Rotterdam Section Research Articles

Cysteine‐rich secretory protein 3 and β‐microseminoprotein on prostate cancer needle biopsies do not have predictive value for subsequent prostatectomy outcome

• 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. • 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 <0.20 ng/mL/g, GS < 7 and ≤ 2 positive biopsy cores; n= 87). • β-MSP and CRISP-3 expression in PC tissue was heterogeneous, with variable staining intensities occurring in the same tissue specimen. • High expression of β-MSP significantly correlated with GS < 7 at RP; it was not a predictor for significant PC at RP neither in the total group (n= 174; odds ratio, OR, 0.319; 95% confidence interval, CI, 0.060-1.695; P= 0.180), nor in the low-risk group (n= 87; OR, 0.227; 95% CI, 0.040-1.274; P= 0.092). • CRISP-3 expression was not related to clinicopathological parameters, and did not predict significant PC at RP in the total group (n= 174; OR, 1.056; 95% CI, 0.438-2.545; P= 0.904) or the low-risk group (n= 87; OR, 1.856; 95% CI, 0.626-5.506; P= 0.265). • High β-MSP expression correlated with low GS in subsequent RP specimens, supporting the view that β-MSP exerts a tumour-suppressive effect. • No significant prognostic value of β-MSP or CRISP-3 in prostate needle biopsies for significant PC at RP was found. • β-MSP or CRISP-3 do not have additional value in the therapeutic stratification of patients with PC.

Under- and upgrading of prostate cancer after radical prostatectomy in a screening setting.

105 Background: It has been well established that there is an upward drift in assigned Gleason score (GS) to prostate cancer (PC) biopsies. However, few studies have examined the concordance between biopsy GS and pathological GS after radical prostatectomy (RP) in a screening setting over time. We assessed the proportion of under and upgrading of PC after RP by comparing the prevalence screen with the incidence screens from the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam. Methods: From 1993 to 1999, a total of 42.376 men identified from population registries in the Rotterdam region (55-74 yrs) were randomized into a screening or control arm. Men with PSA ≥3.0 ng/ml were recommended for sextant prostate biopsy, which were lateralized since 1996. The screening interval was 4 yrs. Men with screen-detected PC, who underwent RP within 1 yr, were eligible for this study. Results: In all, biopsy and pathological GS were known for 639 men who underwent RP. Of these RPs, 405 were performed between 1994 and 2000 (prevalence screen) whereas 235 cases were performed between 1998 and 2008 (incidence screens). In the prevalence screen, 49.8% of the biopsy GS matched the pathological GS ( Table ). This percentage improved to 58.3% in the incidence screens (p=0.045). The proportion of undergrading after RP was 23.0% in the prevalence screen, which declined to 16.2% in the incidence screens (p=0.049). Upgrading occurred in 27.2% of the cases in the prevalence and 25.5% in the incidence screens (p=0.71). Conclusions: We have demonstrated an improved concordance between biopsy and pathological GS over time by comparing cancers detected in the prevalence screen with those detected in the incidence screens, which is in line with the upward shift of GS classification over time. In addition, significant less undergrading occurred in the incidence screens. However, one should keep in mind that within this screening program still a quarter of the biopsy GS were upgraded after RP in the incidence screens. [Table: see text] [Table: see text]

Prediction of prostate cancer in unscreened men: External validation of a risk calculator

BackgroundPrediction models need external validation to assess their value beyond the setting where the model was derived from. ObjectiveTo assess the external validity of the European Randomized study of Screening for Prostate Cancer (ERSPC) risk calculator (www.prostatecancer-riskcalculator.com) for the probability of having a positive prostate biopsy (P(posb)). Design, setting and participantsThe ERSPC risk calculator was based on data of the initial screening round of the ERSPC section Rotterdam and validated in 1825 and 531 men biopsied at the initial screening round in the Finnish and Swedish sections of the ERSPC respectively. P(posb) was calculated using serum prostate specific antigen (PSA), outcome of digital rectal examination (DRE), transrectal ultrasound and ultrasound assessed prostate volume. MeasurementsThe external validity was assessed for the presence of cancer at biopsy by calibration (agreement between observed and predicted outcomes), discrimination (separation of those with and without cancer), and decision curves (for clinical usefulness). Results and limitationsProstate cancer was detected in 469 men (26%) of the Finnish cohort and in 124 men (23%) of the Swedish cohort. Systematic miscalibration was present in both cohorts (mean predicted probability 34% versus 26% observed, and 29% versus 23% observed, both p<0.001). The areas under the curves were 0.76 and 0.78, and substantially lower for the model with PSA only (0.64 and 0.68 respectively). The model proved clinically useful for any decision threshold compared with a model with PSA only, PSA and DRE, or biopsying all men. A limitation is that the model is based on sextant biopsies results. ConclusionsThe ERSPC risk calculator discriminated well between those with and without prostate cancer among initially screened men, but overestimated the risk of a positive biopsy. Further research is necessary to assess the performance and applicability of the ERSPC risk calculator when a clinical setting is considered rather than a screening setting.

Disease-specific mortality may underestimate the total effect of prostate cancer screening

To study the difference between the disease-specific and excess mortality rate in the European Randomized Study of Screening for Prostate Cancer section Rotterdam. A total of 42,376 men were randomized to systematic screening or usual care. The excess number of deaths was defined as the difference between the observed number of deaths in the prostate cancer (PC) patients and the expected number of deaths up to 31 December 2006. The expected number was derived from mortality of all study participants before a possible diagnosis with PC. The disease-specific mortality rate was based on the number of men who died from PC. The excess mortality rate based on the arm-specific excess number of deaths and the disease-specific mortality rate were compared between the two study arms. The overall mortality rate was not significantly different between the intervention and the control arms of the study: RR 1.02 (95% CI 0.98-1.07). The disease-specific mortality rate was 0.42 men per 1000 person-years in the intervention and 0.48 men per 1000 person-years in the control arm: RR 0.86 (95% CI 0.64-1.17). The excess mortality rate was 0.40 per 1000 person-years in the intervention arm and 0.61 men per 1000 person-years in the control arm, and the RR for excess mortality was 0.66 (95% CI 0.39-1.13). In contrast to the disease-specific mortality rates an increased difference in the excess mortality rates was observed between the two arms. This observation may be due to a systematic underestimation of the disease-specific deaths, and/or an additional disease-related mortality that is measured by an excess mortality analysis but not by a disease-specific mortality.

Blinded and uniform causes of death verification in cancer screening: A major influence on the outcome of a prostate cancer screening trial?

Background To assess the agreement between the causes of death assigned by a blinded and uniform review panel of the Rotterdam section of the European Randomised Study of Screening for Prostate Cancer and the official vital statistics and to explore the possible effect of the use of either of these two sources on the outcome of the screening trial. Methods A total of 670 deaths amongst men with prostate cancer, reviewed by the causes of death committee (CODC) up to 31st December 2006 were included in this study. The kappa statistics with confidence intervals (CI), sensitivity and specificity of the official statistics were determined, with the CODC considered the gold standard. The rate ratio (RR) and 95% confidence intervals (95% CI) for prostate cancer mortality, official statistics relative to CODC, were calculated following the Mantel–Haenszel procedure. Results The overall concordance and the kappa between official statistics and the CODC were 90.6% and 0.76 (0.71–0.82), remaining comparable when only the CODC category definitely prostate cancer was applied, with the sensitivity of official statistics increasing from 88.3% to 91.3% and specificity hardly changing (91.3% and 90.5%). High specificity and lower sensitivity is observed in the screening arm, whilst the opposite was seen in the control arm in men aged 55–69 and 70–74 years at entry. Considerable lower false positive rate was seen for both age groups in the screening arm (3.9% and 4.7%) compared to the control arm (8.4% and 14.3%). A statistically significant excess of prostate cancer death was observed for the official statistics in the age group 70–74 years, 1.53 (1.07–2.19), whilst it was not significant for men aged 55–69 at entry, 1.06 (0.83–1.36). Conclusion In the Rotterdam ERSPC section, official statistics tended to overreport prostate cancer as an underlying cause of death, particularly in the age group 70-plus in the control arm, which would overestimate the true effect in favour of screening.

Performance of Prostate Cancer Antigen 3 (PCA3) and Prostate-Specific Antigen in Prescreened Men: Reproducibility and Detection Characteristics for Prostate Cancer Patients with High PCA3 Scores (≥100)

BackgroundProstate cancer antigen 3 (PCA3) is considered to be prostate cancer (PCa) specific and highly overexpressed in cancer. Therefore a high PCA3 score should result in a high positive predictive value (PPV) and specificity for a positive biopsy. ObjectiveOur aim was to reevaluate, retest PCA3, and rebiopsy men with an initial PCA3 ≥100 and no PCa detected and compare the results with a random cohort of men with an initial PCA3<100. Design, setting, and participantsWe invited men 63–75 yr of age with a PCA3 ≥100 for retesting and a control group with an initial PCA3<100 to participate in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. InterventionsBlood and urine sampling were used to determine prostate-specific antigen (PSA) and PCA3. Prostate biopsies were performed if the PSA was ≥2.5ng/ml and/or the PCA3 score was ≥35. MeasurementsWe correlated the initial and reevaluated PCA3 scores. Our assessment of the PPV after rebiopsy was based on the newly determined PCA3 score. Results and limitationsAfter a mean study period of 19 mo, more cases of PCa were detected in rebiopsied men with initial PCA3 scores ≥100 than in the controls with PCA3 scores <100 (30.0% vs 18.8%). Combining initial and rebiopsy data resulted in a PPV of 52.2% in men with PCA3 ≥100. Over time, changes in PSA and PCA3 levels were quite different. ConclusionsIn spite of our rescreened population, PPV and specificity were comparable with all reported studies of men with PCA3 scores ≥100. These findings do not explain why these PCA3 scores were excessively high in spite of the absence of biopsy-detectable PCa.

Prostate Specific Antigen Velocity Does Not Aid Prostate Cancer Detection in Men With Prior Negative Biopsy

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. 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. 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. 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.

Performance of the Prostate Cancer Antigen 3 (PCA3) Gene and Prostate-Specific Antigen in Prescreened Men: Exploring the Value of PCA3 for a First-line Diagnostic Test

BackgroundThe 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. ObjectiveAssess the value of PCA3 as a first-line diagnostic test. Design, setting and participantsParticipants 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. InterventionsLateral sextant biopsies were performed if the serum PSA value was ≥3.0ng/ml and/or the PCA3 score was ≥10. MeasurementsMeasurements 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 limitationsIn 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. ConclusionsPCA3 as a first-line screening test shows improvement of the performance characteristics and identification of serious disease compared with PSA in this prescreened population.

1729 THE EFFECT OF NON-COMPLIANCE AND PSA TESTING BEFORE STUDY IN THE INTERVENTION ARM OF THE EUROPEAN RANDOMIZED STUDY OF SCREENING FOR PROSTATE CANCER SECTION ROTTERDAM

You have accessJournal of UrologyProstate Cancer: Detection and Screening I1 Apr 20101729 THE EFFECT OF NON-COMPLIANCE AND PSA TESTING BEFORE STUDY IN THE INTERVENTION ARM OF THE EUROPEAN RANDOMIZED STUDY OF SCREENING FOR PROSTATE CANCER SECTION ROTTERDAM Pim Van Leeuwen, Roderick van den Bergh, Tineke Wolters, Fritz Schröder, and Monique Roobol Pim Van LeeuwenPim Van Leeuwen More articles by this author , Roderick van den BerghRoderick van den Bergh More articles by this author , Tineke WoltersTineke Wolters More articles by this author , Fritz SchröderFritz Schröder More articles by this author , and Monique RoobolMonique Roobol More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1577AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate cancer (PC) screening has the potential to reduce the distant metastasis and PC specific mortality. Non-compliers in the intervention arm of the ERSPC Gothenburg were found to be at an increased risk for death from PC with respect to compliers, and men who were screened before study participation in the PLCO trial were found to be at a reduced risk of death from PC. These two screening related effects are analysed using data of the Rotterdam section of the ERSPC. METHODS A total of 21,175 men signed informed consent before study participation. Men who had a PSA test during the 4-years before study entry were identified using a questionnaire, i.e. contaminators. The PC mortality and metastasis were attributed to whether the men were compliers in the screening program (attending at first screening) or non-compliers. The PC deaths and distant metastasis were assessed among contaminators and non-contaminators in the intervention arm. RESULTS Up to the end of 2006, 2,153 (10.2%) men were diagnosed with PC, 121 (0.6%) men developed bone metastases and 79 (0.4%) died of PC. Median follow up was 9.2 years. In total 19,950 (94.2%) men who were compliers and 2,403 (11.3%) men reported having had a PSA test within 4-years before study entry, i.e. contaminators. Both the rates of distant metastasis (0.6% vs 0.6%; P=0.905) and PC-specific mortality (0.4% vs 0.4%; P=0.756) were found not to be different among non-compliers compared with compliers. Furthermore, among the 19,950 compliers, the distant metastasis (0.6% vs 0.5%; P=0.226) and PC-specific mortality (0.4% vs 0.4 %; P=0.994) were found not to be different among the contaminators and non-contaminators. Among the contaminators PC was diagnosed in 312 (13.3%) men, PC was diagnosed in 1793 (10.2%) non-contaminators, P=0.001. CONCLUSIONS The intuitively assumed and proven protective effect of PSA testing before study entry and the increasing risk at PC death among non-compliers in the intervention arm of a screening trial could not be established. The unobserved effect among non-compliers might due to the relative high attendance rate in the ERSPC-Rotterdam, and the difference in the randomization between the ERSPC-Gothenburg (randomization before written informed consent) and the ERSPC-Rotterdam (randomization after written informed consent). The insignificant effect of contamination had minor influence in the ERSPC-Rotterdam which might be due the low biopsy rates in men with moderate elevated PSA in the period 1989-1999 in the Netherlands compared to the US. Rotterdam, Netherlands© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e668 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pim Van Leeuwen More articles by this author Roderick van den Bergh More articles by this author Tineke Wolters More articles by this author Fritz Schröder More articles by this author Monique Roobol More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

124 OUTCOMES OF MEN DIAGNOSED WITH SCREEN-DETECTED PROSTATE CANCER INITIALLY WITHHOLDING RADICAL TREATMENT

You have accessJournal of UrologyProstate Cancer: Epidemiology and Natural History I1 Apr 2010124 OUTCOMES OF MEN DIAGNOSED WITH SCREEN-DETECTED PROSTATE CANCER INITIALLY WITHHOLDING RADICAL TREATMENT Roderick van den Bergh, Pim van Leeuwen, Tineke Wolters, Chris Bangma, Monique Roobol, and Fritz Schröder Roderick van den BerghRoderick van den Bergh More articles by this author , Pim van LeeuwenPim van Leeuwen More articles by this author , Tineke WoltersTineke Wolters More articles by this author , Chris BangmaChris Bangma More articles by this author , Monique RoobolMonique Roobol More articles by this author , and Fritz SchröderFritz Schröder More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.175AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Information on the outcomes of patients with expectantly managed prostate cancer (PC) is increasingly important in an era where a proportion of PCs might be overdiagnosed and do not need radical treatment. We assessed the outcomes of men with screen-detected PC who primarily embarked on a strategy of expectant management. METHODS All patients underwent screening for PC in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), were diagnosed with PC, and initially elected expectant management. Patients with adverse disease (T stage >=3, PSA >=20.0 ng/ml, Gleason >7) were excluded. No fixed protocol for diagnostics during expectant management or switching to deferred radical therapy was applied. We provide an update of the active therapy-free, metastases-free, overall, and PC-specific survival, and last known PSA values. RESULTS Our study cohort consisted of 464 patients, median (25-75p) follow-up 4.5 (1.7-8.2) years after diagnosis (T1: 81%, T2: 19%; Gleason 6: 94%, <6: 6%; median PSA 3.6 (3.0-4.7) ng/ml. The 12-year (21 men at risk) active therapy-free survival was 62%. Radical treatment was delayed in 110 men (24 received deferred prostatectomy, 70 radiation therapy, 16 other) for 1.7 (0.9-3.7) years and avoided so far in 354 men for 3.8 (1.5-7.5) years. Men with more favorable disease remained untreated longer. The 12-year overall and PC-specific survival rates were 70% and 99% respectively. A total of 51 men died due to any cause after 4.9 (3.2-8.3) years. Two men died due to PC: 1 man died 0.5 years after diagnosis during treatment of an abdominal aneurysm that was coincidentally found at dissemination studies of PC, in 1 man (T2a, PSA 3.1, volume 39cc, 2/6 positive biopsies) the window of curability was potentially missed due to the initial expectant management. PSA was 8.8 ng/ml 2 mo after diagnosis (evidence of capsular penetration was also found later), he received radiation therapy 0.8 year after diagnosis, but he died due to PC 5.8 years after diagnosis. No other patients developed metastases during follow-up. At the moment of analysis 23/361 still untreated men had a PSA >10 ng/ml. CONCLUSIONS Initially withholding radical treatment in screen-detected PC may delay or even avoid radical treatments and their side effects. Longer-term follow-up and data of trials randomizing for treatment are indispensable to conclude whether this strategy is associated with adverse outcomes; prospective protocol-based active surveillance studies to develop adequate follow-up protocols. Rotterdam, Netherlands© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e51 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Roderick van den Bergh More articles by this author Pim van Leeuwen More articles by this author Tineke Wolters More articles by this author Chris Bangma More articles by this author Monique Roobol More articles by this author Fritz Schröder More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Prostate-Specific Antigen Screening in the United States vs in the European Randomized Study of Screening for Prostate Cancer–Rotterdam

Dissemination of prostate-specific antigen (PSA) testing in the United States coincided with an increasing incidence of prostate cancer, a shift to earlier stage disease at diagnosis, and decreasing prostate cancer mortality. We compared PSA screening performance with respect to prostate cancer detection in the US population vs in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC–Rotterdam). We developed a simulation model for prostate cancer and PSA screening for ERSPC–Rotterdam. This model was then adapted to the US population by replacing demography parameters with US-specific ones and the screening protocol with the frequency of PSA tests in the US population. We assumed that the natural progression of prostate cancer and the sensitivity of a PSA test followed by a biopsy were the same in the United States as in ERSPC–Rotterdam. The predicted prostate cancer incidence peak in the United States was then substantially higher than the observed prostate cancer incidence peak (13.3 vs 8.1 cases per 1000 man-years). However, the actual observed incidence was reproduced by assuming a substantially lower PSA test sensitivity in the United States than in ERSPC–Rotterdam. For example, for nonpalpable local- or regional-stage cancers (ie, stage T1M0), the estimates of PSA test sensitivity were 0.26 in the United States vs 0.94 in ERSPC–Rotterdam. We conclude that the efficacy of PSA screening in detecting prostate cancer was lower in the United States than in ERSPC–Rotterdam.

Effect of the correction for noncompliance and contamination on the estimated reduction of metastatic prostate cancer within a randomized screening trial (ERSPC section Rotterdam)

The European Randomized study of Screening for Prostate Cancer (ERSPC) has recently reported a 20% reduction in death from prostate cancer in a population-based prostate cancer screening (core age group: 55-69 years of age). The effect of screening may be diluted by noncompliance in the screening arm and contamination by PSA testing in the control arm. The purpose is to analyze the effect of prostate cancer screening on the incidence of metastatic prostate cancer, both with and without adjustment for noncompliance and contamination. We analyzed the occurrence of metastases in 42,376 men aged 55-75 years who were randomized in the Rotterdam section of the ERSPC between 1993 and 1999. Contamination adjustment was based on follow-up findings and questionnaire data from all men in the control group who developed prostate cancer and from a random sample of 291 men without cancer who had a PSA test. Prostate cancer screening significantly reduced the occurrence of metastatic prostate cancer in the intention-to-screen analysis [RR 0.75, 95% CI 0.59-0.95, p = 0.02] and more so in adjusted analyses; contamination adjusted RR 0.73, 95% CI 0.56-0.96; noncompliance adjusted RR 0.72, 95% CI 0.55-0.95 and fully adjusted analysis RR 0.68, 95% CI 0.49-0.94, p = 0.02. In the population of ERSPC Rotterdam (N = 42,376 men), screening reduces the risk to be diagnosed with metastatic prostate cancer considerably on population level, an effect which is even more pronounced in men who are in fact screened.

Prostate cancer mortality in screen and clinically detected prostate cancer: Estimating the screening benefit

BackgroundTo estimate the benefits of prostate-specific antigen (PSA) screening on prostate cancer (Pca) metastasis and Pca-specific mortality, we compared two populations with a well-defined difference in intensity of screening. MethodsBetween 1997 and 1999, a total of 11,970 men, aged 55–74years, were included in the intervention arm of the European Randomised Study of Screening for Prostate Cancer (ERSPC) section Rotterdam. Control population consisted of 133,287 men, aged 55–74years, between 1998 and 1999 in Northern Ireland (NI). Men were followed for Pca incidence, Pca metastasis and cause of death until 31st December 2006. ResultsMedian age in both groups was 63years at study entry (p=0.184). In Rotterdam 94.2% of men and in NI 6% of men underwent PSA testing. In Rotterdam, 1153 men (9.6%) were diagnosed with Pca with median baseline PSA of 5.1ng/ml. In NI, 3962 men (3.0%, p<0.001) were diagnosed with Pca with median baseline PSA of 18.0ng/ml (p<0.001). The relative risk of Pca metastasis during observation in the intervention population compared to control population was 0.47 (95% confidence interval (CI), 0.35–0.63; p<0.001). The relative risk of Pca-specific mortality was also lower in the intervention population compared to the control population after a median follow-up of 8.5years: 0.63 (95% CI, 0.45–0.88; p=0.008); absolute mortality reduction was 1.8 deaths per 1000 men. ConclusionsA relative reduction in Pca metastasis of 53% and Pca mortality of 37% was observed in the intervention population after 8.5years of observation. The impact of overdiagnosis, quality of life benefits and cost-effectiveness need to be assessed before population-based PSA screening can be recommended.

Screening: should more biopsies be taken in larger prostates?

To assess the number of missed prostate cancers and the frequency of aggressive disease when taking lateralized sextant prostate biopsies, irrespective of the total prostate volume (Pvol), during screening for prostate cancer. Men participating in the European Randomized Study of Screening for Prostate Cancer, Rotterdam section, aged 55-74 years, with a prostate-specific antigen (PSA) level of ≥3.0 ng/mL, and a negative sextant biopsy result at the initial screening round, were followed for 8 years. Cases of prostate cancer detected during the follow-up by screening, or detected clinically as interval cancers, were assessed. Pvol at the initial screening round was related to the number of cancers found during the follow-up. Furthermore, the frequency of aggressive cancer (N1 or M1, PSA >20 ng/mL, Gleason >7) was evaluated using multivariate logistic regression analysis, including age, PSA level and Pvol. In the total of 1305 men, 152 prostate cancers were detected during 8 years of follow-up (11.6%); 23 were classified as aggressive (15.1%), and 50 (32.9%) were detected as interval cancers. There was a significant relation between a larger Pvol at the initial screening round and fewer cancers (odds ratio 0.1, P < 0.001). In multivariate logistic regression, the initial PSA level (odds ratio 3.21, 95% confidence interval, CI 1.2-8.3) and smaller Pvol (0.08, 95% CI 0.03-0.26) were statistically significant predictors for all cancers and aggressive cancers (PSA odds ratio 70.37, 95% CI 13.5-366.2; Pvol odds ratio 0.03, 95% CI 0.01-0.35). Men with a smaller Pvol and an initially high PSA level were at greater risk of cancer detection and of an aggressive cancer during the follow-up. The use in clinical practice of volume-adjusted biopsy schemes should not be implemented automatically in screening programmes with repeated screening.

A Risk-Based Strategy Improves Prostate-Specific Antigen–Driven Detection of Prostate Cancer

BackgroundScreening for prostate cancer (PC) is controversial due to uncertainties about its efficiency. ObjectiveWe aimed to develop strategies to reduce the number of unnecessary biopsies while still detecting most clinically important PC cases. Design, setting, and participantsIn 1850 men initially screened and biopsied (prostate-specific antigen [PSA] value ≥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. InterventionsThe 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 limitationsAt 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 ≥4.0 ng/ml resulted in similar numbers of biopsied cases saved but considerably higher numbers of missed diagnoses. ConclusionsAn 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.

Should Pathologists Routinely Report Prostate Tumour Volume? The Prognostic Value of Tumour Volume in Prostate Cancer

BackgroundThe independent prognostic value of tumour volume in radical prostatectomy (RP) specimens is controversial, and it remains a matter of debate whether pathologists should report a measure of tumour volume. In addition, tumour volume might be of value in substaging of pathologic tumour stage (pT2) prostate cancer (PCa). ObjectiveTo assess the prognostic value of PCa tumour volume. Design, setting, and participantsThe cohort consisted of 344 participants in the European Randomised Study of Screening for Prostate Cancer (ERSPC), Rotterdam section, whose PCa was treated with RP. Mean time of follow-up was 96.2 mo. MeasurementsTumour volume was measured in totally embedded RP specimens with a morphometric, computer-assisted method and assessed as a continuous variable, as relative tumour volume (tumour volume divided by prostate volume), and in a binary fashion (≥0.5ml or <0.5ml). These variables were related to prostate-specific antigen (PSA) progression, local recurrence, or distant metastasis and PCa-related mortality using univariate and multivariable Cox proportional hazards analyses. The analyses were repeated in the subgroup with pT2 tumours. Results and limitationsTumour volume was related to tumour stage, Gleason score, seminal vesicle invasion (SVI), and surgical margin status. In univariate analyses, tumour volume and relative tumour volume were predictive for all outcome variables. In multivariable analyses, including age, tumour stage, Gleason score, SVI, and surgical margin status, neither tumour volume nor relative volume were independent predictors of progression or mortality. Tumour volume ≥0.5ml was predictive for PSA recurrence and local and/or distant progression in univariate analyses but not in multivariable analyses. Tumour volume was not predictive for recurrence or mortality in univariate or multivariable analyses in the pT2 subgroup. ConclusionsTumour volume did not add prognostic value to routinely assessed pathologic parameters. Therefore, there seems to be little reason to routinely measure tumour volume in RP specimens.

Prostate Cancer: New Insights into Minimal and Localised Disease: Active Surveillance

This paper summarises current views on active surveillance as presented during the session titled, ‘‘Prostate Cancer: New Insights to Minimal and Localised Disease,’’ at the 2nd World Congress on Controversies in Urology (CURy) in Lisbon, Portugal. Prostate-specific antigen (PSA) screening programmes have resulted inan increasedandearlierdetectionofprostate cancer (PCa). An analysis of the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database in the United States showed that in 2000–2001, the proportion of low-risk tumours had almost doubled compared with 1990–1994, when screening was just introduced and exceptional (46.4% vs 27.5%) [1]. On average, clinical T stage, Gleason score, and percent of positive biopsies at diagnosis were lower in 2004–2007 than in 1990–1994 [1]. A significant proportion of patients diagnosed by PSA screening are much more likely to die with than to die from PCa, because they have indolent disease. Based on results of the Rotterdam section of the European Randomised Study of Screening for Prostate Cancer (ERSPC), the overdetection rate of PCa was estimated to be 48% for a screening programme with a 4-yr screening interval from age 55–67 [2]. Themean lead time (ie, time fromdetection at screening until the tumour would have been detected in the absence

Lead Time and Overdiagnosis in Prostate-Specific Antigen Screening: Importance of Methods and Context

The time by which prostate-specific antigen (PSA) screening advances prostate cancer diagnosis, called the lead time, has been reported by several studies, but results have varied widely, with mean lead times ranging from 3 to 12 years. A quantity that is closely linked with the lead time is the overdiagnosis frequency, which is the fraction of screen-detected cancers that would not have been diagnosed in the absence of screening. Reported overdiagnosis estimates have also been variable, ranging from 25% to greater than 80% of screen-detected cancers. We used three independently developed mathematical models of prostate cancer progression and detection that were calibrated to incidence data from the Surveillance, Epidemiology, and End Results program to estimate lead times and the fraction of overdiagnosed cancers due to PSA screening among US men aged 54-80 years in 1985-2000. Lead times were estimated by use of three definitions. We also compared US and earlier estimates from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) that were calculated by use of a microsimulation screening analysis (MISCAN) model. The models yielded similar estimates for each definition of lead time, but estimates differed across definitions. Among screen-detected cancers that would have been diagnosed in the patients' lifetimes, the estimated mean lead time ranged from 5.4 to 6.9 years across models, and overdiagnosis ranged from 23% to 42% of all screen-detected cancers. The original MISCAN model fitted to ERSPC Rotterdam data predicted a mean lead time of 7.9 years and an overdiagnosis estimate of 66%; in the model that was calibrated to the US data, these were 6.9 years and 42%, respectively. The precise definition and the population used to estimate lead time and overdiagnosis can be important drivers of study results and should be clearly specified.

Effectiveness of Antibiotics Given to Asymptomatic Men for an Increased Prostate Specific Antigen

Although there is controversy surrounding this subject, some urologists in daily practice often prescribe antibiotics before biopsy to men with a newly increased prostate specific antigen. We evaluated the effects of antibiotics on serum total prostate specific antigen, free prostate specific antigen, percent free prostate specific antigen and prostate specific antigen density in men with prostate specific antigen between 4 and 10 ng/ml and normal digital rectal examination. We also investigated the incidence of prostate cancer after antibiotic treatment by performing prostate biopsies in all patients regardless of posttreatment prostate specific antigen. Between May 2006 and April 2008 a total of 100 men with total prostate specific antigen between 4 and 10 ng/ml were enrolled in this study. In addition to total prostate specific antigen, free prostate specific antigen, percent free prostate specific antigen and prostate specific antigen density values were evaluated for all of the patients. Patients with pathological digital rectal examination and urinalysis were excluded from the study. All patients received 400 mg ofloxcacin daily for 20 days. After treatment the patients were reevaluated. Regardless of the total prostate specific antigen value after therapy transrectal ultrasound guided prostate biopsy was performed. Overall 23 men (23%) had histologically proven prostate cancer on biopsy. Mean total prostate specific antigen, free prostate specific antigen and prostate specific antigen density decreased after treatment in patients with and without prostate cancer. However, these reductions within these parameters were not significantly different between patients with and without prostate cancer. Only percent free prostate specific antigen change after treatment was found to be significantly different between patients with and without prostate cancer (p = 0.015). In 17 of the 100 men total prostate specific antigen after treatment was less than 4 ng/ml and of these 5 (29.4%) had prostate cancer on biopsy. Although antibiotic therapy will decrease serum total prostate specific antigen, it will not decrease the risk of prostate cancer even if the prostate specific antigen decreases to less than 4 ng/ml. Therefore, prescribing antibiotics for asymptomatic men with a newly increased prostate specific antigen may not be an appropriate method of management.

Defining Increased Future Risk for Prostate Cancer: Evidence From a Population Based Screening Cohort

Previous studies have examined the relationship among prostate specific antigen, other predictive factors and current prostate cancer risk. We examined the population risk during 4 years, defined a prostate specific antigen associated with this risk and clarified the contribution of other predictive factors. The population consisted of men 55 to 70 years old screened at the first and second screening rounds 4 years apart in the Rotterdam Section of the European Randomized Study of Screening for Prostate Cancer. The proportion of men with a positive prostate biopsy (initiated for a prostate specific antigen of 3.0 ng/ml or greater) and the mean population prostate specific antigen were calculated. Multivariate modeling was conducted using a proportional odds regression model to establish significant predictors of a positive biopsy from round 1 to round 2 of screening. Among men with no previous prostate biopsy the 4-year risk of prostate cancer was 5.1%, which was associated with a mean prostate specific antigen of 1.5 ng/ml at the first screening. An increased prostate specific antigen was a highly significant predictive factor for biopsy detectable prostate cancer 4 years later. Increasing log total prostate volume and a previous negative biopsy were associated with a significant reduction in risk of a positive prostate biopsy 4 years later. A prostate specific antigen of 1.5 ng/ml or greater in men older than 50 years represents an indicator for greater than average future risk of prostate cancer. Prostate specific antigen and other factors can be used to define future prostate cancer risk in addition to current use as a diagnostic marker for prostate cancer.