting., Patient Summary: Decision curve analysis can identify risk models that can help us make better clinical decisions. We illustrate appropriate reporting and interpretation of decision curve analysis., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The harm of screening (unnecessary biopsies and overdiagnosis) generally outweighs the benefit of reducing prostate cancer (PCa) mortality in men aged ≥70 yr. Patient selection for biopsy using risk stratification and magnetic resonance imaging (MRI) may improve this benefit-to-harm ratio., Objective: To assess the potential of a risk-based strategy including MRI to selectively identify men aged ≥70 yr with high-grade PCa., Design, Setting, and Participants: Three hundred and thirty-seven men with prostate-specific antigen ≥3.0 ng/ml at a fifth screening (71-75 yr) in the European Randomized study of Screening for Prostate Cancer Rotterdam were biopsied. One hundred and seventy-nine men received six-core transrectal ultrasound biopsy (TRUS-Bx), while 158 men received MRI, 12-core TRUS-Bx, and fusion TBx in case of Prostate Imaging Reporting and Data System ≥3 lesions., Outcome Measurements and Statistical Analysis: The primary outcome was the overall, low-grade (Gleason Score 3+3) and high-grade (Gleason Score ≥ 3+4) PCa rate. Secondary outcome was the low- and high-grade PCa rate detected by six-core TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx. Tertiary outcome was the reduction of biopsies and low-grade PCa detection by upfront risk stratification with the Rotterdam Prostate Cancer Risk Calculator 4., Results and Limitations: Fifty-five percent of men were previously biopsied. The overall, low-grade, and high-grade PCa rates in biopsy naïve men were 48%, 27%, and 22%, respectively. In previously biopsied men these PCa rates were 25%, 20%, and 5%. Sextant TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx had a similar high-grade PCa rate (11%, 12%, and 11%) but a significantly different low-grade PCa rate (17%, 28%, and 7%). Rotterdam Prostate Cancer Risk Calculator 4-based stratification combined with 12-core TRUS-Bx ± MRI-TBx would have avoided 65% of biopsies and 68% of low-grade PCa while detecting an equal percentage of high-grade PCa (83%) compared with a TRUS-Bx all men approach (79%)., Conclusions: After four repeated screens and ≥1 previous biopsies in half of men, a significant proportion of men aged ≥70 yr still harbor high-grade PCa. Upfront risk stratification and the combination of MRI and TRUS-Bx would have avoided two-thirds of biopsies and low-grade PCa diagnoses in our cohort, while maintaining the high-grade PCa detection of a TRUS-Bx all men approach. Further studies are needed to verify these results., Patient Summary: Prostate cancer screening reduces mortality but is accompanied by unnecessary biopsies and overdiagnosis of nonaggressive tumors, especially in repeatedly screened elderly men. To tackle these drawbacks screening should consist of an upfront risk-assessment followed by magnetic resonance imaging and transrectal ultrasound-guided biopsy., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The survival rate for men with International Society of Urological Pathology (ISUP) grade 2 prostate cancer (PCa) without invasive cribriform (CR) and intraductal carcinoma (IDC) is similar to that for ISUP grade 1. If updated into the European Randomized Study of Screening for Prostate Cancer (ERSPC Rotterdam) risk calculator number 3 (RC3), this may further improve upfront selection of men who need a biopsy., Objective: To improve the number of possible biopsies avoided, while limiting undiagnosed clinically important PCa by applying the updated RC3 for risk-based patient selection., Design, Setting, and Participants: The RC3 is based on the first screening round of the ERSPC Rotterdam, which involved 3616 men. In 2015, histopathologic slides for PCa cases (n=885) were re-evaluated. Low-risk (LR) PCa was defined as ISUP grade 1 or 2 without CR/IDC. High-risk (HR) PCa was defined as ISUP grade 2 with CR/IDC and PCa with ISUP grade≥3., Outcome Measurements and Statistical Analysis: We updated the RC3 using multinomial logistic regression analysis, including data on age, PSA, digital rectal examination, and prostate volume, for predicting LR and HR PCa. Predictive accuracy was quantified using receiver operating characteristic analysis and decision curve analysis., Results and Limitations: Men without PCa could effectively be distinguished from men with LR PCa and HR PCa (area under the curve 0.70, 95% confidence interval [CI] 0.68-0.72 and 0.92, 95% CI 0.90-0.94). At a 1% risk threshold, the updated calculator would lead to a 34% reduction in unnecessary biopsies, while only 2% of HR PCa cases would be undiagnosed., Conclusions: A relatively simple risk stratification tool augmented with a highly sensitive contemporary pathologic biopsy classification would result in a considerable decrease in unnecessary prostate biopsies and overdiagnosis of potentially indolent disease., Patient Summary: We improved a well-known prostate risk calculator with a new pathology classification system that better reflects disease burden. This new risk calculator allows individualized prediction of the chance of having (potentially aggressive) biopsy-detectable prostate cancer and can guide shared decision-making when considering prostate biopsy., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The Prostate Cancer Research International Active Surveillance (PRIAS) study was initiated a decade ago to study the most optimal selection and follow-up of men on active surveillance (AS)., Objective: We report on 10 yr of follow-up of men on AS in the PRIAS study and evaluate if criteria used to recommend a switch to active treatment truly predict unfavorable outcome on subsequent radical prostatectomy (RP)., Design, Setting, and Participants: Men with low-risk prostate cancer were included and followed prospectively on AS. Follow-up consisted of regular prostate-specific antigen (PSA) tests, digital rectal examinations, and biopsies. Men with Gleason >3+3, more than two positive biopsy cores, or stage higher than cT2 were advised to switch to active treatment (until 2014, a PSA doubling time [PSA DT] of 0-3 yr was also used)., Outcome Measurements and Statistical Analysis: Reclassification rates, treatment after discontinuation, and outcome on RP after discontinuing AS were reported. Regression analysis on the outcome of RP was used to evaluate the predictive value of criteria currently used to recommend a switch to active treatment. Kaplan-Meier and competing risk analysis were used to report discontinuation rates over time and long-term oncologic end points., Results and Limitations: A total of 5302 men were included in PRIAS across 18 countries. Reclassification rates remained stable on all subsequent biopsies, with 22-33% of men having either Gleason >3+3 or more than two positive cores on any repeat biopsy. At 5 and 10 yr of follow-up, 52% and 73% of men, respectively, had discontinued AS, most of them because of protocol-based reclassification. A third of men undergoing subsequent RP had favorable pathologic tumor features (Gleason 3+3 and pT2). Of the criteria used to recommend a switch to active treatment, more than two positive cores and a PSA DT of 0-3 yr were not predictive of unfavorable pathologic outcome on RP., Conclusions: A substantial group of men discontinued AS without subsequent unfavorable tumor features on RP; therefore, we propose Gleason upgrading and cT3 as the only indicators for an immediate switch to active treatment. Surrogate indicators (eg, more than two positive cores and a fast-rising PSA) should not trigger immediate active treatment but rather further investigation to confirm the suspicion of higher risk disease., Patient Summary: We confirmed the safety of active surveillance as a treatment option for men with low-risk prostate cancer; however, some changes could be made to the follow-up protocol to safely increase the number of men who remain on active surveillance., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Multiparametric magnetic resonance imaging (mpMRI) is increasingly used in men with suspicion of prostate cancer (PCa) after negative transrectal ultrasound (TRUS)-guided random biopsy. Risk-based patient selection for mpMRI could help to avoid unnecessary mpMRIs., Objective: To study the rate of potentially avoided mpMRIs after negative TRUS-guided random biopsy by risk-based patient selection using the Rotterdam Prostate Cancer Risk Calculator (RPCRC)., Design, Setting, and Participants: One hundred and twenty two consecutive men received a mpMRI scan and subsequent MRI-TRUS fusion targeted biopsy in case of suspicious lesion(s) (Prostate Imaging Reporting and Data System ≥ 3) after negative TRUS-guided random biopsy. Men were retrospectively stratified according to the RPCRC biopsy advice to compare targeted biopsy outcomes after risk-based patient selection with standard (prostate specific antigen and/or digital rectal examination-driven) patient selection., Outcome Measurements and Statistical Analysis: The rate of potentially avoided mpMRIs by RPCRC-based patient selection in relation to the rate of missed high-grade (Gleason ≥ 3+4) PCa. Receiver operating characteristic curve analysis was performed to determine the area under the curve of the RPCRC for (high-grade) PCa., Results and Limitations: Of the 60 men with a positive biopsy advice, six (10%) had low-grade PCa and 28 (47%) had high-grade PCa in targeted biopsy. Of the 62 men with a negative advice, two (3%) had low-grade PCa and three (5%) had high-grade PCa. Upfront RPCRC-based patient selection would have avoided 62 (51%) of 122 mpMRIs and two (25%) of eight low-grade PCa diagnoses, missing three (10%) of 31 high-grade PCa. The area under the curve of the RPCRC for PCa and high-grade PCa was respectively 0.76 (95% confidence interval 0.67-0.85) and 0.84 (95% confidence interval 0.76-0.93)., Conclusions: Risk-based patient selection with the RPCRC can avoid half of mpMRIs after a negative prostate specific antigen and/or digital rectal examination-driven TRUS-guided random biopsy. Further improvement in risk-based patient selection for mpMRI could be made by adjusting the RPCRC for MRI-targeted biopsy outcome prediction., Patient Summary: The suspicion of prostate cancer remains in many men after a negative ultrasound-guided prostate biopsy. These men increasingly receive an often unnecessary magnetic resonance imaging (MRI) scan. We found that patient selection for MRI based on the Rotterdam Prostate Cancer Risk Calculator biopsy advice could avoid half of the MRIs., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Men with prostate cancer on active surveillance (AS) are advised to follow strict follow-up schedules and switch to definitive treatment on risk reclassification. However, some men might not adhere to these strict protocols., Objective: To determine the number of noncompliers and disease reclassification rates in men not complying with the follow-up protocol of the Prostate Cancer Research International Active Surveillance (PRIAS) study., Design, Setting, and Participants: A total of 4547 men with low-risk prostate cancer were included and prospectively followed on AS. Men were regularly examined using prostate-specific antigen (PSA), digital rectal examination, and repeat biopsies, and were advised to switch to definitive treatment on disease reclassification (>cT2c, Gleason score > 3+3, >2 cores positive, or PSA doubling time [PSA-DT] 0-3 yr)., Outcome Measurements and Statistical Analysis: Rates of men not complying with follow-up visits or a recommendation to discontinue AS are reported. Biopsy outcome (Gleason ≥7 or >2 cores positive) was compared between compliers and noncompliers using Cox proportional hazards analysis., Results and Limitations: The compliance rate for PSA visits was 91%. By contrast, the compliance rate for standard repeat biopsies decreased over time (81%, 60%, 53%, and 33% at 1, 4, 7, and 10 yr after diagnosis, respectively). Yearly repeat biopsies in men with faster rising PSA (PSA-DT 3-10 yr) was low at <30%, although these men had higher upgrading rates at repeat biopsy (25-30% vs 16%). PSA-DT of 0-3 yr was the most common recommendation for discontinuation, but 71% continued on AS. Men with PSA-DT of 0-3 yr were at higher risk of upgrading on repeat biopsy (hazard ratio 2.02, 95% confidence interval 1.36-3.00) compared to men without fast rising PSA., Conclusion: Some men and their physicians do not comply with AS follow-up protocols. In particular, yearly repeat biopsies in men with fast rising PSA are often ignored, as is the recommendation to discontinue AS because of very fast rising PSA. Although these men are at greater risk of higher Gleason scores on repeat biopsy, the majority still exhibit favorable tumor characteristics. Fast rising PSA should therefore not trigger a recommendation to receive active treatment, but should rather serve as a criterion for stricter follow-up. In addition, we should aim to find ways of safely reducing the number of biopsies to increase adherence to AS protocols., Patient Summary: We looked at compliance with an active surveillance protocol for low-risk prostate cancer in a large active surveillance study. We observed reluctance to undergo yearly biopsies because of fast rising prostate-specific antigen, despite a higher risk of disease progression. Further research should aim to safely reduce the number of repeat biopsies in men on active surveillance to increase protocol adherence., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer (PCa) mortality and a 1.6-fold increase in PCa incidence with prostate-specific antigen (PSA)-based screening (at 13 yr of follow-up). We evaluated PCa incidence by risk category at diagnosis across the study arms to assess the potential impact on PCa mortality., Design, Setting, and Participants: Information on arm, centre, T and M stage, Gleason score, serum PSA at diagnosis, age at randomisation, follow-up time, and vital status were extracted from the ERSPC database. Four risk categories at diagnosis were defined: 1, low; 2, intermediate; 3, high; 4, metastatic disease. PSA (≤100 or >100 ng/ml) was used as the indicator of metastasis., Outcome Measurements and Statistical Analysis: Incidence rate ratios (IRRs) for screening versus control arm by risk category at diagnosis and follow-up time were calculated using Poisson regression analysis for seven centres. Follow-up was truncated at 13 yr. Missing data were imputed using chained equations. The analyses were carried out on an intention-to-treat basis., Results and Limitations: In the screening arm, 7408 PCa cases were diagnosed and 6107 in the control arm. The proportion of missing stage, Gleason score, or PSA value was comparable in the two arms (8% vs 10%), but differed among centres. The IRRs were elevated in the screening arm for the low-risk (IRR: 2.14; 95% CI, 2.03-2.25) and intermediate-risk (IRR: 1.24; 95% CI, 1.16-1.34) categories at diagnosis, equal to unity for the high-risk category at diagnosis (IRR: 1.00; 95% CI, 0.89-1.13), and reduced for metastatic disease at diagnosis (IRR: 0.60; 95% CI, 0.52-0.70). The IRR of metastatic disease had temporal pattern similar to mortality, shifted forwards an average of almost 3 yr, although the mortality reduction was smaller., Conclusions: The results confirm a reduction in metastatic disease at diagnosis in the screening arm, preceding mortality reduction by almost 3 yr., Patient Summary: The findings of this study indicate that the decrease in metastatic disease at diagnosis is the major determinant of the prostate cancer mortality reduction in the European Randomized study of Screening for Prostate Cancer., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Multiparametric magnetic resonance imaging (MRI) of the prostate may improve the diagnostic accuracy of prostate cancer detection in MRI-targeted biopsy (MRI-TBx) in comparison to transrectal ultrasound-guided biopsy (TRUS-Bx)., Objective: Systematic review and meta-analysis of evidence regarding the diagnostic benefits of MRI-TBx versus TRUS-Bx in detection of overall prostate cancer (primary objective) and significant/insignificant prostate cancer (secondary objective)., Evidence Acquisition: A systematic review of Embase, Medline, Web of Science, Scopus, PubMed, Cinahl, and the Cochrane library was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Identified reports were critically appraised according to the Quality Assessment of Diagnostic Accuracy Studies criteria. Only men with a positive MRI were included., Evidence Synthesis: The reports we included (16 studies) used both MRI-TBx and TRUS-Bx for prostate cancer detection. A cumulative total of 1926 men with positive MRI were included, with prostate cancer prevalence of 59%. MRI-TBx and TRUS-Bx did not significantly differ in overall prostate cancer detection (sensitivity 0.85, 95% confidence interval [CI] 0.80-0.89, and 0.81, 95% CI 0.70-0.88, respectively). MRI-TBx had a higher rate of detection of significant prostate cancer compared to TRUS-Bx (sensitivity 0.91, 95% CI 0.87-0.94 vs 0.76, 95% CI 0.64-0.84) and a lower rate of detection of insignificant prostate cancer (sensitivity 0.44, 95% CI 0.26-0.64 vs 0.83, 95% confidence interval 0.77-0.87). Subgroup analysis revealed an improvement in significant prostate cancer detection by MRI-TBx in men with previous negative biopsy, rather than in men with initial biopsy (relative sensitivity 1.54, 95% CI 1.05-2.57 vs 1.10, 95% CI 1.00-1.22). Because of underlying methodological flaws of MRI-TBx, the comparison of MRI-TBx and TRUS-Bx needs to be regarded with caution., Conclusions: In men with clinical suspicion of prostate cancer and a subsequent positive MRI, MRI-TBx and TRUS-Bx did not differ in overall prostate cancer detection. However, MRI-TBx had a higher rate of detection of significant prostate cancer and a lower rate of detection of insignificant prostate cancer compared with TRUS-Bx., Patient Summary: We reviewed recent advances in magnetic resonance imaging (MRI) for guidance and targeting of prostate biopsy for prostate cancer detection. We found evidence to suggest that MRI-guided targeted biopsy benefits the diagnosis of prostate cancer., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Unlabelled: Screening for prostate cancer (PCa) results in a favorable stage shift. However, even if screening did not result in a clinically apparent lower stage or grade, it might still lead to less disease recurrence after treatment with curative intent (radical prostatectomy [RP] and radiation therapy [RT]) because the tumor had less time to develop outside the prostate. The outcome after treatment could also differ because of variations in treatment quality (eg, radiation dosage/adjuvant hormonal therapy). To test these hypotheses, we compared differences in the treatment quality of the screening and control arms of the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam and disease-free survival (DFS) after curative treatment in PCa patients with similar stage and grade. A total of 2595 men were initially treated with RP or RT. In the control arm, RT was more often combined with hormonal therapy; treatment dosage was often ≥69Gy. This most likely resulted from changes over time in treatment that coincided with the later detection in the control arm. DFS was higher in the screening arm in all risk groups. After correction for lead time, these differences were minimal, however. We concluded that treatment quality differed between the screening and control arms of the ERSPC Rotterdam. RT quality was especially superior in the control arm with higher dosages and more often RT in combination with hormonal therapy. Despite these differences favoring the control arm, DFS differences were minimal., Patient Summary: We looked at differences in prostate cancer (PCa) treatment and outcome after PCa treatment in men diagnosed after screening and men diagnosed after normal clinical practice. Treatment differed with superior treatment given to men diagnosed in normal clinical practice. We propose a likely explanation for this apparently counterintuitive finding (progressive insight combined with, on average, a later detection of tumors in unscreened men). Although unscreened men received better treatment, this advantage seemed to be outweighed by the advantage associated with the earlier detection, on average, of the tumor in screened men., Trial Registration: ISRCTN49127736., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Context: Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of progression while on AS are debated., Objective: To review primary data on markers, genetic factors, and risk stratification for patient selection and predictors of progression during AS., Evidence Acquisition: Electronic searches were conducted in PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 2014 for original articles on biomarkers and risk stratification for AS., Evidence Synthesis: Patient factors associated with AS outcomes in some studies include age, race, and family history. Multiple studies provide consistent evidence that a lower percentage of free prostate-specific antigen (PSA), a higher Prostate Health Index (PHI), a higher PSA density (PSAD), and greater biopsy core involvement at baseline predict a greater risk of progression. During follow-up, serial measurements of PHI and PSAD, as well as repeat biopsy results, predict later biopsy progression. While some studies have suggested a univariate relationship between urinary prostate cancer antigen 3 (PCA3) and transmembrane protease, serine 2-v-ets avian erythroblastosis virus E26 oncogene homolog gene fusion (TMPRSS2:ERG) with adverse biopsy features, these markers have not been consistently shown to independently predict AS outcomes. No conclusive data support the use of genetic tests in AS. Limitations of these studies include heterogeneous definitions of progression and limited follow-up., Conclusions: There is a growing body of literature on patient characteristics, biopsy features, and biomarkers with potential utility in AS. More data are needed on practical applications such as combining these tests into multivariable clinical algorithms and long-term outcomes to further improve AS in the future., Patient Summary: Several PSA-based tests (free PSA, PHI, PSAD) and the extent of cancer on biopsy can help to stratify the risk of progression during active surveillance. Investigation of several other markers is under way., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Prostate-specific antigen (PSA) testing has limited accuracy for the early detection of prostate cancer (PCa)., Objective: To assess the value added by percentage of free to total PSA (%fPSA), prostate cancer antigen 3 (PCA3), and a kallikrein panel (4k-panel) to the European Randomised Study of Screening for Prostate Cancer (ERSPC) multivariable prediction models: risk calculator (RC) 4, including transrectal ultrasound, and RC 4 plus digital rectal examination (4+DRE) for prescreened men., Design, Setting, and Participants: Participants were invited for rescreening between October 2007 and February 2009 within the Dutch part of the ERSPC study. Biopsies were taken in men with a PSA level ≥3.0 ng/ml or a PCA3 score ≥10. Additional analyses of the 4k-panel were done on serum samples., Outcome Measurements and Statistical Analysis: Outcome was defined as PCa detectable by sextant biopsy. Receiver operating characteristic curve and decision curve analyses were performed to compare the predictive capabilities of %fPSA, PCA3, 4k-panel, the ERSPC RCs, and their combinations in logistic regression models., Results and Limitations: PCa was detected in 119 of 708 men. The %fPSA did not perform better univariately or added to the RCs compared with the RCs alone. In 202 men with an elevated PSA, the 4k-panel discriminated better than PCA3 when modelled univariately (area under the curve [AUC]: 0.78 vs. 0.62; p=0.01). The multivariable models with PCA3 or the 4k-panel were equivalent (AUC: 0.80 for RC 4+DRE). In the total population, PCA3 discriminated better than the 4k-panel (univariate AUC: 0.63 vs. 0.56; p=0.05). There was no statistically significant difference between the multivariable model with PCA3 (AUC: 0.73) versus the model with the 4k-panel (AUC: 0.71; p=0.18). The multivariable model with PCA3 performed better than the reference model (0.73 vs. 0.70; p=0.02). Decision curves confirmed these patterns, although numbers were small., Conclusions: Both PCA3 and, to a lesser extent, a 4k-panel have added value to the DRE-based ERSPC RC in detecting PCa in prescreened men., Patient Summary: We studied the added value of novel biomarkers to previously developed risk prediction models for prostate cancer. We found that inclusion of these biomarkers resulted in an increase in predictive ability., (Copyright © 2014. Published by Elsevier B.V.)

Background: Positive surgical margins (PSMs) are a known risk factor for biochemical recurrence in patients with prostate cancer (PCa) and are potentially affected by surgical technique and volume., Objective: To investigate whether radical prostatectomy (RP) modality and volume affect PSM rates., Design, Setting, and Participants: Fourteen institutions in Europe, the United States, and Australia were invited to participate in this study, all of which retrospectively provided margins data on 9778 open RP, 4918 laparoscopic RP, and 7697 robotic RP patients operated on between January 2000 and October 2011., Outcome Measurements and Statistical Analyses: The outcome measure was PSM rate. Multivariable logistic regression analyses and propensity score methods identified odds ratios for risk of a PSM for one modality compared with another, after adjustment for age, preoperative prostate-specific antigen, postoperative Gleason score, pathologic stage, and year of surgery. Classic adjustment using standard covariates was also implemented to compare PSM rates based on center volume for each minimally invasive surgical cohort., Results and Limitations: Open RP patients had higher-risk PCa at time of surgery on average and were operated on earlier in the study time period on average, compared with minimally invasive cohorts. Crude margin rates were lowest for robotic RP (13.8%), intermediate for laparoscopic RP (16.3%), and highest for open RP (22.8%); significant differences persisted, although were ameliorated, after statistical adjustments. Lower-volume centers had increased risks of PSM compared with the highest-volume center for both laparoscopic RP and robotic RP. The study is limited by its nonrandomized nature; missing data across covariates, especially year of surgery in many of the open cohort cases; lack of standardized histologic processing and central pathology review; and lack of information regarding potential confounders such as patient comorbidity, nerve-sparing status, lymph node status, tumor volume, and individual surgeon caseload., Conclusions: This multinational, multi-institutional study of 22 393 patients after RP suggests that PSM rates might be lower after minimally invasive techniques than after open RP and that PSM rates are affected by center volume in laparoscopic and robotic cases., Patient Summary: In this study, we compared the effectiveness of different types of surgery for prostate cancer by looking at the rates of cancer cells left at the margins of what was removed in the operations. We compared open, keyhole, and robotic surgery from many centers across the globe and found that robotic and keyhole operations appeared to have lower margin rates than open surgeries. How many cases a center and surgeon do seems to affect this rate for both robotic and keyhole procedures., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To describe the results of 3 rounds of diagnostic testing and linkage to the Dutch Cancer Registry for men with an initial prostate cancer antigen 3 (PCA3) score ≥100., Methods: Within an earlier reported comparative study of PCA3 vs prostate-specific antigen in a prescreened population, 90 men with a PCA3 score ≥100 were identified and underwent biopsy, 28 prostate cancers (PCs) were found, 62 men remained at risk of a diagnosis of PC. All men were offered repeat testing; 6 PCs were found in 20 men at rebiopsy. Men with at least 1 negative biopsy (n = 56) were invited to undergo magnetic resonance imaging (MRI) studies and MRI-guided biopsies if indicated. Linkage to the Dutch Cancer Registry after 2.8 years of follow-up was performed for men with negative biopsies., Results: Of the 56 men at risk, 28 agreed to participate in further testing. They were offered MRI studies; only 7 men agreed, and in 2, suspicious lesions were found and biopsies carried out. Only 1 PC was diagnosed and classified as T1c, Gleason 3 + 3 = 6. The overall findings of 3 rounds of testing and of linkage to the cancer registry show that eventually 35 PCs were detected in 90 men with PCA3 scores ≥100 (positive predictive value 38.9%)., Conclusion: Finding no PC despite extended diagnostic efforts in many men with initial PCA3 scores ≥100 is unexpected and might be clinically relevant., (Copyright © 2014 Elsevier Inc. All rights reserved.)