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Supplementary Table 2 from Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer

Supplementary Table 1 from Evidence of Limited Contributions for Intratumoral Steroidogenesis in Prostate Cancer

INTRODUCTION AND OBJECTIVE:With a median follow–up of 16 years the European Randomized Study of Screening for Prostate Cancer (ERSPC) shows a relative reduction of prostate cancer (PCa) specific mo...

Background: The European Randomized study of Screening for Prostate Cancer (ERSPC) has previously demonstrated that prostate-specific antigen (PSA) screening decreases prostate cancer (PCa) mortality. Objective: To determine whether PSA screening decreases PCa mortality for up to 16 yr and to assess results following adjustment for nonparticipation and the number of screening rounds attended. Design, setting, and participants: This multicentre population-based randomised screening trial was conducted in eight European countries. Report includes 182 160 men, followed up until 2014 (maximum of 16 yr), with a predefined core age group of 162 389 men (55-69 yr), selected from population registry. Outcome measurements and statistical analysis: The outcome was PCa mortality, also assessed with adjustment for nonparticipation and the number of screening rounds attended. Results and limitations: The rate ratio of PCa mortality was 0.80 (95% confidence interval [CI] 0.72-0.89, p 20 ng/ml (9.9% compared with 4.1% in the second round, p

We assessed the effect of screening in the European Randomized study of Screening for Prostate Cancer (ERSPC) Rotterdam pilot 1 study cohort with men randomized in 1991-1992. A total of 1134 men were randomized on a 1:1 basis to a screening (S) and control (C) arm after prostate-specific antigen (PSA) testing (PSA ≥10.0ng/ml was excluded from randomization). Further PSA testing was offered to all men in the S-arm with 4-yr intervals starting at age 55yr and screened up to the age of 74yr. Overall, a PSA level of ≥3.0ng/ml triggered biopsy. At time of analysis, 63% of men had died. Overall relative risk of metastatic (M+) disease and prostate cancer (PCa) death was 0.46 (95% confidence interval [CI]: 0.19-1.11) and 0.48 (95% CI: 0.17-1.36), respectively, in favor of screening. This ERSPC Rotterdam pilot 1 study cohort, screened in a period without noteworthy contamination, shows that PSA-based screening could result in considerable reductions of M+ disease and mortality which if confirmed in larger datasets should trigger further discussion on pros/cons of PCa screening. PATIENT SUMMARY: In a cohort with 19yr of follow-up, we found indications for a more substantial reduction in metastatic disease and cancer-specific mortality in favor of prostate cancer screening than previously reported. If confirmed in larger cohorts, these findings should be considered in the ongoing discussion on harms and benefits of prostate cancer screening.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Purpose: We determined the characteristics of Chinese men undergoing initial prostate biopsy and evaluated the relationship between prostate specific antigen levels and prostate cancer/high grade prostate cancer detection in a large Chinese multicenter cohort.Materials and Methods: This retrospective study included 13,904 urology outpatients who had undergone biopsy for the indications of prostate specific antigen greater than 4.0 ng/ml or prostate specific antigen less than 4.0 ng/ml but with abnormal digital rectal examination results. The prostate specific antigen measurements were performed in accordance with the standard procedures at the respective institutions. The type of assay used was documented and recalibrated to the WHO standard.Results: The incidence of prostate cancer and high grade prostate cancer was lower in the Chinese cohort than the Western cohorts at any given prostate specific antigen level. Around 25% of patients with a prostate specific antigen of 4.0 to 10.0 ng/ml were found to h...

Purpose: The balance of benefits and harms in prostate cancer screening has not been sufficiently characterized. We related indicators of mortality reduction and overdetection by center within the European Randomized Study of Prostate Cancer Screening (ERSPC). Experimental Design: We analyzed the absolute mortality reduction expressed as number needed to invite (NNI = 1/absolute risk reduction; indicating how many men had to be randomized to screening arm to avert a prostate cancer death) for screening and the absolute excess of prostate cancer detection as number needed for overdetection (NNO = 1/absolute excess incidence; indicating the number of men invited per additional prostate cancer case), and compared their relationship across the seven ERSPC centers. Results: Both absolute mortality reduction (NNI) and absolute overdetection (NNO) varied widely between the centers: NNI, 200–7,000 and NNO, 16–69. Extent of overdiagnosis and mortality reduction was closely associated [correlation coefficient, r = 0.76; weighted linear regression coefficient, β = 33; 95% confidence interval (CI), 5–62; R2 = 0.72]. For an averted prostate cancer death at 13 years of follow-up, 12 to 36 excess cases had to be detected in various centers. Conclusions: The differences between the ERSPC centers likely reflect variations in prostate cancer incidence and mortality, as well as in screening protocol and performance. The strong interrelation between the benefits and harms suggests that efforts to maximize the mortality effect are bound to increase overdiagnosis and might be improved by focusing on high-risk populations. The optimal balance between screening intensity and risk of overdiagnosis remains unclear. Clin Cancer Res; 22(1); 243–9. ©2015 AACR.

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

Purpose: We assessed differences in treatment between the screening and control arms of ERSPC Rotterdam and studied whether possible treatment differences could explain the positive study outcome. Materials and Methods: In ERSPC Rotterdam men 55 to 74 years old were randomized to a screening arm of 21,210 and a control arm of 21,166. Treatment after diagnosis was at the discretion of the care provider chosen by the patient. Initial treatment was compared in 4 risk groups. The relation between prostate cancer incidence and prostate cancer mortality was assessed by risk group by correlating the incidence RR and the mortality RR. A direct relation would have supported a stage shift as the main cause of changes in prostate cancer mortality. Results: Initial treatment differed between the arms in the low, intermediate and high risk groups but not in the metastatic group. The RRs of prostate cancer incidence and mortality per risk group were related 1:1 (regression line slope 1.00, 95% CI 0.30-1.74). Of changes in prostate cancer mortality 94% could be explained by changes in prostate cancer incidence. This made treatment differences unlikely as the reason for the observed decrease in prostate cancer mortality. Conclusions: Differences in treatment between the ERSPC Rotterdam screening and control arms were unlikely to explain the differences in prostate cancer mortality. Results are instead consistent with a decrease in prostate cancer mortality as the result of a favorable stage through screening.

Screening for a disease must be clearly defined and differentiated from early detection. ‘Screening’ refers to the application of tests to the whole population or to defined segments such as males within certain defined high risk age groups. If applied in such a fashion ‘screening’ for prostate cancer may also be described epidemiologically as ‘secondary prevention’. While high-quality randomized studies show that screening reduces prostate cancer mortality by 21–44%, there is wide agreement that the introduction of population-based screening is at present premature because harms, mainly the high rate of overdiagnosis seen currently outweighs the benefits. This chapter attempts to put current knowledge into perspective with a set of recognized prerequirements for the application of screening, established by Wilson and Jungner in 1968.

Background: The European Randomised study of Screening for Prostate Cancer (ERSPC) is a multicentre, randomised screening trial on men aged 55-69 years at baseline without known prostate cancer (PrCa) at randomisation to an intervention arm invited to screening or to a control arm. The ERSPC has shown a significant 21% reduction in PrCa mortality at 13 years of follow-up. The effect of screening appears to vary across centres, for which several explanations are possible. We set to assess if the apparent differences in PrCa mortality reduction between the centres can be explained by differences in screening protocols. Methods: We examined the centre differences by developing a simulation model and estimated how alternative screening protocols would have affected PrCa mortality. Results: Our results showed outcomes similar to those observed, when the results by centres were reproduced by simulating the screening regimens with PSA threshold of 3 versus 4 ng/ml, or screening interval of two versus four years. The findings suggest that the differences are only marginally attributable to the different screening protocols. Conclusion: The small screening impact in Finland was not explained by the differences in the screening protocols. A possible reason for it was the contamination of and the unexpectedly low PrCa mortality in the Finnish control arm. (C) 2016 Elsevier Ltd. All rights reserved.

ObjectivePatients with potentially indolent prostate cancer (PC) can be managed with active surveillance (AS). Our objective was to analyse how anxiety and distress develop in men with untreated PC and whether highly anxious men quit AS. MethodsOne hundred and fifty Dutch patients who opted for AS in the Prostate cancer Research International: Active Surveillance Study were invited to participate in an additional prospective, longitudinal quality of life (QoL) study within 6months after diagnosis. Participants completed questionnaires with validated measures on anxiety and distress at inclusion (t=0), 9 (t=9) and 18 (t=18) months after diagnosis. We assessed changes in scores on depression (Center for Epidemiologic Studies Depression (CES-D) scale), generic anxiety (State-Trait Anxiety Inventory (STAI-6)), PC-specific anxiety (Memorial Anxiety Scale for Prostate Cancer (MAX-PC)) and decisional conflict (Decisional Conflict Scale (DCS)) about patients' treatment choice between t=0, t=9 and t=18 using repeated measures analysis. ResultsResponse rates for patients still on AS at t=0, t=9 and t=18 assessments were 86%, 90% and 96%, respectively. Nine patients (7%, 9/129) between t=0 and t=9 and 33 of 108 patients (31%) between t=9 and t=18 stopped AS, mostly (86%) because of protocol-based reasons. CES-D, total MAX-PC and DCS scores did not change significantly (p>0.05) when comparing t=18 with t=9 and t=0 scores, but generic anxiety (STAI-6; p=0.033) and fear of disease progression (sub-score of the MAX-PC; p=0.007) decreased significantly. These differences, however, were clinically modest (0.089 SD and 0.281 SD). Overall, six of 129 men (5%) discontinued AS because of anxiety and distress. ConclusionsWhen men with low-risk PC are managed with AS, fear of disease progression and general anxiety decreased, and only few may discontinue AS because of anxiety and distress. This suggests that negative QoL effects are limited in men with favourable clinical characteristics who opted for AS. (Registered trial number, NTR1718) Copyright (c) 2014 John Wiley & Sons, Ltd

To compare intermittent treatment (IT) versus continuous treatment (CT) using cyproterone acetate (CPA) in bone metastatic prostate cancer patients, we conducted an open-label, multicenter randomized trial. Continuous androgen deprivation therapy is the standard treatment in metastatic prostate cancer. Intermittent treatment might maintain efficacy while toxicity and costs are reduced. Patients received CPA 100 mg tid in the prephase. Patients with a PSA decline of a parts per thousand yen90 % or PSA < 4 ng/ml were randomized. If patients were progressive, LHRH analogues were added. Primary end point was time to PSA progression. A total of 366 patients were recruited; 258 reached a good response after 3 or 6 months and were randomized. A total of 131 patients randomized to IT and 127 to CT. Patients on IT had an average of 1.7 episodes on CPA, before LHRH analogues were started. The mean time without treatment in IT was 463 days versus 422 days on treatment. There were statistical significant differences between IT and CT in 3 of the 5 functional scales of EORTC QLQ C 30; however, the clinical relevance of this finding appears modest. Symptom and potency scales showed significant advantages for IT. There were no differences in time to PSA progression on CPA, time to PSA and/or clinical progression on LHRH analogues and time to cancer-specific and overall survival. IT by CPA is associated with less symptoms and modest advantages in QOL domains. There were no differences in time to PSA progression, clinical progression or survival.

OBJECTIVES: To assess the applicability of the Prostate Cancer Prevention Trial High Grade (Gleason grade ≥ 7) Risk Calculator (PCPTHG) in ten international cohorts, representing a range of populations. METHODS: A total of 25,512 biopsies from 10 cohorts (6 European, 1 UK and 3 US) were included; 4 implemented 6-core biopsies, and the remaining had 10 or higher schemes; 8 were screening cohorts, and 2 were clinical. PCPTHG risks were calculated using prostate-specific antigen, digital rectal examination, age, African origin and history of prior biopsy and evaluated in terms of calibration plots, areas underneath the receiver operating characteristic curve (AUC) and net benefit curves. RESULTS: The median AUC of the PCPTHG for high-grade disease detection in the 10- and higher-core cohorts was 73.5% (range, 63.9-76.7%) compared with a median of 78.1% (range, 72.0-87.6%) among the four 6-core cohorts. Only the 10-core Cleveland Clinic cohort showed clear evidence of under-prediction by the PCPTHG, and this was restricted to risk ranges less than 15%. The PCPTHG demonstrated higher clinical net benefit in higher-core compared with 6-core biopsy cohorts, and among the former, there were no notable differences observed between clinical and screening cohorts, nor between European and US cohorts. CONCLUSIONS: The PCPTHG requires minimal patient information and can be applied across a range of populations. PCPTHG risk thresholds ranging from 5 to 20%, depending on patient risk averseness, are recommended for clinical prostate biopsy decision-making.

OBJECTIVE To demonstrate the safety and efficacy of up to 5 years of degarelix treatment and the effects of crossing over from leuprolide to degarelix in the extension phase of a phase III pivotal 1-year trial. METHODS Patients receiving degarelix who completed the 1-year trial continued on 80 mg (n = 125) or 160 mg (n = 126) maintenance doses. Patients who received leuprolide were rerandomized to degarelix 240/80 mg (n = 69) or 240/160 mg (n = 65). Safety and tolerability were assessed (primary end point), as well as testosterone and prostate-specific antigen levels and prostate-specific antigen progression-free survival (secondary end points). RESULTS Adverse event frequency was similar between both the groups. Adverse events included initial injection site reactions, hot flushes, and increased weight. Testosterone and prostate-specific antigen values during the extension study were similar to those seen during the 1-year trial in patients who continued on degarelix or crossed over from leuprolide. The prostate-specific antigen progression-free survival hazard rate was decreased significantly after the crossover in the leuprolide to degarelix group (from 0.20 to 0.09; P = .002), whereas in patients who continued on degarelix, the rate did not change significantly. In patients with baseline prostate-specific antigen > 20 ng/mL, the same hazard rate change pattern was observed on crossover (from 0.38 to 0.19; P = .019). CONCLUSION Degarelix was well tolerated; no safety concerns were identified. The significant prostate-specific antigen progression-free survival benefit established for degarelix over leuprolide during year 1 remained consistent at 5 years. UROLOGY 83: 1122-1128, 2014. (C) 2014 Elsevier Inc.

BACKGROUND Stem cells are postulated to mediate prostate cancer progression, and represent a small fraction of the entire tumor. Various proteins (α2-integrin, α6-integrin, CD117, CD133, EZH2, OCT3/4) are associated with a prostate cancer stem cell phenotype in cell lines and xenografts. Our objective was to investigate expression of stem cell markers in clinical prostate cancer in relation to outcome. METHODS We validated immunohistochemical expression of stem cell markers in 481 prostate cancer patients and correlated expression with clinicopathologic parameters. RESULTS Sporadic expression of α2-integrin was present in a fraction of tumor cells ( 10 ng/ml (P = 0.04). α6-Integrin expression (

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 Gteborg (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 Gteborg. 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 Gteborg). 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. (Less)

Active surveillance (AS) is an important management strategy for men diagnosed with low-risk prostate cancer (PCa). The need for AS is increasing due to the awareness that many PCa are identified that show a low growth potential and therefore are likely to remain clinically asymptomatic during the lifetime of an individual. Currently there is no good method to prevent the overdiagnosis of indolent cancers upfront. During the last decade, several studies on AS around the world have made observations that feed the discussion on how to select and monitor these patients, how to proceed with the research to develop a better and more precise clinical definition of indolent cancers and how to manage men under AS clinically. Furthermore, patients' perspectives have become clearer, and quality of life studies give direction to the practical approach and care for patients and partners. This paper reflects the consensus on the state of the art and the future direction of AS, based on the Inside Track Conference "Active Surveillance for low risk prostate cancer" (Chairmen: C.H. Bangma, NL, and L. Klotz, CA; Co-Chairmen: L.J. Denis, BE, and C. Parker, UK; Scientific Coordinators: M. J. Roobol, NL, and E.W. Steyerberg, NL), organized by the European School of Oncology in collaboration with Europa Uomo in Rotterdam, the Netherlands in January 2012. Topics for discussion were the optimisation of patient selection based on indolent disease definition, the incorporation of therapeutic agents into AS programs, the optimisation of patient care, and the application of emerging technologies and biomarkers.

Background: Men with screen-detected prostate cancer can choose to undergo immediate curative treatment or enter into an expectant management programme. We quantified how the benefits and harms of immediate treatment vary according to the prognostic factors of clinical T-stage, Gleason score, and patient age. Methods: A microsimulation model based on European Randomized Study of Screening for Prostate Cancer data was used to predict the benefits and harms of immediate treatment versus delayed treatment of local–regional prostate cancer in men aged 55–74 years. Benefits included life-years gained and reduced probability of death from prostate cancer. Harms included lead time and probability of overdiagnosis. Results: The ratio of mean lead time to mean life-years gained ranged from 1.8 to 31.2, and the additional number of treatments required per prostate cancer death prevented ranged from 0.3 to 11.6 across the different prognostic groups. Both harm–benefit ratios were lowest, most favourable, for men aged 55–59 years and diagnosed with moderate-risk prostate cancer. Ratios were high for men aged 70–74 years regardless of clinical T-stage and Gleason score. Conclusion: Men aged 55–59 years with moderate-risk prostate cancer are predicted to derive greatest benefit from immediate curative treatment. Immediate treatment is least favourable for men aged 70–74 years with either low-risk or high-risk prostate cancer.

Despite the prevalence of hypogonadism (HG) and widespread use of testosterone therapy, little is known about the safety/effectiveness of long-term testosterone use. The Registry of Hypogonadism in Men (RHYME) is a multi-national patient registry assessing prostate health and other outcomes associated with testosterone treatment in men.Observational patient disease registry.RHYME is a non-interventional disease registry with longitudinal data collection on a large sample (N = 999) of well-characterized, hypogonadal men aged 18 years or older. The Registry will prospectively evaluate male patients diagnosed with HG, who have not previously been treated with testosterone therapy. Key design features include: (1) broad inclusion/exclusion criteria, (2) standardized central laboratory hormone assays, (3) independent adjudication of prostate biopsies and mortalities, (4) standard of care treatment, (5) comprehensive medical record and questionnaire data at six months and annually post-enrollment and (6) adequate statistical power for assessing prostate endpoints at 36 months.A total of 25 clinical sites in six European countries (Germany, Italy, the Netherlands, Spain, Sweden and the United Kingdom) have completed recruitment for the study. Recruitment was initiated in May 2009, and completed in December 2011. Data collection is ongoing with a minimum of two years of follow-up on all patients.

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.

Objective In addition to disease-specific mortality, a randomized controlled cancer screening trial may be evaluated in terms of excess mortality, in which case no patient-specific information on causes of death is needed. We studied the effect of not accounting for attendance on the calculated excess mortality in a prostate cancer screening trial. Methods The numerator of the excess mortality rate related to prostate cancer diagnoses in each study arm equals the excess number of deaths observed in the cancer patients. The estimation of the expected number of deaths in the absence of the prostate cancer diagnoses has to account for the self-selection of those participating in the trial, particularly if the proportion of non-participants is substantial. Setting The European prostate cancer screening trial (ERSPC). Results In the screening arm, non-attendees had roughly twice the mortality rate of attendees. Approximately twice as many cancers were detected in the screening arm compared with the control arm, primarily in attendees. Unless attendance is properly accounted for, the expected mortality of prostate cancer patients in the screening arm is overestimated by 0.9–3.6 deaths per 1000 person-years. Conclusions Attendees have a lower all-cause mortality rate (are healthier) and a higher probability of a prostate cancer diagnosis than non-attendees and the men randomized to the control arm. If attendance is not accounted for, the excess mortality and the between-arm excess mortality rate ratio are underestimated and screening is considered more effective than it actually is. These effects may be sizeable, notably if non-attendance is common. Correcting for attendance status is important in the calculation of the excess mortality rate in prostate cancer patients that can be used in conjunction with a disease-specific mortality analysis in a randomized controlled cancer screening trial.

Background: Rising prostate-specific antigen (PSA) levels after radical therapy are indicative of recurrent or residual prostate cancer (PCa). This biochemical recurrence typically predates clinically detectable metastatic disease by several years. Management of patients with biochemical recurrence is controversial. Objective: To assess the effect of dutasteride on progression of PCa in patients with biochemical failure after radical therapy. Design, setting, and participants: Randomised, double-blind, placebo-controlled trial in 294 men from 64 centres across 9 European countries. Intervention: The 5α-reductase inhibitor, dutasteride. Outcome measurements and statistical analysis: The primary end point was time to PSA doubling from start of randomised treatment, analysed by log-rank test stratified by previous therapy and investigative-site cluster. Secondary end points included time to disease progression and the proportion of subjects with disease progression. Results and limitations: Of the 294 subjects randomised (147 in each treatment group), 187 (64%) completed 24 mo of treatment and 107 discontinued treatment prematurely (71 [48%] of the placebo group, 36 [24%] of the dutasteride group). Dutasteride significantly delayed the time to PSA doubling compared with placebo after 24 mo of treatment (p < 0.001); the relative risk (RR) reduction was 66.1% (95% confidence interval [CI], 50.35-76.90) for the overall study period. Dutasteride also significantly delayed disease progression (which included PSA- and non-PSA-related outcomes) compared with placebo (p < 0.001); the overall RR reduction in favour of dutasteride was 59% (95% CI, 32.53-75.09). The incidence of adverse events (AEs), serious AEs, and AEs leading to study withdrawal were similar between the treatment groups. A limitation was that investigators were not blinded to PSA levels during the study. Conclusions: Dutasteride delayed the biochemical progression of PCa in patients with biochemical failure after radical therapy for clinically localised disease. The safety and tolerability of dutasteride were generally consistent with previous experience. Clinical trial registry: ClinicalTrials.gov, NCT00558363.

OBJECTIVES: To compare the predictive performance and potential clinical usefulness of risk calculators of the European Randomized Study of Screening for Prostate Cancer (ERSPC RC) with and without information on prostate volume. METHODS: We studied 6 cohorts (5 European and 1 US) with a total of 15,300 men, all biopsied and with pre-biopsy TRUS measurements of prostate volume. Volume was categorized into 3 categories (25, 40, and 60 cc), to reflect use of digital rectal examination (DRE) for volume assessment. Risks of prostate cancer were calculated according to a ERSPC DRE-based RC (including PSA, DRE, prior biopsy, and prostate volume) and a PSA + DRE model (including PSA, DRE, and prior biopsy). Missing data on prostate volume were completed by single imputation. Risk predictions were evaluated with respect to calibration (graphically), discrimination (AUC curve), and clinical usefulness (net benefit, graphically assessed in decision curves). RESULTS: The AUCs of the ERSPC DRE-based RC ranged from 0.61 to 0.77 and were substantially larger than the AUCs of a model based on only PSA + DRE (ranging from 0.56 to 0.72) in each of the 6 cohorts. The ERSPC DRE-based RC provided net benefit over performing a prostate biopsy on the basis of PSA and DRE outcome in five of the six cohorts. CONCLUSIONS: Identifying men at increased risk for having a biopsy detectable prostate cancer should consider multiple factors, including an estimate of prostate volume.

OBJECTIVES: To evaluate the discrimination, calibration, and net benefit performance of the Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) across five European randomized study of screening for prostate cancer (ERSPC), 1 United Kingdom, 1 Austrian, and 3 US biopsy cohorts. METHODS: PCPTRC risks were calculated for 25,733 biopsies using prostate-specific antigen (PSA), digital rectal examination, family history, history of prior biopsy, and imputation for missing covariates. Predictions were evaluated using the areas underneath the receiver operating characteristic curves (AUC), discrimination slopes, chi-square tests of goodness of fit, and net benefit decision curves. RESULTS: AUCs of the PCPTRC ranged from a low of 56% in the ERSPC Goeteborg Rounds 2-6 cohort to a high of 72% in the ERSPC Goeteborg Round 1 cohort and were statistically significantly higher than that of PSA in 6 out of the 10 cohorts. The PCPTRC was well calibrated in the SABOR, Tyrol, and Durham cohorts. There was limited to no net benefit to using the PCPTRC for biopsy referral compared to biopsying all or no men in all five ERSPC cohorts and benefit within a limited range of risk thresholds in all other cohorts. CONCLUSIONS: External validation of the PCPTRC across ten cohorts revealed varying degree of success highly dependent on the cohort, most likely due to different criteria for and work-up before biopsy. Future validation studies of new calculators for prostate cancer should acknowledge the potential impact of the specific cohort studied when reporting successful versus failed validation.

BACKGROUND: Most men with elevated levels of prostate-specific antigen (PSA) do not have prostate cancer, leading to a large number of unnecessary biopsies. A statistical model based on a panel of four kallikreins has been shown to predict the outcome of a first prostate biopsy. In this study, we apply the model to an independent data set of men with previous negative biopsy but persistently elevated PSA. METHODS: The study cohort consisted of 925 men with a previous negative prostate biopsy and elevated PSA (>= 3 ngml(-1)), with 110 prostate cancers detected (12%). A previously published statistical model was applied, with recalibration to reflect the lower positive biopsy rates on rebiopsy. RESULTS: The full-kallikrein panel had higher discriminative accuracy than PSA and DRE alone, with area under the curve (AUC) improving from 0.58 (95% confidence interval (CI): 0.52, 0.64) to 0.68 (95% CI: 0.62, 0.74), P= 7) at biopsy with AUC improving from 0.76 (95% CI: 0.64, 0.89) to 0.87 (95% CI: 0.81, 0.94), P 0.003). Application of the panel to 1000 men with persistently elevated PSA after initial negative biopsy, at a 15% risk threshold would reduce the number of biopsies by 712; would miss (or delay) the diagnosis of 53 cancers, of which only 3 would be Gleason 7 and the rest Gleason 6 or less. CONCLUSIONS: Our data constitute an external validation of a previously published model. The four-kallikrein panel predicts the result of repeat prostate biopsy in men with elevated PSA while dramatically decreasing unnecessary biopsies. British Journal of Cancer (2010) 103, 708-714. doi:10.1038/sj.bjc.6605815 www.bjcancer.com Published online 27 July 2010 (C) 2010 Cancer Research UK

Purpose We previously reported that a panel of four kallikrein forms in blood—total, free, and intact prostate-specific antigen (PSA) and kallikrein-related peptidase 2 (hK2)—can reduce unnecessary biopsy in previously unscreened men with elevated total PSA. We aimed to replicate our findings in a large, independent, representative, population-based cohort. Patients and Methods The study cohort included 2,914 previously unscreened men undergoing biopsy as a result of elevated PSA (≥ 3 ng/mL) in the European Randomized Study of Screening for Prostate Cancer, Rotterdam, with 807 prostate cancers (28%) detected. The cohort was randomly divided 1:3 into a training and validation set. Levels of kallikrein markers were compared with biopsy outcome. Results Addition of free PSA, intact PSA, and hK2 to a model containing total PSA and age improved the area under the curve from 0.64 to 0.76 and 0.70 to 0.78 for models without and with digital rectal examination results, respectively (P < .001 for both). Application of the panel to 1,000 men with elevated PSA would reduce the number of biopsies by 513 and miss 54 of 177 low-grade cancers and 12 of 100 high-grade cancers. Findings were robust to sensitivity analysis. Conclusion We have replicated our previously published finding that a panel of four kallikreins can predict the result of biopsy for prostate cancer in men with elevated PSA. Use of this panel would dramatically reduce biopsy rates. A small number of men with cancer would be advised against immediate biopsy, but these men would have predominately low-stage, low-grade disease.

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

Background Metastatic disease is a major morbidity of prostate cancer (PCa). Its prevention is an important goal. Objective To assess the effect of screening for PCa on the incidence of metastatic disease in a randomized trial. Design, setting, and participants Data were available for 76 813 men aged 55–69 yr coming from four centers of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The presence of metastatic disease was evaluated by imaging or by prostate-specific antigen (PSA) values >100 ng/ml at diagnosis and during follow-up. Intervention Regular screening based on serum PSA measurements was offered to 36270 men randomized to the screening arm, while no screening was provided to the 40543 men in the control arm. Outcome measurements and statistical analysis The Nelson-Aalen technique and Poisson regression were used to calculate cumulative incidence and rate ratios of M+ disease. Results and limitations After a median follow-up of 12 yr, 666 men with M+ PCa were detected, 256 in the screening arm and 410 in the control arm, resulting in cumulative incidence of 0.67% and 0.86% per 1000 men, respectively ( p p =0.001) in the intention-to-screen analysis and a 42% ( p =0.0001) reduction for men who were actually screened. An absolute risk reduction of metastatic disease of 3.1 per 1000 men randomized (0.31%) was found. A large discrepancy was seen when comparing the rates of M+ detected at diagnosis and all M+ cases that emerged during the total follow-up period, a 50% reduction (HR: 0.50; 95% CI, 0.41–0.62) versus the 30% reduction. The main limitation is incomplete explanation of the lack of an effect of screening during follow-up. Conclusions PSA screening significantly reduces the risk of developing metastatic PCa. However, despite earlier diagnosis with screening, certain men still progress and develop metastases. The ERSPC trial is registered under number ISRCTN49127736.

• Prostate-specific antigen (PSA) has been widely applied to diagnosis and follow-up of prostate cancer, which led to research on its potential role in the early detection of the disease and its use in screening. • The value of PSA screening in reducing disease mortality is controversial and several studies have been conducted to determine the actual benefits. One of the early studies, the Tyrol Screening Study conducted in 1993, showed that during 2004 to 2008 there was a significant reduction in prostate cancer mortality in men aged >60 years compared with the mortality rate during 1989 to 1993. • Two studies that showed no benefit of screening in terms of prostate cancer death were conducted in Sweden in 1987 and 1988. • The Prostate, Lung, Colorectal, and Ovarian Screening Study conducted in the USA during 1993 to 2001 and involving 76 693 men showed no benefit of screening at 10 years but the trial can be criticised due to excessive contamination of the unscreened group. • In contrast, the European Randomized Study of Screening for Prostate Cancer (ERSPC), the largest randomised study with 162 388 participants study, showed that at a median follow-up of 9 years a prostate cancer mortality reduction of 20% resulted (P= 0.04). In an analysis limited to four ERSPC centres with a follow-up of 12.0 years, screening resulted in an overall reduction of metastatic disease of 31%. • The arguments against PSA screening include the risks associated with screening tests themselves, e.g. biopsy-related haematuria, urosepsis, and over diagnosis and overtreatment of prostate cancer. The overall evidence points in favour of PSA screening and steps can be taken to avoid overtreatment by offering patients active surveillance.

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.

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.

Since Huggins and Hodges demonstrated the responsiveness of prostate cancer to androgen deprivation therapy (ADT), androgen-suppressing strategies have formed the cornerstone of management of advanced prostate cancer. Approaches to ADT have included orchidectomy, oestrogens, luteinizing hormone-releasing hormone (LHRH) agonists, anti-androgens and more recently the gonadotrophin-releasing hormone antagonists. The most extensively studied antagonist, degarelix, avoids the testosterone surge and clinical flare associated with LHRH agonists, offering more rapid PSA and testosterone suppression, improved testosterone control and improved PSA progression-free survival compared with agonists. The clinical profile of degarelix appears to make it a particularly suitable therapeutic option for certain subgroups of patients, including those with metastatic disease, high baseline PSA (>20 ng/mL) and highly symptomatic disease. As well as forming the mainstay of treatment for advanced prostate cancer, ADT is increasingly used in earlier disease stages. While data from clinical trials support the use of ADT neoadjuvant/adjuvant to radiotherapy for locally advanced or high-risk localized prostate cancer, it remains to be established whether specific ADT classes/agents provide particular benefits in this clinical setting.

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 60 cm(3)) 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. (C) 2011 European Association of Urology. Published by Elsevier B. V. All rights reserved.

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.

Contains fulltext : 109206.pdf (Publisher’s version ) (Open Access) BACKGROUND: Accurate pretreatment assessment of prostate cancer (PCa) aggressiveness is important in decision making. Gleason grade is a critical predictor of the aggressiveness of PCa. Transrectal ultrasound-guided biopsies (TRUSBxs) show substantial undergrading of Gleason grades found after radical prostatectomy (RP). Diffusion-weighted magnetic resonance imaging (MRI) has been shown to be a biomarker of tumour aggressiveness. OBJECTIVE: To improve pretreatment assessment of PCa aggressiveness, this study prospectively evaluated MRI-guided prostate biopsies (MR-GBs) of abnormalities determined on diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) maps. The results were compared with a 10-core TRUSBx cohort. RP findings served as the gold standard. DESIGN, SETTING, AND PARTICIPANTS: A 10-core TRUSBx (n=64) or MR-GB (n=34) was used for PCa diagnosis before RP in 98 patients. MEASUREMENTS: Using multiparametric 3-T MRI: T2-weighted, dynamic contrast-enhanced imaging, and DWI were performed to identify tumour-suspicious regions in patients with a negative TRUSBx. The regions with the highest restriction on ADC maps within the suspicions regions were used to direct MR-GB. A 10-core TRUSBx was used in a matched cohort. Following RP, the highest Gleason grades (HGGs) in biopsies and RP specimens were identified. Biopsy and RP Gleason grade results were evaluated using chi-square analysis. RESULTS AND LIMITATIONS: No significant differences on RP were observed for proportions of patients having a HGG of 3 (35% vs 28%; p=0.50), 4 (32% vs 41%; p=0.51), and 5 (32% vs 31%; p=0.61) for the MR-GB and TRUSBx cohort, respectively. MR-GB showed an exact performance with RP for overall HGG: 88% (30 of 34); for TRUS-GB it was 55% (35 of 64; p=0.001). In the MR-GB cohort, an exact performance with HGG 3 was 100% (12 of 12); for HGG 4, 91% (10 of 11); and for HGG 5, 73% (8 of 11). The corresponding performance rates for TRUSBx were 94% (17 of 18; p=0.41), 46% (12 of 26; p=0.02), and 30% (6 of 20; p=0.01), respectively. CONCLUSIONS: This study shows prospectively that DWI-directed MR-GBs significantly improve pretreatment risk stratification by obtaining biopsies that are representative of true Gleason grade. 01 januari 2012

Objective To assess the impact of different study designs on outcome data within the European Randomized Study of Screening for Prostate Cancer (ERSPC). Methods Observed data from the Gothenburg centre (effectiveness trial with upfront randomization before informed consent) and the Rotterdam centre (efficacy trial with randomization after informed consent) were compared with expected data, which were retrieved from national cancer registries and life tables. Endpoints were 11-year cumulative prostate cancer (PC) incidence, overall mortality and PC-specific mortality. Results In Gothenburg, the 11-year PC incidence was higher than predicted (5.8%) in both the intervention (12.4%) and control arms (7.3%). The observed overall mortality was higher than predicted (15.9%) in both the intervention (17.8%) and control arms (18.5%). The observed PC-specific mortality in the intervention arm was 0.56% versus 0.83% in the control arm, while the expected mortality was 0.83%. In Rotterdam, the observed PC incidence in the intervention arm (10.4%) was higher than expected (4.4%). The incidence in the control arm was 4.6%. The observed overall mortality was lower than expected: 13.6% in the intervention arm and 14.0% in the control arm versus an expected mortality of 16.1%. The observed PC-specific mortality was lower than expected (0.65%) in both the intervention (0.27%) and control arms (0.41%). Conclusions Our results suggest that an efficacy trial with informed consent prior to randomization may have introduced a ‘healthy screenee bias’. Therefore, an effectiveness trial with consent after randomization may more accurately estimate the PC-specific mortality reduction if population-based screening is introduced.

Background After 11 years of follow-up, the European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 29% reduction in prostate-cancer mortality among men who underwent screening for prostate-specific antigen (PSA) levels. However, the extent to which harms to quality of life resulting from overdiagnosis and treatment counterbalance this benefit is uncertain. Methods On the basis of ERSPC follow-up data, we used Microsimulation Screening Analysis (MISCAN) to predict the number of prostate cancers, treatments, deaths, and quality-adjusted life-years (QALYs) gained after the introduction of PSA screening. Various screening strategies, efficacies, and quality-of-life assumptions were modeled. Results Per 1000 men of all ages who were followed for their entire life span, we predicted that annual screening of men between the ages of 55 and 69 years would result in nine fewer deaths from prostate cancer (28% reduction), 14 fewer men receiving palliative therapy (35% reduction), and a total of 73 life-years gained (average, 8.4 years per prostate-cancer death avoided). The number of QALYs that were gained was 56 (range, -21 to 97), a reduction of 23% from unadjusted life-years gained. To prevent one prostate-cancer death, 98 men would need to be screened and 5 cancers would need to be detected. Screening of all men between the ages of 55 and 74 would result in more life-years gained (82) but the same number of QALYs (56). Conclusions The benefit of PSA screening was diminished by loss of QALYs owing to postdiagnosis long-term effects. Longer follow-up data from both the ERSPC and quality-of-life analyses are essential before universal recommendations regarding screening can be made. (Funded by the Netherlands Organization for Health Research and Development and others.)

Context: Prostate cancer screening is highly controversial, including the age to begin prostate-specific antigen (PSA) testing. Several studies have evaluated the usefulness of baseline PSA measurements at a young age. Objective: Review the literature on baseline PSA testing at a young age (

The complications of prostate needle biopsy (PNB) are important when considering the benefits and harms of prostate cancer screening. Studies from the United States and Canada have recently reported increasing numbers of hospitalizations for infectious complications after PNB.Examine the risk of infectious complications and hospital admissions after PNB in a European screening trial.From 1993 to 2011, 10 474 PNBs were performed in the European Randomized Study of Screening for Prostate Cancer (Rotterdam section). Prophylaxis originally consisted of trimethoprim-sulfamethoxazole. Beginning in 2008, it was changed to ciprofloxacin.Febrile complications and hospital admissions were assessed by questionnaires 2 wk after PNB. Logistic regression was used to identify risk factors for biopsy-related fever and hospital admission.Fever and hospital admission were reported on 392 of 9241 questionnaires (4.2%) and 78 of 9198 questionnaires (0.8%), respectively. Although most fevers were managed on an outpatient basis, 81% of hospital admissions were for infection. Of the 56 available blood cultures, 34 were positive with Escherichia coli as the predominant organism. On multivariable analysis, prostate enlargement and diabetes were significantly associated with an increased risk of fever after PNB, whereas later year of biopsy was the only factor significantly associated with an increased risk of hospital admission.In a European screening trial,5% PNBs resulted in febrile complications. Significant risk factors included diabetes and prostatic enlargement. Although most fevers were managed on an outpatient basis, infection remained the leading cause of hospital admission after PNB. Consistent with prior international reports, the frequency of hospital admissions after PNB significantly increased over time. Nevertheless, the absolute frequency of hospital admissions related to PNB was low and should not dissuade healthy men who would benefit from early prostate cancer diagnosis from undergoing biopsy when clinically indicated.

Purpose: We investigated the efficacy and safety of degarelix treatment and the effects of switching from leuprolide to degarelix in an ongoing extension study with a median 27.5-month followup of a pivotal 1-year prostate cancer trial. Materials and Methods: Patients who completed a 1-year pivotal phase III trial continued on the same monthly degarelix maintenance dose (160 or 80 mg in 125 each), or were re-randomized from leuprolide 7.5 mg to degarelix 240/80 mg (69) or 240/160 mg (65). Data are shown on the approved degarelix 240/80 mg dose. The primary end point was safety/tolerability and the secondary end points were testosterone, prostate specific antigen, luteinizing hormone and follicle-stimulating hormone responses, and prostate specific antigen failure and progression-free survival. Results: During followup testosterone and prostate specific antigen suppression were similar to those in the 1-year trial in patients who continued on degarelix or switched from leuprolide. The prostate specific antigen progression-free survival hazard rate was decreased significantly after the switch in the leuprolide/degarelix group while the rate in those who continued on degarelix was consistent with the rate in treatment year 1. The same hazard rate change pattern occurred in the group with baseline prostate specific antigen greater than 20 ng/ml. Adverse event frequency was similar between the groups and decreased with time. Conclusions: Data support the statistically significant prostate specific antigen progression-free survival benefit for degarelix over leuprolide seen during year 1 and the use of degarelix as first line androgen deprivation therapy as an alternative to a gonadotropin-releasing hormone agonist.

BACKGROUND We developed a Korean Prostate Cancer Risk Calculator (KPCRC) for predicting the probability of a positive initial prostate biopsy using clinical and laboratory data from a Korean male population (http://pcrc.korea.ac.kr). We compared its performance to prostate-specific antigen (PSA) testing and the Prostate Risk Calculator 3 (PRC 3) based on data from the Dutch part of European Randomized Study of Screening for Prostate Cancer (ERSPC), which predicts biopsy results for previously unscreened men. METHODS Data were collected from 602 Korean men who were previously unscreened and underwent initial ten-core prostate biopsies. Multiple logistic regression analysis was performed to determine the significant predictors. Area under the receiver operating characteristic curve (AUC) and calibration plots of both calculators were evaluated. RESULTS Prostate cancer (PCa) was detected in 172 (28.6%) men. Independent predictors of a positive biopsy included advanced age, elevated PSA levels, reduced volume of the transition zone, and abnormal digital rectal examination findings. The AUC of the KPCRC was higher than the PRC 3 and PSA alone on internal and external validation. Calibration plots of the KPCRC showed better performance than the other models on internal and external validation. Applying a cut-off of 10% of KPCRC implied that 251 of the 602 men (42%) would not have been biopsied and that 12 of the 172 PCa cases (7%) would not have been diagnosed. CONCLUSIONS The KPCRC improves the performance of the PRC 3 and PSA testing in predicting Korean population's risk of PCa. It implies that Asian populations need their own risk calculators for PCa. Prostate 72:721–729, 2012. © 2011 Wiley Periodicals, Inc.

Context Prostate cancer (PCa) is the most common cancer in the adult male, and benign prostatic hyperplasia (BPH) represents the most frequent urologic diagnosis in elderly males. Recent data suggest that prostatic inflammation is involved in the pathogenesis and progression of both conditions. Objective This review aims to evaluate the available evidence on the role of prostatic inflammation as a possible common denominator of BPH and PCa and to discuss its possible clinical implication for the management, prevention, and treatment of both diseases. Evidence acquisition The National Library of Medicine Database was searched for the following Patient population, Intervention, Comparison, Outcome (PICO) terms: male, inflammation, benign prostatic hyperplasia, prostate cancer, diagnosis, progression, prognosis, treatment, and prevention. Basic and clinical studies published in the past 10 yr were reviewed. Additional references were obtained from the reference list of full-text manuscripts. Evidence synthesis The histologic signature of chronic inflammation is a common finding in benign and malignant prostate tissue. The inflammatory infiltrates are mainly represented by CD3 + T lymphocytes (70–80%, mostly CD4), CD19 or CD20 B lymphocytes (10–15%), and macrophages (15%). Bacterial infections, urine reflux, dietary factors, hormones, and autoimmune response have been considered to cause inflammation in the prostate. From a pathophysiologic standpoint, tissue damage associated with inflammatory response and subsequent chronic tissue healing may result in the development of BPH nodules and proliferative inflammatory atrophy (PIA). The loss of glutathione S-transferase P1 (GSTP1) may be responsible in patients with genetic predisposition for the transition of PIA into high-grade intraepithelial neoplasia (HGPIN) and PCa. Although there is growing evidence of the association among inflammatory response, BPH, and PCa, we can only surmise on the immunologic mechanisms involved, and further research is required to better understand the role of prostatic inflammation in the initiation of BPH and PCa. There is not yet proof that targeting prostate inflammation with a pharmacologic agent results in a lower incidence and progression or regression of either BPH or PCa. Conclusions Evidence in the peer-reviewed literature suggested that chronic prostatic inflammation may be involved in the development and progression of chronic prostatic disease, such as BPH and PCa, although there is still no evidence of a causal relation. Inflammation should be considered a new domain in basic and clinical research in patients with BPH and PCa.

OBJECTIVES: • To investigate whether cysteine-rich secretory protein 3 (CRISP-3) and/or β-microseminoprotein (β-MSP) expression in diagnostic prostate needle biopsies have predictive value for prostate cancer (PC) on radical prostatecomy (RP). • To evaluate their potential clinical implementation in a preoperative setting. PATIENTS AND METHODS: • In total, 174 participants from the European Randomized Study of Screening for Prostate Cancer, Rotterdam section, treated by RP for PC were included in the present study. • CRISP-3 and β-MSP immunohistochemistry was performed on corresponding diagnostic needle biopsies. • Outcome was correlated with clinicopathological parameters (prostate-specific-antigen, PSA; number of positive biopsies; Gleason score, GS; pT-stage; surgical margins at RP) and significant PC at RP (pT3/4, or GS > 6, or tumour volume ≥0.5 mL) in the total cohort (n= 174) and in a subgroup with low-risk features at biopsy (PSA ≤ 10 ng/ml, cT ≤ 2, PSA density

Contains fulltext : 96235.pdf (Publisher’s version ) (Closed access) CONTEXT: We addressed the question whether the change of serum prostate-specific antigen (PSA) in men who use 5alpha-reductase inhibitor (5-ARI) dutasteride is sensitive for the detection of aggressive prostate cancer (PCa). OBJECTIVE: The case of a man using dutasteride diagnosed with Gleason 7 transition zone cancer at biopsy indicated by a rising PSA is described. The following issues are discussed: (1) Is a rise of PSA in patients using dutasteride predictive of aggressive PCa in men with prior negative biopsies? (2) Is it safe not to biopsy men using dutasteride who do not show a rising PSA? (3) How can we avoid potentially unnecessary biopsies in men using dutasteride without a rising PSA? EVIDENCE ACQUISITION: We reviewed the recent literature addressing our objective that relates to two studies: the Prostate Cancer Prevention Trial and the Reduction by Dutasteride of Prostate Cancer Events trial. EVIDENCE SYNTHESIS: In men using dutasteride, the positive predictive value/detection rate of Gleason 7-10 PCa is 13.2% and 4.0% for men with and without a rising PSA, respectively. However, a substantial proportion of Gleason 7-10 cases (42.9%) would be missed if a rising PSA was used as the only biopsy indication. Currently available data do not provide selective mechanisms to diagnose these cancers. CONCLUSIONS: A rising PSA for a patient using dutasteride should be an indication for prostate biopsies. Currently, in the case of stable PSA a biopsy may still be considered. Options for a selective approach are therefore suggested in this review to avoid unnecessary biopsies and to achieve a more selective PCa detection in men on 5-ARI treatment. 01 februari 2011