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Objective: To develop a model and methodology for predicting the risk of Gleason upgrading in patients with prostate cancer on active surveillance (AS) and using the predicted risks to create risk-based personalised biopsy schedules as an alternative to one-size-fits-all schedules (e.g. annually). Furthermore, to assist patients and doctors in making shared decisions on biopsy schedules, by providing them quantitative estimates of the burden and benefit of opting for personalised vs any other schedule in AS. Lastly, to externally validate our model and implement it along with personalised schedules in a ready to use web-application., Patients and Methods: Repeat prostate-specific antigen (PSA) measurements, timing and results of previous biopsies, and age at baseline from the world's largest AS study, Prostate Cancer Research International Active Surveillance (PRIAS; 7813 patients, 1134 experienced upgrading). We fitted a Bayesian joint model for time-to-event and longitudinal data to this dataset. We then validated our model externally in the largest six AS cohorts of the Movember Foundation's third Global Action Plan (GAP3) database (>20 000 patients, 27 centres worldwide). Using the model predicted upgrading risks; we scheduled biopsies whenever a patient's upgrading risk was above a certain threshold. To assist patients/doctors in the choice of this threshold, and to compare the resulting personalised schedule with currently practiced schedules, along with the timing and the total number of biopsies (burden) planned, for each schedule we provided them with the time delay expected in detecting upgrading (shorter is better)., Results: The cause-specific cumulative upgrading risk at the 5-year follow-up was 35% in PRIAS, and at most 50% in the GAP3 cohorts. In the PRIAS-based model, PSA velocity was a stronger predictor of upgrading (hazard ratio [HR] 2.47, 95% confidence interval [CI] 1.93-2.99) than the PSA level (HR 0.99, 95% CI 0.89-1.11). Our model had a moderate area under the receiver operating characteristic curve (0.6-0.7) in the validation cohorts. The prediction error was moderate (0.1-0.2) in theGAP3 cohorts where the impact of the PSA level and velocity on upgrading risk was similar to PRIAS, but large (0.2-0.3) otherwise. Our model required re-calibration of baseline upgrading risk in the validation cohorts. We implemented the validated models and the methodology for personalised schedules in a web-application (http://tiny.cc/biopsy)., Conclusions: We successfully developed and validated a model for predicting upgrading risk, and providing risk-based personalised biopsy decisions in AS of prostate cancer. Personalised prostate biopsies are a novel alternative to fixed one-size-fits-all schedules, which may help to reduce unnecessary prostate biopsies, while maintaining cancer control. The model and schedules made available via a web-application enable shared decision-making on biopsy schedules by comparing fixed and personalised schedules on total biopsies and expected time delay in detecting upgrading., (© 2020 The Authors BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Objectives: To investigate whether serial prostate magnetic resonance imaging (MRI) may guide the utility of repeat targeted (TBx) and systematic biopsy (SBx) when monitoring men with low-risk prostate cancer (PCa) at 1-year of active surveillance (AS)., Patients and Methods: We retrospectively included 111 consecutive men with low-risk (International Society of Urological Pathology [ISUP] Grade 1) PCa, who received protocolled repeat MRI with or without TBx and repeat SBx at 1-year of AS. TBx was performed in Prostate Imaging-Reporting and Data System (PI-RADS) score ≥3 lesions (MRI-positive men). Upgrading defined as ISUP Grade ≥2 PCa (I), Grade ≥2 with cribriform growth/intraductal carcinoma PCa (II), and Grade ≥3 PCa (III) was investigated. Upgrading detected by TBx only (not by SBx) and SBx only (not by TBx) was investigated in MRI-positive and -negative men, and related to radiological progression on MRI (Prostate Cancer Radiological Estimation of Change in Sequential Evaluation [PRECISE] score)., Results: Overall upgrading (I) was 32% (35/111). Upgrading in MRI-positive and -negative men was 48% (30/63) and 10% (5/48) (P < 0.001), respectively. In MRI-positive men, there was upgrading in 23% (seven of 30) by TBx only and in 33% (10/30) by SBx only. Radiological progression (PRECISE score 4-5) in MRI-positive men was seen in 27% (17/63). Upgrading (I) occurred in 41% (seven of 17) of these MRI-positive men, while this was 50% (23/46) in MRI-positive men without radiological progression (PRECISE score 1-3) (P = 0.534). Overall upgrading (II) was 15% (17/111). Upgrading in MRI-positive and -negative men was 22% (14/63) and 6% (three of 48) (P = 0.021), respectively. In MRI-positive men, there was upgrading in three of 14 by TBx only and in seven of 14 by SBx only. Overall upgrading (III) occurred in 5% (five of 111). Upgrading in MRI-positive and -negative men was 6% (four of 63) and 2% (one of 48) (P = 0.283), respectively. In MRI-positive men, there was upgrading in one of four by TBx only and in two of four by SBx only., Conclusion: Upgrading is significantly lower in MRI-negative compared to MRI-positive men with low-risk PCa at 1-year of AS. In serial MRI-negative men, the added value of repeat SBx at 1-year surveillance is limited and should be balanced individually against the harms. In serial MRI-positive men, the added value of repeat SBx is substantial. Based on this cohort, SBx is recommended to be performed in combination with TBx in all MRI-positive men at 1-year of AS, also when there is no radiological progression., (© 2020 The Authors BJU International Published by John Wiley & Sons Ltd on behalf of BJU International.)

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.)

Aims: Invasive cribriform and/or intraductal carcinoma have been identified as independent adverse parameters for prostate cancer outcome. Little is known on biopsy undersampling of cribriform architecture. Our aim was to determine the extent of cribriform architecture undersampling and to find predictive factors for identifying false cribriform-negative cases., Methods and Results: We reviewed 186 matched prostate biopsies and radical prostatectomy specimens. Of 97 biopsy grade group 2 (Gleason score 3 + 4 = 7) patients, 22 (23%) had true cribriform-negative (TN), 39 (40%) false-negative (FN) and 36 (37%) true-positive (TP) biopsies. Patients with FN biopsies had higher, although not statistically significant (P = 0.06), median PSA levels than patients with TP biopsies (12 versus 8 ng/ml). A PI-RADS 5 lesion was present in nine of 16 (54%) FN and three of 11 (27%) TN biopsies (P = 0.05). Positive biopsy rate (P = 0.47), percentage Gleason pattern 4 (P = 0.55) and glomeruloid architecture (P = 1.0) were not different. Logistic regression identified PSA as an independent predictor (odds ratio = 3.5; 95% confidence interval = 1.2-9.4, P = 0.02) for cribriform architecture on radical prostatectomy, but not PI-RADS score. The FN rate for large cribriform architecture at radical prostatectomy was 27%, which was lower than for any cribriform architecture (P = 0.01). During follow-up (median 27 months), biochemical recurrence-free survival of patients with TP biopsies was significantly shorter than that of those with FN biopsies (P = 0.03)., Conclusion: In conclusion, 40% of grade group 2 prostate cancer biopsies were FN for cribriform architecture. These patients had higher PSA levels and more frequent PI-RADS score 5 lesions than men with TN biopsies., (© 2019 The Authors. Histopathology Published by John Wiley & Sons Ltd.)

Background. Low-risk prostate cancer patients enrolled in active surveillance programs commonly undergo biopsies for examination of cancer progression. Biopsies are conducted as per a fixed and frequent schedule (e.g., annual biopsies). Since biopsies are burdensome, patients do not always comply with the schedule, which increases the risk of delayed detection of cancer progression. Objective. Our aim is to better balance the number of biopsies (burden) and the delay in detection of cancer progression (less is beneficial) by personalizing the decision of conducting biopsies. Data Sources. We used patient data of the world's largest active surveillance program (Prostate Cancer Research International Active Surveillance; PRIAS). It enrolled 5270 patients, had 866 cancer progressions, and an average of 9 prostate-specific antigen (PSA) and 5 digital rectal examination (DRE) measurements per patient. Methods. Using joint models for time-to-event and longitudinal data, we model the historical DRE and PSA measurements and biopsy results of a patient at each follow-up visit. This results in a visit and patient-specific cumulative risk of cancer progression. If this risk is above a certain threshold, we schedule a biopsy. We compare this personalized approach with the currently practiced biopsy schedules via an extensive and realistic simulation study, based on a replica of the patients from the PRIAS program. Results. The personalized approach saved a median of 6 biopsies (median: 4, interquartile range [IQR]: 2-5) compared with the annual schedule (median: 10, IQR: 3-10). However, the delay in detection of progression (years) is similar for the personalized (median: 0.7, IQR: 0.3-1.0) and the annual schedule (median: 0.5, IQR: 0.3-0.8). Conclusions. We conclude that personalized schedules provide substantially better balance in the number of biopsies per detected progression for men with low-risk prostate cancer.

Background: Multiparametric magnetic resonance imaging (MRI), with or without MRI-targeted biopsy, 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., Objectives: To determine the diagnostic accuracy of the index tests MRI only, MRI-targeted biopsy, the MRI pathway (MRI with or without MRI-targeted biopsy) and systematic biopsy as compared to template-guided biopsy as the reference standard in detecting clinically significant prostate cancer as the target condition, defined as International Society of Urological Pathology (ISUP) grade 2 or higher. Secondary target conditions were the detection of grade 1 and grade 3 or higher-grade prostate cancer, and a potential change in the number of biopsy procedures., Search Methods: We performed a comprehensive systematic literature search up to 31 July 2018. We searched CENTRAL, MEDLINE, Embase, eight other databases and one trials register., Selection Criteria: We considered for inclusion any cross-sectional study if it investigated one or more index tests verified by the reference standard, or if it investigated the agreement between the MRI pathway and systematic biopsy, both performed in the same men. We included only studies on men who were biopsy naïve or who previously had a negative biopsy (or a mix of both). Studies involving MRI had to report on both MRI-positive and MRI-negative men. All studies had to report on the primary target condition., Data Collection and Analysis: Two reviewers independently extracted data and assessed the risk of bias using the QUADAS-2 tool. To estimate test accuracy, we calculated sensitivity and specificity using the bivariate model. To estimate agreement between the MRI pathway and systematic biopsy, we synthesised detection ratios by performing random-effects meta-analyses. To estimate the proportions of participants with prostate cancer detected by only one of the index tests, we used random-effects multinomial or binary logistic regression models. For the main comparisions, we assessed the certainty of evidence using GRADE., Main Results: The test accuracy analyses included 18 studies overall.MRI compared to template-guided biopsy: Based on a pooled sensitivity of 0.91 (95% confidence interval (CI): 0.83 to 0.95; 12 studies; low certainty of evidence) and a pooled specificity of 0.37 (95% CI: 0.29 to 0.46; 12 studies; low certainty of evidence) using a baseline prevalence of 30%, MRI may result in 273 (95% CI: 249 to 285) true positives, 441 false positives (95% CI: 378 to 497), 259 true negatives (95% CI: 203 to 322) and 27 (95% CI: 15 to 51) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations and inconsistency.MRI-targeted biopsy compared to template-guided biopsy: Based on a pooled sensitivity of 0.80 (95% CI: 0.69 to 0.87; 8 studies; low certainty of evidence) and a pooled specificity of 0.94 (95% CI: 0.90 to 0.97; 8 studies; low certainty of evidence) using a baseline prevalence of 30%, MRI-targeted biopsy may result in 240 (95% CI: 207 to 261) true positives, 42 (95% CI: 21 to 70) false positives, 658 (95% CI: 630 to 679) true negatives and 60 (95% CI: 39 to 93) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations and inconsistency.The MRI pathway compared to template-guided biopsy: Based on a pooled sensitivity of 0.72 (95% CI: 0.60 to 0.82; 8 studies; low certainty of evidence) and a pooled specificity of 0.96 (95% CI: 0.94 to 0.98; 8 studies; low certainty of evidence) using a baseline prevalence of 30%, the MRI pathway may result in 216 (95% CI: 180 to 246) true positives, 28 (95% CI: 14 to 42) false positives, 672 (95% CI: 658 to 686) true negatives and 84 (95% CI: 54 to 120) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations, inconsistency and imprecision.Systemic biopsy compared to template-guided biopsy: Based on a pooled sensitivity of 0.63 (95% CI: 0.19 to 0.93; 4 studies; low certainty of evidence) and a pooled specificity of 1.00 (95% CI: 0.91 to 1.00; 4 studies; low certainty of evidence) using a baseline prevalence of 30%, systematic biopsy may result in 189 (95% CI: 57 to 279) true positives, 0 (95% CI: 0 to 63) false positives, 700 (95% CI: 637 to 700) true negatives and 111 (95% CI: 21 to 243) false negatives per 1000 men. We downgraded the certainty of evidence for study limitations and inconsistency.Agreement analyses: In a mixed population of both biopsy-naïve and prior-negative biopsy men comparing the MRI pathway to systematic biopsy, we found a pooled detection ratio of 1.12 (95% CI: 1.02 to 1.23; 25 studies). We found pooled detection ratios of 1.44 (95% CI 1.19 to 1.75; 10 studies) in prior-negative biopsy men and 1.05 (95% CI: 0.95 to 1.16; 20 studies) in biopsy-naïve men., Authors' Conclusions: Among the diagnostic strategies considered, the MRI pathway has the most favourable diagnostic accuracy in clinically significant prostate cancer detection. Compared to systematic biopsy, it increases the number of significant cancer detected while reducing the number of insignificant cancer diagnosed. The certainty in our findings was reduced by study limitations, specifically issues surrounding selection bias, as well as inconsistency. Based on these findings, further improvement of prostate cancer diagnostic pathways should be pursued.

Low-risk prostate cancer patients enrolled in active surveillance (AS) programs commonly undergo biopsies on a frequent basis for examination of cancer progression. AS programs employ a fixed schedule of biopsies for all patients. Such fixed and frequent schedules may schedule unnecessary biopsies. Since biopsies are burdensome, patients do not always comply with the schedule, which increases the risk of delayed detection of cancer progression. Motivated by the world's largest AS program, Prostate Cancer Research International Active Surveillance (PRIAS), we present personalized schedules for biopsies to counter these problems. Using joint models for time-to-event and longitudinal data, our methods combine information from historical prostate-specific antigen levels and repeat biopsy results of a patient, to schedule the next biopsy. We also present methods to compare personalized schedules with existing biopsy schedules., (© 2018 The Authors. Biometrics published by Wiley Periodicals, Inc. on behalf of International Biometric Society.)

Background: Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited., Methods: In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer., Results: A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001)., Conclusions: The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .).

Objective: To investigate biopsy complications and hospital admissions that could be reduced by the use of European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators., Materials and Methods: All biopsies performed in the Rotterdam section of the ERSPC between 1993 and 2015 were included. Biopsy complications and hospital admission data were prospectively recorded in questionnaires that were completed 2 weeks after biopsy. The ERSPC risk calculators 3 (RC3) and 4 (RC4) were applied to men attending the first and subsequent rounds of screening, respectively. Applying the predefined RC3/4 probability thresholds for prostate cancer (PCa) risk of ≥12.5% and high-grade PCa risk ≥3%, we assessed the number of complications, admissions and costs that could be reduced by avoiding biopsies in men below these thresholds., Results: A total of 10 747 biopsies with complete questionnaires were included. For these biopsies a complication rate of 67.9% (7294/10 747), a post-biopsy fever rate of 3.9% (424/10747) and a hospital admission rate of 0.9% (92/10747) were recorded. The fever rate was found to be static over the years, but the hospital admission rate tripled from 0.6% (1993-1996) to 2.1% (2009-2015). Among 7704 biopsies which fit the criteria for RC3 or RC4, 35.8% of biopsies (2757/7704), 37.4% of complications (1972/5268), 39.4% of fever events (128/325) and 42.3% of admissions (30/71) could have been avoided by using one of the risk calculators. More complications could have been avoided if RC4 had been used and for more recent biopsies (2009-2015). Our findings show that 35.9% of the total cost of biopsies and complication treatment could have been avoided., Conclusion: A significant proportion of biopsy complications, hospital admissions and costs could be reduced if biopsy decisions were based on ERSPC risk calculators instead of PSA only. This effect was most prominent in more recent biopsies and in men with repeated biopsies or screening., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Objective: To investigate if pathologic biopsy reevaluation and implementation of immunohistochemical biomarkers could improve prediction of radical prostatectomy outcome in men initially on active surveillance., Methods: Biopsy specimens from diagnosis until switching to radical prostatectomy in men initially on active surveillance in the Dutch part of the Prostate cancer Research International Active Surveillance (PRIAS) study were collected and revised by a single pathologist. Original and revised biopsy Gleason score were compared and correlated with radical prostatectomy Gleason score. Biopsy specimens were immunohistochemically stained for Ki67 and ERG. Predictive ability of clinical characteristics and biomarkers on Gleason ≥7 or ≥pT3 on radical prostatectomy was tested using logistic regression and ROC curve analysis., Results: A total of 150 biopsies in 95 men were revised. In 13% of diagnostic or second-to-last biopsies and 20% of the last biopsies on active surveillance revision of Gleason score resulted in change of recommendation (ie, active treatment or active surveillance). Concordance with Gleason score on radical prostatectomy was however similar for both the revised and original Gleason on biopsy. Ki67 and ERG were not statistically significant predictors of Gleason ≥7 or ≥pT3 on radical prostatectomy., Conclusions: Although interobserver differences in pathology reporting on biopsy could result in a change of management strategy in approximately 13-20% of men on active surveillance, both pathological revision and tested biomarkers (Ki67 and ERG) did not improve prediction of outcome on radical prostatectomy. Undersampling of most aggressive tumor remains the main focus in order to increase accurate grading at time of treatment decision making., (© 2017 Wiley Periodicals, Inc.)

Unlabelled: Study Type--Diagnosis (validating cohort) Level of Evidence 1b. What's known on the subject? and What does the study add? The European Randomized study of Screening for Prostate Cancer (ERSPC) showed a reduction in prostate cancer mortality of 21% for PSA-based screening at a median follow-up of 11 years. In the ERSPC, men are screened at 4-year intervals. A prostate biopsy is recommended for men with a PSA level ≥ 3.0 ng/mL. The study shows that the positive predictive value (PPV) of a prostate biopsy indicated by PSA-based screening remains equal throughout consecutive screening rounds in men without a previous biopsy. In men who have previously had a benign biopsy, the PPV drops considerably, but 20% of the cancers detected still show aggressive characteristics., Objective: • To assess the positive predictive value (PPV) of prostate biopsy, indicated by a prostate-specific antigen (PSA) threshold of ≥ 3.0 ng/mL, over time, in the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC)., Patients and Methods: • In the Rotterdam section of the ERSPC, a total of 42,376 participants, aged 55-74 years, identified from population registries were randomly assigned to a screening or control arm. • For the ERSPC men undergo PSA screening at 4-year intervals. A total of three screening rounds were evaluated; therefore, only men aged 55-69 years at the first screening were eligible for the present study., Results: • PPVs for men without previous biopsy remained equal throughout the three subsequent screenings (25.5, 22.3 and 24.8% respectively). • Conversely, PPVs for men with a previous negative biopsy dropped significantly (12.0 and 15.2% at the second and third screening, respectively). • Additionally, in men with and without previous biopsy, the percentage of aggressive prostate cancers (clinical stage >T2b, Gleason score ≥ 7) decreased after the first round of screening from 44.4 to 23.8% in the second (P < 0.001) and 18.6% in the third round (P < 0.001). • Repeat biopsies accounted for 24.6% of all biopsies, but yielded only 8.6% of all aggressive cancers., Conclusions: • In consecutive screening rounds the PPV of PSA-based screening remains equal in previously unbiopsied men. • In men with a previous negative biopsy the PPV drops considerably, but 20% of cancers detected still show aggressive characteristics. • Individualized screening algorithms should incorporate previous biopsy status in the decision to perform a repeat biopsy with the aim of further reducing unnecessary biopsies., (© 2012 BJU INTERNATIONAL.)

Background: Prediction models need validation to assess their value outside the development setting., Objective: To assess the external validity of the European Randomised study of Screening for Prostate Cancer (ERSPC) Risk Calculator (RC) in a contemporary clinical cohort., Methods: The RC calculates the probability of a positive sextant prostate biopsy (P(posb)) using serum prostate-specific antigen (PSA), results of digital rectal examination, transrectal ultrasound (TRUS) and ultrasound assessed prostate volume. We prospectively validated the RC in 320 biopsied men (55-75 years), with no previous prostate biopsy, included in five Dutch hospitals in 2008-2011. If the P(posb) was ≥ 20% a biopsy was recommended. The performance of the RC was tested by comparing the observed outcomes to predicted probabilities, using the area under the curve (AUC) and decision curves analyses., Results: Compared to the screening cohort, men in the clinical cohort differed. They had higher PSA levels (median 6.8 versus 4.3 ng/ml, p<0.01), less TRUS-lesions (27% versus 34%, p = 0.01) and more prostate cancer (PCa) at biopsy (43% versus 25%, p<0.01). Mainly eight biopsy cores were taken. Despite the differences between these cohorts, the mean observed probability agreed with the mean predicted probability (43% versus 40%). The RC predicted P(posb) better than a model with PSA and digital rectal examination, AUC 0.77 (95% confidence interval (CI) 0.72-0.83) and 0.71 (95%CI 0.65-0.76, p<0.01), respectively. This was confirmed by the decision curves analysis. Under the 20% threshold, 17% (11/63) of the biopsied men were diagnosed with PCa. Two of 11 men had an important cancer (Gleason 3+4)., Conclusions: The ERSPC RC performs well in a Dutch clinical cohort in men with previous PSA tests and contemporary biopsy schemes, and outperforms a PSA and DRE-based approach in the decision to perform a biopsy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Screening for prostate cancer (PC) is controversial due to uncertainties about its efficiency., Objective: We aimed to develop strategies to reduce the number of unnecessary biopsies while still detecting most clinically important PC cases., Design, Setting, and Participants: In 1850 men initially screened and biopsied (prostate-specific antigen [PSA] value > or =3.0 ng/ml) in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, we calculated both the probability of having a positive lateralized sextant biopsy [P(biop+)] and the probability of having an indolent cancer [P(ind)] if PC was detected at biopsy (n=541). Analyses of repeat screening included 225 cancers in 1201 men., Interventions: The P(biop+) was based on applying a logistic regression model that included ultrasound volume, digital rectal exam, and transrectal ultrasound in addition to the PSA value. The P(ind) was based on a recently validated nomogram. MEASUREMENTS AND LIMITATIONS: At initial screening the fraction of positive biopsies was 29% (541 of 1850). Applying an additional P(biop+) cut-off of 12.5% implied that 613 of the 1850 men (33%) would not have been biopsied. This would result in an increase in the positive predictive value (PPV) to 38% (468 of 1237). At repeat screening a similar P(biop+) cut-off would result in an increase in the PPV from 19% (225 of 1201) to 25% (188 of 760). Thirteen percent of PC cases would not have been diagnosed, of which 70% (initial screening) and 81% (repeat screening) could be considered as potentially indolent. None of the deadly PC cases would have been missed. A PSA cut-off of > or =4.0 ng/ml resulted in similar numbers of biopsied cases saved but considerably higher numbers of missed diagnoses., Conclusions: An individualized screening algorithm using other available prebiopsy information in addition to PSA level can result in a considerable reduction of unnecessary biopsies. Very few important PC cases, for which diagnosis at a subsequent screening visit might be too late for treatment with curative intent, would be missed.

Context: The European Randomized Study of Screening for Prostate Cancer (ERSPC) section Rotterdam was initiated in 1993. Men who initially presented with prostate-specific antigen (PSA) values <3.0 ng/ml were not biopsied (with few exceptions). In the Prostate Cancer Prevention Trial (PCPT) eligible men who initially presented with PSA values <3.0 ng/ml were all biopsied during or at the end of a 7-yr study period., Objective: To compare biopsy rates in PCPT and cancer detection rates, interval cancers, and prostate cancer deaths in ERSPC. Report the number of additional biopsies needed to detect these cases using PCPT policy., Evidence Acquisition: 21,210 men, aged 55-74 yr, were randomised to screening; 19,970 were actually screened between November 1993 and December 1999. A total of 15,852 initially presented with PSA values of <3.0 ng/ml; after excluding 79 detected at first screens, 15,773 remained as the study population. A second and third screening round followed after 4- and 8-yr intervals. All cancers found in three rounds of screening or as interval cancers during the 12-yr interval were identified and characterised., Evidence Synthesis: Screening for prostate cancer and routine clinical management, comparison of detection rates and outcome data. During the 12-yr observation period, which may be too short, 700 cancers were found, 620 through screening and 80 as interval cancers. None of the screen-detected cases but 6 of the 80 men with interval cancers died of prostate cancer. Applying the positive predictive value of 21.7% of the PCPT trial 3472 cancers would have been detected in ERSPC Rotterdam had all men with PSA values <3.0 ng/ml been biopsied. Assuming 80 interval cancers and 6 deaths from prostate cancer might have been prevented if all 15,773 eligible men had undergone biopsy., Conclusions: The present data suggest a very much unfavourable "number needed to be biopsied" to find one missed cancer or to detect the deadly interval cancers.

Objective: To determine the value of a hypoechoic lesion (HL)-directed biopsy in addition to a systematic sextant biopsy for detecting prostate cancer., Subjects and Methods: Within the European Randomized study of Screening for Prostate Cancer, 37 627 assays for prostate-specific antigen (PSA) were done in men aged 55-75 years (screening round 1-3, interval 4 years). A PSA level of >or=3.0 ng/mL prompted a systematic transrectal ultrasonography (TRUS)-guided lateralized sextant biopsy (4986 biopsy sessions were evaluated). If there was a HL, an additional lesion-directed biopsy was taken., Results: At the initial screening, 1840 men were biopsied and 532 cancers were detected (28.9%). Of the men biopsied, 436 had a HL and an additional biopsy (23.7%). In these men, 230 cancers were detected (52.8%). In 3.5% (eight of 230) only the HL-directed core showed malignancy. At the repeat and third screening, respectively, 19.3% and 18.9% of the men biopsied had prostate cancer, 16.8% and 9.3% had an HL and the additional core detected two (2.2%) and one (5.9%) cancers. At the first screen most cancers found by the additional core were clinically relevant. In later screens these cancers seemed to be minimal., Conclusion: The performance of TRUS as a screening tool is poor. The value of the additional core was limited as only 3.5% of the visible cancers were detected solely by the additional biopsy (round 1). However, a substantial part of these cancers were clinically relevant and would have been missed without the additional biopsy. This finding was less clear in screening round 2 and 3, even in men who were not previously biopsied.

Objectives: To evaluate the complication rates and possible risk factors of biopsy of the prostate, with the aim of improving patient counseling and the safety of the procedure. Biopsy of the prostate has to be a relatively safe procedure and the participants have to be well informed about the possible complications., Methods: Within the biopsy protocol of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, we evaluated 5802 transrectal ultrasound-guided systematic sextant biopsies. All participants received prophylactic antibiotic therapy., Results: We performed 5802 biopsies. Hematuria lasting longer than 3 days and hematospermia were present after 22.6% and 50.4% of the procedures, respectively. More severe complications were far less frequent. Two hundred participants (3.5%) developed fever after biopsy. Urinary retention was seen 20 times (0.4%), and hospitalization was needed in 27 cases (0.5%). Twenty-five of these men were admitted because of signs of prostatitis and/or urosepsis. Risk factor analyses revealed that an earlier episode of prostatitis was significantly associated with hospital admission and pain after biopsy. Characteristics of prostatic hyperplasia, such as prostate volume, transition zone volume/total prostate volume ratio, and a higher International Prostate Symptom Score, were all predictors of urinary retention., Conclusions: Minor complications are frequently seen but major complications are rare after prostate biopsy. Assessment of the risk factors before biopsy can help to improve the adequacy of counseling, and precautionary measures can be taken to minimize the risk of complications after the procedure. Transrectal ultrasound-guided sextant biopsy remains a safe procedure for the diagnosis of prostate cancer within the general population.

BackgroundThe optimal interval for repeat biopsy during active surveillance (AS) for prostate cancer is yet to be defined. This study examined whether risk of upgrading (to grade group ≥ 2) or risk of converting to treatment varied according to intensity of repeat biopsy using data from the GAP3 consortium's global AS database.Materials and methodsIntensity of surveillance biopsy schedules was categorized according to centers' protocols: (a) Prostate Cancer Research International Active Surveillance project (PRIAS) protocols with biopsies at years 1, 4, and 7 (10 centers; 7532 men); (b) biennial biopsies, that is, every other year (8 centers; 4365 men); and (c) annual biopsy schedules (4 centers; 1602 men). Multivariable Cox regression was used to compare outcomes according to biopsy intensity.ResultsOut of the 13,508 eligible participants, 56% were managed according to PRIAS protocols (biopsies at years 1, 4, and 7), 32% via biennial biopsy, and 12% via annual biopsy. After adjusting for baseline characteristics, risk of converting to treatment was greater for those on annual compared with PRIAS biopsy schedules (hazard ratio [HR] = 1.66; 95% confidence interval [CI] = 1.51-1.83; p

This study aimed to estimate the rates of biopsy undersampling and progression for four prostate cancer (PCa) active surveillance (AS) cohorts within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) consortium. We used a hidden Markov model (HMM) to estimate factors that define PCa dynamics for men on AS including biopsy under-sampling and progression that are implied by longitudinal data in four large cohorts included in the GAP3 database. The HMM was subsequently used as the basis for a simulation model to evaluate the biopsy strategies previously proposed for each of these cohorts. For the four AS cohorts, the estimated annual progression rate was between 6%-13%. The estimated probability of a biopsy successfully sampling undiagnosed non-favorable risk cancer (biopsy sensitivity) was between 71% and 80%. In the simulation study of patients diagnosed with favorable risk cancer at age 50, the mean number of biopsies performed before age 75 was between 4.11 and 12.60, depending on the biopsy strategy. The mean delay time to detection of non-favorable risk cancer was between 0.38 and 2.17 years. Biopsy undersampling and progression varied considerably across study cohorts. There was no single best biopsy protocol that is optimal for all cohorts, because of the variation in biopsy under-sampling error and annual progression rates across cohorts. All strategies demonstrated diminishing benefits from additional biopsies.

BackgroundCareful assessment of the reasons for discontinuation of active surveillance (AS) is required for men with prostate cancer (PCa).ObjectiveUsing Movember's Global Action Plan Prostate Cancer Active Surveillance initiative (GAP3) database, we report on reasons for AS discontinuation.Design, setting, and participantsWe compared data from 10296 men on AS from 21 centres across 12 countries.Outcome measurements and statistical analysisCumulative incidence methods were used to estimate the cumulative incidence rates of AS discontinuation.Results and limitationsDuring 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

Aims: Invasive cribriform and intraductal carcinoma (IDC) are associated with adverse outcome in prostate cancer patients, with the large cribriform pattern having the worst outcome in radical prostatectomies. Our objective was to determine the impact of the large and small cribriform patterns in prostate cancer biopsies. Methods and results: Pathological revision was carried out on biopsies of 1887 patients from the European Randomised Study of Screening for Prostate Cancer. The large cribriform pattern was defined as having at least twice the size of adjacent benign glands. The median follow‐up time was 13.4 years. Hazard ratios for metastasis‐free survival (MFS) and disease‐specific survival (DSS) were calculated using Cox proportional hazards regression. Any cribriform pattern was found in 280 of 1887 men: 1.1% IDC in grade group (GG) 1, 18.2% in GG2, 57.1% in GG3, 55.4% in GG4 and 59.3% in GG5; the large cribriform pattern was present in 0, 0.5, 9.8, 18.1 and 17.3%, respectively. In multivariable analyses, small and large cribriform patterns were both (P < 0.005) associated with worse MFS [small: hazard ratio (HR) = 3.04, 95% confidence interval (CI) = 1.93–4.78; large: HR = 3.17, 95% CI = 1.68–5.99] and DSS (small: HR = 4.07, 95% CI = 2.51–6.62; large: HR = 4.13, 95% CI = 2.14–7.98). Patients with the large cribriform pattern did not have worse MFS (P = 0.77) or DSS (P = 0.96) than those with the small cribriform pattern. Conclusions: Both small and large cribriform patterns are associated with worse MFS and DSS in prostate cancer biopsies. Patients with the large cribriform pattern on biopsy have a similar adverse outcome as those with the small cribriform pattern. [ABSTRACT FROM AUTHOR]

Objective: To externally validate and compare the performance of the European Randomized Study of Screening for Prostate Cancer risk calculator 3/4 (ERSPC‐RC3/4), the Prostate Biopsy Collaborative Group risk calculator (PBCG‐RC) and the van Leeuwen model to determine which prediction model would perform the best in a contemporary Australian cohort undergoing transperineal (TP) biopsy. Materials and Methods: A retrospective review identified all patients undergoing TP biopsy across two centres. Of the 797 patients identified, 373 had the data required to test all three risk calculators. The probability of high‐grade prostate cancer, defined as International Society of Urological Pathology Grade Group >1, was calculated for each patient. For each prediction model discrimination was assessed using area under the receiver‐operating characteristic curve (AUC), calibration using numerical and graphical summaries, and net benefit using decision curve analysis. Results: Assessment of model discrimination for detecting high‐grade prostate cancer showed AUCs of 0.79 (95% confidence interval [CI] 0.74–0.84) for the ERSPC‐RC3/4, 0.81 (95% CI 0.77–0.86) for the van Leeuwen model, and 0.68 (95% CI 0.63–0.74) for the PBCG‐RC, compared to 0.58 (95% CI 0.52–0.65) for prostate‐specific antigen alone. The ERSPC‐RC3/4 was the best calibrated in the moderate‐risk range of 10–40%, whilst the van Leeuwen model was the best calibrated in the low‐risk range of 0–10%. The van Leeuwen model demonstrated the greatest net benefit from 10% risk onwards, followed closely by the ERSPC‐RC3/4 and then the PBCG‐RC. Conclusion: The ERPSC‐RC3/4 demonstrated good performance and was comparable to the van Leeuwen model with regard to discrimination, calibration and net benefit for an Australian population undergoing TP prostate biopsy. It is one of the most accessible risk calculators with an easy‐to‐use online platform, therefore, we recommend that Australian urologists use the ERSPC‐RC3/4 to predict risk in the clinical setting. [ABSTRACT FROM AUTHOR]

Objectives: To validate, in an external cohort, three novel risk models, including the recently updated European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculator, that combine multiparametric magnetic resonance imaging (mpMRI) and clinical variables to predict clinically significant prostate cancer (PCa). Patients and Methods: We retrospectively analysed 307 men who underwent mpMRI prior to transperineal ultrasound fusion biopsy between October 2015 and July 2018 at two German centres. mpMRI was rated by Prostate Imaging Reporting and Data System (PI‐RADS) v2.0 and clinically significant PCa was defined as International Society of Urological Pathology Gleason grade group ≥2. The prediction performance of the three models (MRI‐ERSPC‐3/4, and two risk models published by Radtke et al. and Distler et al., ModRad and ModDis) were compared using receiver‐operating characteristic (ROC) curve analyses, with area under the ROC curve (AUC), calibration curve analyses and decision curves used to assess net benefit. Results: The AUCs of the three novel models (MRI‐ERSPC‐3/4, ModRad and ModDis) were 0.82, 0.85 and 0.83, respectively. Calibration curve analyses showed the best intercept for MRI‐ERSPC‐3 and ‐4 of 0.35 and 0.76. Net benefit analyses indicated clear benefit of the MRI‐ERSPC‐3/4 risk models compared with the other two validated models. The MRI‐ERSPC‐3/4 risk models demonstrated a discrimination benefit for a risk threshold of up to 15% for clinically significant PCa as compared to the other risk models. Conclusion: In our external validation of three novel prostate cancer risk models, which incorporate mpMRI findings, a head‐to‐head comparison indicated that the MRI‐ERSPC‐3/4 risk model in particular could help to reduce unnecessary biopsies. [ABSTRACT FROM AUTHOR]

Abstract 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. Take Home Message The magnetic resonance imaging-based Rotterdam European Randomized Study of Screening for Prostate Cancer (MRI-ERSPC) risk calculators include age and Prostate Imaging Reporting and Data System as parameters, and predict (Gleason ≥3 + 4) prostate cancer in transrectal ultrasound-guided systematic biopsy and MRI-targeted biopsy. The MRI-ERSPC risk calculator could help avoid one-third of biopsies following MRI in previously biopsied men. [ABSTRACT FROM AUTHOR]

Objective: To systematically review and meta‐analyse evidence regarding the additional value of magnetic resonance imaging (MRI) and MRI‐targeted biopsies to confirmatory systematic biopsies in identifying high‐grade prostate cancer in men with low‐risk disease on transrectal ultrasonography (TRUS) biopsy, as active surveillance (AS) of prostate cancer is recommended for men with Gleason 3 + 3 on standard TRUS‐guided biopsy. Confirmatory assessment can include repeat standard TRUS‐guided biopsy, and/or MRI with targeted biopsy when indicated. Methods: A systematic review of the Embase, Medline, Web‐of‐science, Google scholar, and Cochrane library was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Identified reports were critically appraised according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)‐2 criteria. Studies reporting men with Gleason 3 + 3 prostate cancer who had chosen AS based on transrectal systematic biopsy findings and had undergone MRI with systematic ± targeted biopsy at confirmatory assessment were included. The primary outcome was detection of any Gleason pattern ≥4. Results: Included reports (six) of men on AS (n = 1 159) showed cancer upgrading (Gleason ≥3 + 4) in 27% (95% confidence interval [CI] 22–34%) using a combined approach of MRI‐targeted biopsies and confirmatory systematic biopsies. MRI‐targeted biopsies alone would have missed cancer upgrading in 10% (95% CI 8–14%) and standard biopsies alone would have missed cancer upgrading in 7% (95% CI 5–10%). No pathway was more favourable than the other (relative risk [RR] 0.92, 95% CI 0.79–1.06). In all, 35% (95% CI 27–43%) of men with a positive MRI were upgraded, compared to 12% (95% CI 8–18%) of men with a negative MRI being upgraded (RR 2.77, 95% CI 1.76–4.38). Conclusions: A pre‐biopsy MRI should be performed before confirmatory systematic TRUS‐guided biopsies in men on AS, together with MRI‐targeted biopsies when indicated. A combined approach maximises cancer detection, although other factors within multivariate risk prediction can be used to aid the decision to biopsy in these men. [ABSTRACT FROM AUTHOR]

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

Objectives To assess the level of agreement between digital rectal examination findings of two urologists and its effect on risk prediction using the digital rectal examination-based Rotterdam Prostate Cancer Risk Calculator. Methods The study sample consisted of a prospective cohort of asymptomatic unscreened men with prostate-specific antigen ≤50.0 ng/mL and transrectal ultrasound volume ≤110 mL who underwent transrectal ultrasound-guided prostate biopsy. Both urologists' digital rectal examination findings were graded normal or abnormal (nodularity and/or induration), and volume classified as 25, 40 or 60 mL, according to the risk calculator algorithm. Interrater agreement analysis using Cohen's kappa (κ) statistic was carried out to determine consistency of digital rectal examination outcome and volume assessment. Receiver operating characteristic curve analysis and calibration plots were constructed to determine the effect of interrater differences. Decision curve analysis was applied to evaluate the clinical usefulness of the model. Results Of the 241 men included in the study, 41% ( n = 98) had prostate cancer (81 were clinically significant, i.e. Gleason ≥3 + 4). There was substantial agreement in the digital rectal examination (abnormal/normal; κ = 0.78; P < 0.001) and volume estimation (κ = 0.79; P < 0.001). Receiver operating characteristic analyses showed good discrimination (0.75-0.78) and were comparable for both urologists. In the high-risk cohort, at a probability threshold of 25%, the risk calculator reduced the prostate biopsy rate by 9%, without missing cancers. Conclusions Slight differences in digital rectal examination findings seem to have very limited impact on the performance of the Rotterdam Prostate Cancer Risk Calculator. Therefore, this can be considered a useful prostate biopsy outcome prediction tool. [ABSTRACT FROM AUTHOR]

Objectives To assess the value of risk-stratification based on magnetic resonance imaging (MRI) and prostate-specific antigen density (PSA-D) in reducing unnecessary biopsies without missing Gleason pattern 4 prostate cancer in men on active surveillance (AS). Patients and Methods In all, 210 men on AS with Gleason score 3 + 3 prostate cancer received a first MRI and if indicated [Prostate Imaging Reporting and Data System (PI-RADS) score ≥3] targeted biopsy (TBx) using MRI-transrectal ultrasonography (TRUS) fusion. The MRI was performed 3 months after diagnosis (group A: n = 97), at confirmatory biopsy (group B: n = 39) or at surveillance biopsy after one or more repeat TRUS-guided systematic biopsies (TRUS-Bx) (group C: n = 74). The primary outcome was upgrading to Gleason score ≥3 + 4 prostate cancer based on MRI ± TBx in groups A, B and C. Biopsy outcomes were stratified for the overall PI-RADS score and PSA-D to identify a subgroup of men in whom a biopsy could have been avoided as no Gleason score upgrading was detected. Results In all, 134/210 (64%) men had a positive MRI and 51/210 (24%) men had Gleason score upgrading based on MRI±TBx. The percentage of Gleason score upgrading based on MRI-TBx was 23% (22/97), 23% (9/39) and 27% (20/74) in respectively groups A, B and C. Additional Gleason score upgrading detected by TRUS-Bx occurred in 8% (3/39) of men in group B and 6% (1/17) of men who received TRUS-Bx in group C. No Gleason score upgrading was detected by MRI-TBx in men with a PI-RADS score of 3 and a PSA-D of <0.15 ng/mL2(n = 15), nor by TRUS-Bx in men with a PI-RADS score of 1–3 and a PSA-D of <0.15 ng/mL2 (n = 15). Conclusion At least one out of five men on AS with Gleason score 3 + 3 prostate cancer at diagnostic TRUS-Bx show Gleason score upgrading based on first MRI ± TBx at baseline, confirmatory or surveillance biopsy. Men with a PIRADS score of 1–3 and PSA-D of <0.15 ng/mL2 did not show Gleason score upgrading at MRI ± TBx or TRUS-Bx at each time point of surveillance. Thus risk-stratification based on PI-RADS and PSA-D may reduce unnecessary follow-up biopsy procedures in men on AS. [ABSTRACT FROM AUTHOR]

Objective To study the risk of serial prostate biopsies on complications in men on active surveillance (AS) and determine the effect of complications on receiving further biopsies. Patients and methods In the global Prostate cancer Research International: Active Surveillance (PRIAS) study, men are prospectively followed on AS and repeat prostate biopsies are scheduled at 1, 4, and 7 years after the diagnostic biopsy, or once yearly if prostate-specific antigen-doubling time is <10 years. Data on complications after biopsy, including infection, haematuria, haematospermia, and pain, were retrospectively collected for all biopsies taken during follow-up in men from several large participating centres. Generalised estimating equations were used to test predictors of infection after biopsy. Competing risk analysis was used to compare the rates of men receiving further biopsies between men with and without previous complications. Results In all, 2 184 biopsies were taken in 1 164 men. Infection was reported after 55 biopsies (2.5%), and one in five men reported any form of complication. At multivariable analysis, the number of previous biopsies was not a significant predictor of infection (odds ratio 1.04, 95% confidence interval 0.76-1.43). The only significant predictor for infection was the type of prophylaxis used. Of all men with a complication at the diagnostic or first repeat biopsy, 21% did not have a repeat biopsy at the time a repeat biopsy was scheduled according to protocol, vs 12% for men without a previous biopsy complication. Conclusion In our present cohort of men on AS, we found no evidence that repeat prostate biopsy in itself posed a risk of infection. However, complications after biopsy were not uncommon and after a complication men were less likely to have further biopsies. We should aim to safely reduce the amount of repeat biopsies in men on AS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Evidence from randomized trials on the effects of screening for prostate cancer (PCa) on disease-specific mortality accumulates slowly with increasing follow-up. Objective: To assess data on PCa-specific mortality in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial. Design, setting, and participants: A randomized controlled trial with randomization after signed, written informed consent (efficacy trial). In the period 1993–1999, a total of 42 376 men aged 54–74 yr were randomized to a screening arm (S-arm) (n = 21 210 with screening every 4 yr, applying a total prostate-specific antigen [PSA] level cut-off ≥3.0 ng/ml as biopsy indication) or a control arm (C-arm) (n = 21 166; no intervention). Outcome measurements and statistical analysis: Number of PCas detected per arm depicted by predefined time periods and prognostic groups. PCa-specific mortality analyses using Poisson regression in age group 55–74 yr at randomization and separately in the predefined age group of 55–69 yr. Results and limitations: After a median follow-up of 12.8 yr, 19 765 men (94.2%) were screened at least once and 2674 PCas were detected (of which 561 [21.0%] were interval PCas). In the C-arm, 1430 PCas were detected, resulting in an excess incidence of 59 PCas per 1000 men randomized (61 PCas per 1000 in age group 55–69 yr). Thirty-two percent of all men randomized have died. PCa-specific mortality relative-risk (RR) reductions of 20.0% overall (age: 55–74 yr; p = 0.042) and 31.6% (age: 55–69 yr; p = 0.004) were found. A 14.1% increase was found in men aged 70–74 yr (not statistically significant). Absolute PCa mortality was 1.8 per 1000 men randomized (2.6 per 1000 men randomized in age group 55–69 yr). The number needed to invite and number needed to manage were 565 and 33, respectively, for age group 55–74 yr, and 392 and 24, respectively, for age group 65–69 yr. Given the slow natural history of the disease, follow-up might be too short. Conclusions: Systematic PSA-based screening reduced PCa-specific mortality by 32% in the age range of 55–69 yr. The roughly twofold higher incidence in the S-arm underlines the importance of tools to better identify those men who would benefit from screening. [Copyright &y& Elsevier]

What's known on the subject? and What does the study add? Previous studies have shown that a statistical model based on a panel of kallikrein markers in blood (total, free and intact PSA and kallikrein-related peptidase 2) can predict prostate cancer on biopsy., The current study explores the relationship between the above-mentioned panel and prostate volume, and whether this panel could be an alternative for clinical measures such as DRE and TRUS in predicting prostate cancer on biopsy., Objective To explore whether a panel of kallikrein markers in blood: total, free and intact prostate-specific antigen ( PSA) and kallikrein-related peptidase 2, could be used as a non-invasive alternative for predicting prostate cancer on biopsy in a screening setting., Subjects and Methods The study cohort comprised previously unscreened men who underwent sextant biopsy owing to elevated PSA (≥3 ng/mL) in two different centres of the European Randomized Study of Screening for Prostate Cancer, Rotterdam ( n = 2914) and Göteborg ( n = 740)., A statistical model, based on kallikrein markers, was compared with one based on established clinical factors for the prediction of biopsy outcome., Results The clinical tests were found to be no better than blood markers, with an area under the curve in favour of the blood measurements of 0.766 vs. 0.763 in Rotterdam and 0.809 vs. 0.774 in Göteborg., Adding digital rectal examination ( DRE) or DRE plus transrectal ultrasonography ( TRUS) volume to the markers improved discrimination, although the increases were small. Results were similar for predicting high-grade cancer., There was a strong correlation between the blood measurements and TRUS-estimated prostate volume ( Spearman's correlation 0.60 in Rotterdam and 0.57 in Göteborg)., Conclusions In previously unscreened men, each with indication for biopsy, a statistical model based on kallikrein levels was similar to a clinical model in predicting prostate cancer in a screening setting, outside the day-to-day clinical practice., Whether a clinical approach can be replaced by laboratory analyses or used in combination with decision models (nomograms) is a clinical judgment that may vary from clinician to clinician depending on how they weigh the different advantages and disadvantages (harms, costs, time, invasiveness) of both approaches. [ABSTRACT FROM AUTHOR]

Abstract: Background: Inconclusive test results often occur after prostate-specific antigen (PSA)–based screening for prostate cancer (PCa), leading to uncertainty on whether, how, and when to repeat testing. Objective: To develop and validate a prediction tool for the risk of PCa 4 yr after an initially negative screen. Design, setting, and participants: We analyzed data from 15 791 screen-negative men aged 55–70 yr at the initial screening round of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. Outcome measurements and statistical analysis: Follow-up and repeat screening at 4 yr showed either no PCa, low-risk PCa, or potentially high-risk PCa (defined as clinical stage >T2b and/or biopsy Gleason score ≥7 and/or PSA ≥10.0 ng/ml). A multinomial logistic regression analysis included initial screening data on age, PSA, digital rectal examination (DRE), family history, prostate volume, and having had a previous negative biopsy. The 4-yr risk predictions were validated with additional follow-up data up to 8 yr after initial screening. Results and limitations: Positive family history and, especially, PSA level predicted PCa, whereas a previous negative biopsy or a large prostate volume reduced the likelihood of future PCa. The risk of having PCa 4 yr after an initially negative screen was 3.6% (interquartile range: 1.0–4.7%). Additional 8-yr follow-up data confirmed these predictions. Although data were based on sextant biopsies and a strict protocol-based biopsy indication, we suggest that men with a low predicted 4-yr risk (eg, ≤1.0%) could be rescreened at longer intervals or not at all, depending on competing risks, while men with an elevated 4-yr risk (eg, ≥5%) might benefit from immediate retesting. These findings need to be validated externally. Conclusions: This 4-yr future risk calculator, based on age, PSA, DRE, family history, prostate volume, and previous biopsy status, may be a promising tool for reducing uncertainty, unnecessary testing, and overdiagnosis of PCa. [Copyright &y& Elsevier]

The article presents a study that assesses the impact of screening of excess mortality in men with prostate cancer (PC). It outlines the method of the study which observes a total of 141,578 men aged 55-69 who have undergone randomized to systematic screening or usual care in European Randomized Study of Screening for Prostate Cancer (ERSPC). It notes the result of the study which indicates that the reduction in PC mortality in ERSPC trial was not due to a bias in cause of death adjudication.

Study Type - Therapy (outcomes) Level of Evidence 2b What's known on the subject? and What does the study add? Active surveillance aims to reduce overtreatment by selecting patients with low risk prostate cancer (PCa) based on favourable disease characteristics. However, most studies on active surveillance do not have long-term results available; in particular, data on patients with intermediate risk disease are lacking. Our findings demonstrate that withholding radical treatment in men with low or intermediate risk screen-detected localized PCa leads to a substantial delay or even avoidance of radical treatment in a majority of men. Favourable disease-specific outcomes confirm the feasibility of active surveillance for low risk PCa and also support a role for active surveillance in selected patients with intermediate risk PCa. OBJECTIVE To assess the longer-term feasibility of active surveillance, we aimed to evaluate outcomes of patients with screen-detected localized prostate cancer (PCa) who initially elected to withhold radical treatment for either low or intermediate risk disease., PATIENTS AND METHODS All men underwent screening for PCa in the Rotterdam and Helsinki arms of the European Randomized Study of Screening for Prostate Cancer (ERSPC); eligible men were diagnosed with PCa prior to the establishment of the ERSPC-affiliated Prostate Cancer Research International: Active Surveillance (PRIAS) study (1994-2007) and were initially expectantly managed in the absence of a fixed follow-up protocol., Low risk PCa was defined as clinical stage T1/T2, PSA ≤ 10 ng/mL, PSA density < 0.2 ng/mL/mL, Gleason ≤ 6 and maximum two positive biopsy cores, whereas PSA 10-20 ng/mL, Gleason score 7 and three positive biopsy cores were considered intermediate risk features., Disease-specific, overall and treatment-free survival were analysed using the Kaplan-Meier and competing risks methods., RESULTS In all, 509 patients with PCa were eligible, of whom 381 were considered low risk and 128 intermediate risk., During a median follow-up of 7.4 years, a total of 221 patients (43.4%) switched to deferred treatment after a median of 2.6 years., The calculated 10-year disease-specific survival rates were 99.1% and 96.1% for low and intermediate risk patients, respectively ( P= 0.44), and for overall survival 79.0% and 64.5%, respectively ( P= 0.003)., Competing risks analysis showed similar results., CONCLUSIONS Withholding radical treatment in men with low to intermediate risk screen-detected PCa leads to a substantial delay or even avoidance of radical treatment and its potential side-effects in a majority of patients., Disease-specific outcomes at 7.4 years of follow-up are favourable in low as well as intermediate risk patients., This confirms the feasibility of active surveillance according to contemporary criteria, and also suggests a potential role for active surveillance in selected men with intermediate risk features. [ABSTRACT FROM AUTHOR]

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

Study Type - Prognosis (case control) Level of Evidence 3a What's known on the subject? and What does the study add? Treatment of advanced PC might put patients at an increased risk of cardiovascular events. Recent studies have suggested that the excess mortality is lower among men who were diagnosed with screen detected PC in comparison to men with clinically diagnosed PC, possibly due to the use of medications for cardiovascular disease and the change to a healthier lifestyle of men with a screen detected PC. Men with clinically diagnosed PC have an increased risk of death unrelated to PC itself, i.e., the excess mortality is based on an increased risk of dying from other neoplasm and diseases of the circulatory or respiratory system. OBJECTIVE To assess the cause-specific mortality unrelated to prostate cancer (PC) itself in patients with screen- and clinically diagnosed PC., PATIENTS AND METHODS The present study was conducted among participants of the European Randomized Study of Screening for Prostate Cancer., Based on consensus of the causes of death committee (CODC), all patients who died from PC were excluded., In the intervention arm, cases were patients with a screen-detected PC, aged 55-74 years, between 1993 and 2001., These cases were matched to two controls in whom no cancer was found after biopsy, and two controls in whom no cancer was suspected after screening. In the control arm, cases were patients with clinically diagnosed PC, aged 55-74 years, between 1993 and 2001. These cases were matched to four controls without PC. Matching was done with respect to date of birth, screening and/or diagnosis. Men were followed up to 31 December 2007., RESULTS No statistically significant difference in overall mortality between cases and controls in the intervention arm was observed: relative risk (RR) 1.26 (95% confidence interval [CI] 0.96-1.65; P = 0.102) and RR 1.13 (95% CI 0.86-1.47; P = 0.381)., In the control arm, the overall mortality was statistically significantly higher in cases relative to controls: RR 1.43 (95% CI 1.03-2.00; P = 0.033)., This difference was because of an increased risk of dying from neoplasms and disease of the circulatory or respiratory system among cases: RR 1.61 (95% CI 1.12-2.29; P = 0.009)., The present study was limited by the relatively small sample size., CONCLUSIONS Increased mortality unrelated to PC itself was observed in men with clinically diagnosed PC, but not in screen-detected PC., The excess mortality in men with clinically diagnosed PC seems to be as a result of a significantly increased risk of dying from neoplasm and disease of the circulatory or respiratory system., Results have to be studied more thoroughly in further clinical trials. [ABSTRACT FROM AUTHOR]

Study Type - Diagnostic (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? So far, few publications have shown that a prediction model influences the behaviour of both physicians and patients. To our knowledge, it was unknown whether urologists and patients are compliant with the recommendations of a prostate cancer risk calculator and their reasons for non-compliance. Recommendations of the European Randomized study of Screening for Prostate Cancer risk calculator (ERSPC RC) about the need of a prostate biopsy were followed in most patients. In most cases of non-compliance with 'no biopsy' recommendations, a PSA level ≥3 ng/mL was decisive to opt for biopsy. Before implementation of the ERSPC RC in urological practices at a large scale, it is important to obtain insight into the use of guidelines that might counteract the adoption of the use of the RC as a result of opposing recommendations. OBJECTIVES To assess both urologist and patient compliance with a 'no biopsy' or 'biopsy' recommendation of the European Randomized study of Screening for Prostate Cancer (ERSPC) Risk Calculator (RC), as well as their reasons for non-compliance., To assess determinants of patient compliance., PATIENTS AND METHODS The ERSPC RC calculates the probability on a positive sextant prostate biopsy ( Pposb) using serum prostate-specific antigen (PSA) level, outcomes of digital rectal examination and transrectal ultrasonography, and ultrasonographically assessed prostate volume. A biopsy was recommended if Pposb≥20%., Between 2008 and 2011, eight urologists from five Dutch hospitals included 443 patients (aged 55-75 years) after a PSA test with no previous biopsy., Urologists calculated the Pposb using the RC in the presence of patients and completed a questionnaire about compliance., Patients completed a questionnaire about prostate cancer knowledge, attitude towards prostate biopsy, self-rated health (12-Item Short Form Health Survey), anxiety (State Trait Anxiety Inventory-6, Memorial Anxiety Scale for Prostate Cancer) and decision-making measures (Decisional Conflict Scale)., RESULTS Both urologists and patients complied with the RC recommendation in 368 of 443 (83%) cases., If a biopsy was recommended, almost all patients (96%; 257/269) complied, although 63 of the 174 (36%) patients were biopsied against the recommendation of the RC., Compliers with a 'no biopsy' recommendation had a lower mean Pposb than non-compliers (9% vs 14%; P < 0.001)., Urologists opted for biopsies against the recommendations of the RC because of an elevated PSA level (≥3 ng/mL) (78%; 49/63) and patients because they wanted certainty (60%; 38/63)., CONCLUSIONS Recommendations of the ERSPC RC on prostate biopsy were followed in most patients., The RC hence may be a promising tool for supporting clinical decision-making. [ABSTRACT FROM AUTHOR]

Abstract: Background: The European Randomized Study of Screening for Prostate Cancer (ERSPC) risk calculators (RCs) are validated tools for prostate cancer (PCa) risk assessment and include prostate volume (PV) data from transrectal ultrasound (TRUS). Objective: Develop and validate an RC based on digital rectal examination (DRE) that circumvents the need for TRUS but still includes information on PV. Design, setting, and participants: For development of the DRE-based RC, we studied the original ERSPC Rotterdam RC population including 3624 men (885 PCa cases) and 2896 men (547 PCa cases) detected at first and repeat screening 4 yr later, respectively. A validation cohort consisted of 322 men, screened in 2010–2011 as participants in ERSPC Rotterdam. Measurements: Data on TRUS-assessed PV in the development cohorts were re-coded into three categories (25, 40, and 60cm3) to assess the loss of information by categorization of volume information. New RCs including PSA, DRE, and PV categories (DRE-based RC) were developed for men with and without a previous negative biopsy to predict overall and clinically significant PCa (high-grade [HG] PCa) defined as T stage >T2b and/or Gleason score ≥7. Predictive accuracy was quantified by the area under the receiver operating curve. We compared performance with the Prostate Cancer Prevention Trial (PCPT) RC in the validation study. Results and limitations: Areas under the curve (AUC) of prostate-specific antigen (PSA) alone, PSA and DRE, the DRE-based RC, and the original ERSPC RC to predict PCa at initial biopsy were 0.69, 0.73, 0.77, and 0.79, respectively. The corresponding AUCs for predicting HG PCa were higher (0.74, 0.82, 0.85, and 0.86). Similar results were seen in men previously biopsied and in the validation cohort. The DRE-based RC outperformed the PCPT RC (AUC 0.69 vs 0.59; p =0.0001) and a model based on PSA and DRE only (AUC 0.69 vs 0.63; p =0.0075) in the relatively small validation cohort. Further validation is required. Conclusions: An RC should contain volume estimates based either on TRUS or DRE. Replacing TRUS measurements by DRE estimates may enhance implementation in the daily practice of urologists and general practitioners. [Copyright &y& Elsevier]

Abstract: Background: The rate of decrease in advanced cancers is an estimate for determining prostate cancer (PCa) screening program effectiveness. Objective: Assess the effectiveness of PCa screening programs using a 2- or 4-yr screening interval. Design, setting, and participants: Men aged 55–64 yr were participants at two centers of the European Randomized Study of Screening for Prostate Cancer: Gothenburg, Sweden (2-yr screening interval, n =4202), and Rotterdam, the Netherlands (4-yr screening interval, n =13 301). We followed participants until the date of PCa, the date of death, or the last follow-up at December 31, 2008, or up to a maximum of 12 yr after initial screening. Potentially life-threatening (advanced) cancer was defined as cancer with at least one of following characteristics: clinical stage ≥T3a, M1, or N1; serum prostate-specific antigen (PSA) >20.0 ng/ml; or Gleason score ≥8 at biopsy. Intervention: We compared the proportional total (advanced) cancer incidence (screen-detected and interval cases), defined as the ratio of the observed number of (advanced) cancers to the expected numbers of (advanced) cancers based on the control arm of the study. Measurements: The proportional cancer incidence from the second screening round until the end of observation was compared using a 2- or 4-yr screening interval. Results and limitations: From screening round 2 until the end of observation, the proportional cancer incidence was 3.64 in Gothenburg and 3.08 in Rotterdam (relative risk [RR]: 1.18; 95% confidence interval [CI], 1.04–1.33; p =0.009). The proportional advanced cancer incidence was 0.40 in Gothenburg and 0.69 in Rotterdam (RR: 0.57; 95% CI, 0.33–0.99; p =0.048); the RR for detection of low-risk PCa was 1.46 (95% CI, 1.25–1.71; p <0.001). This study was limited by the assumption that PSA testing in the control arm was similar in both centers. Conclusions: A 2-yr screening interval significantly reduced the incidence of advanced PCa; however, the 2-yr interval increased the overall risk of being diagnosed with (low-risk) PCa compared with a 4-yr interval in men aged 55–64 yr. Individualized screening algorithms must be improved to provide the strategy for this issue. [Copyright &y& Elsevier]

OBJECTIVE • To assess possible excess mortality associated with prostate biopsy among screening participants of the European Randomized Study of Screening for Prostate Cancer (ERSPC). PATIENTS AND METHODS • From three centres in the ERSPC (Finland, The Netherlands and Sweden) 50 194 screened men aged 50.2-78.4 years were prospectively followed. A cohort of 12 959 first-time screening-positive men (i.e. with biopsy indication) was compared with another cohort of 37 235 first-time screening-negative men. • Overall mortality rates (i.e. other cause than prostate cancer mortality) were calculated and the 120-day and 1-year cumulative mortality were calculated by the Kaplan-Meier method, with a log-rank test for statistical significance. • Incidence rate ratios (RR) and statistical significance were evaluated using Poisson regression analyses, adjusting for age, total PSA level, screening centre and whether a biopsy indication was present, or whether a biopsy was actually performed or not. RESULTS • There was no statistically significant difference in cumulative 120-day other cause mortality between the two groups of men: 0.24% (95% CI, 0.17-0.34) for screening-positive men vs 0.24% (95% CI, 0.20-0.30) for screening-negative men ( P = 0.96). This implied no excess mortality for screening-positive men. • Screening-positive men who were not biopsied ( n = 1238) had a more than fourfold risk of other cause mortality during the first 120 days compared to screening-negative men: RR, 4.52 (95% CI, 2.63-7.74) ( P < 0.001), adjusted for age, whereas men who were actually biopsied ( n = 11 721) had half the risk: RR, 0.41 (95% CI, 0.23-0.73) ( P = 0.002), adjusted for age. • Only 14/31 (45%) of the screeningpositive men who died within 120 days were biopsied and none died as an obvious complication to the biopsy. CONCLUSION • Prostate biopsy is not associated with excess mortality and fatal complications appear to be very rare. [ABSTRACT FROM AUTHOR]

Abstract: Background: The performance characteristics of serum prostate-specific antigen (PSA) as a diagnostic test for prostate cancer (PCa) are poor. The performance of the PCa antigen 3 (PCA3) gene as a primary diagnostic is unknown. Objective: Assess the value of PCA3 as a first-line diagnostic test. Design, setting and participants: Participants included men aged 63–75 who were invited for rescreening in the period from September 2007 to February 2009 within the European Randomised Study of Screening for Prostate Cancer, Rotterdam section. Interventions: Lateral sextant biopsies were performed if the serum PSA value was ≥3.0ng/ml and/or the PCA3 score was ≥10. Measurements: Measurements included distribution and correlation of PSA value and PCA3 score and their relation to the number of cases and the characteristics of PCa detected. Additional value of PCA3 was included in men with previous negative biopsy and/or PSA <3.0ng/ml. Results and limitations: In 721 men, all biopsied, 122 PCa cases (16.9%) were detected. Correlation between PSA and PCA3 is poor (Spearman rank correlation: ρ=0.14; p <0.0001). A PSA ≥3.0ng/ml misses 64.7% of the total PCa that can be detected with the sextant biopsy technique and 57.9% of serious PCa (T2a or higher and/or Gleason grade ≥4, n =19), and 68.2% of biopsies could have been avoided; the respective data for PCA3 ≥35 are 32%, 26.3%, and 51.7%. Performance of PCA3 in men with low PSA (area under the curve [AUC]: 0.63) and/or previous negative biopsy (AUC: 0.68) is unclear but has limited reliability due to small numbers. Conclusions: PCA3 as a first-line screening test shows improvement of the performance characteristics and identification of serious disease compared with PSA in this prescreened population. [Copyright &y& Elsevier]

Purpose: Prostate specific antigen velocity has been proposed as a marker to aid in prostate cancer detection. We determined whether prostate specific antigen velocity could predict repeat biopsy results in men with persistently increased prostate specific antigen after initial negative biopsy. Materials and Methods: We identified 1,837 men who participated in the Göteborg or Rotterdam section of the European Randomized Screening study of Prostate Cancer and who underwent 1 or more subsequent prostate biopsies after an initial negative finding. We evaluated whether prostate specific antigen velocity improved predictive accuracy beyond that of prostate specific antigen alone. Results: Of the 2,579 repeat biopsies 363 (14%) were positive for prostate cancer, of which 44 (1.7%) were high grade (Gleason score 7 or greater). Prostate specific antigen velocity was statistically associated with cancer risk but had low predictive accuracy (AUC 0.55, p <0.001). There was some evidence that prostate specific antigen velocity improved AUC compared to prostate specific antigen for high grade cancer. However, the small increase in risk associated with high prostate specific antigen velocity (from 1.7% to 2.8% as velocity increased from 0 to 1 ng/ml per year) had questionable clinical relevance. Conclusions: Men with prior negative biopsy are at lower risk for prostate cancer at subsequent biopsies with high grade disease particularly rare. We found little evidence to support prostate specific antigen velocity to aid in decisions about repeat biopsy for prostate cancer. [ABSTRACT FROM AUTHOR]

Study Type – Therapy (prospective cohort) Level of Evidence 2b OBJECTIVE To evaluate the short-term outcomes of the prospective international Prostate Cancer Research International: Active Surveillance (‘PRIAS’) study (Dutch Trial Register NTR1718), as active surveillance (AS) for early prostate cancer might provide a partial solution to the current overtreatment dilemma in this disease. PATIENTS AND METHODS The first 500 (of >950) participants with asymptomatic T1c/T2 prostate cancer, with a prostate-specific antigen (PSA) level of ≤10.0 ng/mL, a PSA density of <0.2 ng/mL/mL, a Gleason score of ≤3 + 3 = 6, and one or two positive biopsy cores, were analysed. The follow-up protocol consisted of frequent PSA measurements, digital rectal examinations, and standard repeat biopsies (the first after 1 year). The primary outcome is survival free of active therapy; the secondary endpoints are reasons for stopping AS, findings in 1-year repeat biopsies, and outcomes after radical prostatectomy (RP). RESULTS Patients were included between December 2006 and July 2008. The median (25–75th percentile) follow-up after diagnosis was 1.02 (0.6–1.5) years. The 2-year survival rate free from active therapy was 73%. Of the 82 men who changed to active therapy during the follow-up, 68 (83%) did so based on the protocol. Of the 261 repeat biopsies available for analysis, 90 (34%) showed no cancer, while 57 (22%) showed a Gleason score of >6 or more than two positive biopsy cores. There was a relatively unfavourable PSA doubling time of 0–10 years in 53% (102/194) and 62% (33/53) of men with favourable and unfavourable re-biopsy results, respectively. After RP, four of 24 (17%) men had T3 disease and 12 (50%) had a Gleason score of >6. CONCLUSION AS seems feasible, but mortality outcomes are unknown. A strict follow-up protocol including standard 1-year repeat biopsies resulted in a quarter of men stopping AS after 2 years. [ABSTRACT FROM AUTHOR]