Testosterone treatment is not associated with increased risk of prostate cancer or worsening of lower urinary tract symptoms: prostate health outcomes in the Registry of Hypogonadism in Men.

OBJECTIVES: To evaluate the effects of testosterone-replacement therapy (TRT) on prostate health indicators in hypogonadal men, including rates of prostate cancer diagnoses, changes in prostate-specific antigen (PSA) levels and lower urinary tract symptoms (LUTS) over time. PATIENTS AND METHODS: The Registry of Hypogonadism in Men (RHYME) is a multi-national patient registry of treated and untreated, newly-diagnosed hypogonadal men (n = 999). Follow-up assessments were performed at 3-6, 12, 24, and 36 months. Baseline and follow-up data collection included medical history, physical examination, blood sampling, and patient questionnaires. Prostate biopsies underwent blinded independent adjudication for the presence and severity of prostate cancer; PSA and testosterone levels were measured via local and central laboratory assays; and LUTS severity was assessed via the International Prostate Symptom Score (IPSS). Incidence rates per 100 000 person-years were calculated. Longitudinal mixed models were used to assess effects of testosterone on PSA levels and IPSS. RESULTS: Of the 999 men with clinically diagnosed hypogonadism (HG), 750 (75%) initiated TRT, contributing 23 900 person-months of exposure. The mean testosterone levels increased from 8.3 to 15.4 nmol/L in treated men, compared to only a slight increase from 9.4 to 11.3 nmol/L in untreated men. In all, 55 biopsies were performed for suspected prostate cancer, and 12 non-cancer related biopsies were performed for other reasons. Overall, the proportion of positive biopsies was nearly identical in men on TRT (37.5%) compared to those not on TRT (37.0%) over the course of the study. There were no differences in PSA levels, total IPSS, or the IPSS obstructive sub-scale score by TRT status. Lower IPSS irritative sub-scale scores were reported in treated compared to untreated men. CONCLUSIONS: Results support prostate safety of TRT in newly diagnosed men with HG.

Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up.

BACKGROUND: The European Randomised study of Screening for Prostate Cancer (ERSPC) has shown significant reductions in prostate cancer mortality after 9 years and 11 years of follow-up, but screening is controversial because of adverse events such as overdiagnosis. We provide updated results of mortality from prostate cancer with follow-up to 2010, with analyses truncated at 9, 11, and 13 years. METHODS: ERSPC is a multicentre, randomised trial with a predefined centralised database, analysis plan, and core age group (55-69 years), which assesses prostate-specific antigen (PSA) testing in eight European countries. Eligible men aged 50-74 years were identified from population registries and randomly assigned by computer generated random numbers to screening or no intervention (control). Investigators were masked to group allocation. The primary outcome was prostate cancer mortality in the core age group. Analysis was by intention to treat. We did a secondary analysis that corrected for selection bias due to non-participation. Only incidence and no mortality data at 9 years' follow-up are reported for the French centres. This study is registered with Current Controlled Trials, number ISRCTN49127736. FINDINGS: With data truncated at 13 years of follow-up, 7408 prostate cancer cases were diagnosed in the intervention group and 6107 cases in the control group. The rate ratio of prostate cancer incidence between the intervention and control groups was 1·91 (95% CI 1·83-1·99) after 9 years (1·64 [1·58-1·69] including France), 1·66 (1·60-1·73) after 11 years, and 1·57 (1·51-1·62) after 13 years. The rate ratio of prostate cancer mortality was 0·85 (0·70-1·03) after 9 years, 0·78 (0·66-0·91) after 11 years, and 0·79 (0·69-0·91) at 13 years. The absolute risk reduction of death from prostate cancer at 13 years was 0·11 per 1000 person-years or 1·28 per 1000 men randomised, which is equivalent to one prostate cancer death averted per 781 (95% CI 490-1929) men invited for screening or one per 27 (17-66) additional prostate cancer detected. After adjustment for non-participation, the rate ratio of prostate cancer mortality in men screened was 0·73 (95% CI 0·61-0·88). INTERPRETATION: In this update the ERSPC confirms a substantial reduction in prostate cancer mortality attributable to testing of PSA, with a substantially increased absolute effect at 13 years compared with findings after 9 and 11 years. Despite our findings, further quantification of harms and their reduction are still considered a prerequisite for the introduction of populated-based screening. FUNDING: Each centre had its own funding responsibility.

Prostate-cancer mortality at 11 years of follow-up.

BACKGROUND: Several trials evaluating the effect of prostate-specific antigen (PSA) testing on prostate-cancer mortality have shown conflicting results. We updated prostate-cancer mortality in the European Randomized Study of Screening for Prostate Cancer with 2 additional years of follow-up. METHODS: The study involved 182,160 men between the ages of 50 and 74 years at entry, with a predefined core age group of 162,388 men 55 to 69 years of age. The trial was conducted in eight European countries. Men who were randomly assigned to the screening group were offered PSA-based screening, whereas those in the control group were not offered such screening. The primary outcome was mortality from prostate cancer. RESULTS: After a median follow-up of 11 years in the core age group, the relative reduction in the risk of death from prostate cancer in the screening group was 21% (rate ratio, 0.79; 95% confidence interval [CI], 0.68 to 0.91; P=0.001), and 29% after adjustment for noncompliance. The absolute reduction in mortality in the screening group was 0.10 deaths per 1000 person-years or 1.07 deaths per 1000 men who underwent randomization. The rate ratio for death from prostate cancer during follow-up years 10 and 11 was 0.62 (95% CI, 0.45 to 0.85; P=0.003). To prevent one death from prostate cancer at 11 years of follow-up, 1055 men would need to be invited for screening and 37 cancers would need to be detected. There was no significant between-group difference in all-cause mortality. CONCLUSIONS: Analyses after 2 additional years of follow-up consolidated our previous finding that PSA-based screening significantly reduced mortality from prostate cancer but did not affect all-cause mortality. (Current Controlled Trials number, ISRCTN49127736.).

Quality-of-life effects of prostate-specific antigen screening.

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.).

Do Treatment Differences between Arms Affect the Main Outcome of ERSPC Rotterdam?

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.

A longitudinal study on the impact of active surveillance for prostate cancer on anxiety and distress levels.

OBJECTIVE: Patients 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. METHODS: One 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 6 months 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. RESULTS: Response 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. CONCLUSIONS: When 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) .

Prevention and early detection of prostate cancer.

Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.

Validation of stem cell markers in clinical prostate cancer: α6-integrin is predictive for non-aggressive disease.

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 (<5%) in 94.7% of tumors and associated with PSA > 10 ng/ml (P = 0.04). α6-Integrin expression (<5%) occurred in 28.4% patients, while ≥5% α6-integrin expression was associated with PSA≤10 ng/ml (P = 0.01), Gleason score <7 (P < 0.01) and pT2-disease (P = 0.02). α6-integrin was predictive for biochemical recurrence (P < 0.01), local recurrence (P = 0.03) and disease specific death (P = 0.03). EZH2 expression was generally low with 2.6% of tumors showing ≥1% positive cells. EZH2 was associated with Gleason score ≥7 (P = 0.01) and biochemical recurrence (P = 0.01). We did not identify expression of CD117, CD133, and OCT3/4 in prostate cancer samples. CONCLUSIONS: Expression of α2-integrin and EZH2 in a small fraction of prostate cancer cells is supportive for their role as stem cell marker. Although α6-integrin was not a unique stem cell marker, it was predictive for prostate cancer biochemical and local recurrence, and disease specific death. The validity of CD117, CD133, and OCT3/4 as prostate cancer stem cell marker is questionable since these proteins were not expressed in clinical prostate cancer.

Intermittent versus continuous cyproterone acetate in bone metastatic prostate cancer: results of a randomized trial.

BACKGROUND: 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. METHODS: Patients received CPA 100 mg tid in the prephase. Patients with a PSA decline of ≥ 90 % or PSA <4 ng/ml were randomized. If patients were progressive, LHRH analogues were added. Primary end point was time to PSA progression. RESULTS: 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. CONCLUSIONS: 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.

Evaluating the Prostate Cancer Prevention Trial High Grade Prostate Cancer Risk Calculator in 10 international biopsy cohorts: results from the Prostate Biopsy Collaborative Group.

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.

Screening for prostate cancer: current status of ERSPC and screening-related issues.

The "European Randomized Study of Screening for Prostate Cancer" (ERSPC) was initiated in 1993 and up to 1998 six other European countries were joined. The main goal is to establish the effect of Prostate Specific Antigen (PSA)-based screening on prostate cancer (PCa) mortality with morbidity as secondary end point. At present, with 11 and 12 years of follow-up significant relative reductions of 21 % and 31 % relating to both end points have been reported. The diagnosis of non-life threatening PCA (over diagnosis) is estimated to be in the range of 50 % and represents the main "harm", which prevents the introduction of population-based screening. As a result, the prevention of over diagnosis is now given top research priority. PSA as a screening test has poor performance characteristics including a low specificity. With the cut-off value of 3.0 ng/ml chosen within ERSPC, about 25 % of men aged 55--69 test positively, 75 % have "negative" test results, which do not definitely exclude the presence of PCa. Research to establish empirical schemes of follow-up based on PSA levels and other parameters are ongoing worldwide. In the meantime, we are, by approximation, capable to identify over diagnosed PCa detected by screening. Active surveillance can be applied to avoid side effects and expenses of treatment and is, among others, based on the grade of differentiation determined on biopsies. The assignment of the most favorable "Gleason score 6" is a crucial decision element. Unfortunately, biopsy pathology underestimates the true degree of PC aggressiveness by 25--30 % which establishes the need of careful follow-up.

ERSPC, PLCO studies and critique of cochrane review 2013.

Screening for prostate cancer by use of serum prostate specific antigen (PSA) remains controversial. In the recent Cochrane analysis, an attempt is made to clarify the issue by conducting a meta analysis of available randomized screening trials. Two large trials are considered to provide data of similar and sufficient quality to conduct a separate meta analysis. However, in the view of this author, this analysis fails because standard Cochrand quality criteria are not observed. Details are given and the outcome suggests that one of the trials, the European Randomized Study of Screening for Prostate Cancer (ERSPC) should be considered superior to the Prostate, Lung, Colon, Ovary screening trial (PLCO) conducted in the USA.

Can one blood draw replace transrectal ultrasonography-estimated prostate volume to predict prostate cancer risk?

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

Registry of Hypogonadism in Men (RHYME): design of a multi-national longitudinal, observational registry of exogenous testosterone use in hypogonadal men.

OBJECTIVE: 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. DESIGN: Observational patient disease registry. METHODS: 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. RESULTS: 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.

Overestimation of prostate cancer mortality and other-cause mortality by the Kaplan-Meier method.

INTRODUCTION: To assess the extent of overestimation of the cumulative probability of death by the Kaplan-Meier method with the competing-risks regression analysis as reference approach. MATERIALS AND METHODS: Data were derived from the screening arm of the Rotterdam branch of the European Randomized Study of Screening for Prostate Cancer (ERSPC). The screening arm consisted of 21210 men between the ages of 55 and 74 at study entry. Follow up concerning mortality was complete through 2008. Endpoints were 5 and 10 year cumulative probabilities of prostate cancer death and death from other causes. Relative bias was defined as the ratio of the cumulative probability of death as determined by the Kaplan-Meier method, relative to the cumulative probability obtained by the competing-risks analysis. RESULTS: According to the Kaplan-Meier method, the 5 year cumulative probability of death from prostate cancer was 0.0101, compared with 0.0099 according to the competing-risk analysis [1.8% overestimation]. At 10 year, these numbers were 0.0347 and 0.0321, respectively [8.0% overestimation]. For death from other causes, the cumulative probabilities at 5 year were 0.0399 and 0.0397 according to the Kaplan-Meier and the competing-risks method [0.6% overestimation], respectively. At 10 year, the probabilities were 0.141 and 0.139 [1.7% overestimation], respectively. CONCLUSIONS: When competing events are present, the competing-risks regression analysis is to be preferred over the Kaplan-Meier method in the estimation of the cumulative probability of the event of interest.

Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and Prostate Cancer Death: Long-term Follow-up from the European Randomized Study of Screening for Prostate Cancer.

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

Can the prostate risk calculator based on Western population be applied to Asian population?

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.

Comparison of incidentally detected prostate cancer with screen-detected prostate cancer treated by prostatectomy.

BACKGROUND: The prostate may often harbor a prostate cancer (PC) which will not cause morbidity if left untreated. Screening for PC leads to increased detection of these insignificant cancers. Objective of this study is to compare PC detected by PSA screening at subsequent screening rounds and treated by radical prostatectomy (RP) with PC incidentally found in cystoprostatectomy specimens. METHODS: Radical prostatectomy specimens of 617 screen-detected PC were compared with 123 PC identified in cystoprostatectomy specimens. Surgical specimens were systematically examined and stage, grade, tumor volume were recorded. Next, we classified PC as clinically significant or insignificant (i.e., tumor volume <0.5 cm(3), absence of Gleason pattern 4/5, organ confined). Pathological features of incidentally detected PC were compared with PC detected in subsequent screening rounds and with screen-detected T1c PC. RESULTS: Screen-detected PC overall were more often multifocal, larger in volume, more advanced in tumor stage and of higher grade, while the frequency of insignificant PC was lower as compared to those in cystoprostatectomy specimens. This effect became more pronounced during subsequent screening rounds. Screen-detected T1c PC were also more often multifocal (73% vs. 37%) in average fivefold larger (0.85 cm(3) vs. 0.16 cm(3)), less often organ confined (81% vs. 94%), and less frequently clinically insignificant (33% vs. 81%). CONCLUSIONS: Screen-detected (T1c) PC treated with RP shows more aggressive features than incidentally found PC. This PSA screening-related selection seems to be mainly driven by tumor volume and-in later screening rounds-by the preferential treatment by prostatectomy of more aggressive PC.

Screening and prostate-cancer mortality in a randomized European study.

BACKGROUND: The European Randomized Study of Screening for Prostate Cancer was initiated in the early 1990s to evaluate the effect of screening with prostate-specific-antigen (PSA) testing on death rates from prostate cancer. METHODS: We identified 182,000 men between the ages of 50 and 74 years through registries in seven European countries for inclusion in our study. The men were randomly assigned to a group that was offered PSA screening at an average of once every 4 years or to a control group that did not receive such screening. The predefined core age group for this study included 162,243 men between the ages of 55 and 69 years. The primary outcome was the rate of death from prostate cancer. Mortality follow-up was identical for the two study groups and ended on December 31, 2006. RESULTS: In the screening group, 82% of men accepted at least one offer of screening. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio for death from prostate cancer in the screening group, as compared with the control group, was 0.80 (95% confidence interval [CI], 0.65 to 0.98; adjusted P=0.04). The absolute risk difference was 0.71 death per 1000 men. This means that 1410 men would need to be screened and 48 additional cases of prostate cancer would need to be treated to prevent one death from prostate cancer. The analysis of men who were actually screened during the first round (excluding subjects with noncompliance) provided a rate ratio for death from prostate cancer of 0.73 (95% CI, 0.56 to 0.90). CONCLUSIONS: PSA-based screening reduced the rate of death from prostate cancer by 20% but was associated with a high risk of overdiagnosis. (Current Controlled Trials number, ISRCTN49127736.)

ERG immunohistochemistry is not predictive for PSA recurrence, local recurrence or overall survival after radical prostatectomy for prostate cancer.

In prostate cancer genomic rearrangements involving genes encoding ETS transcription factors are commonly present, with androgen-regulated transmembrane protease, serine 2 (TMPRSS2)-v-ets erythroblastosis virus E26 oncogen homologue (ERG) gene fusion occurring in 40-70%. Studies on the predictive value of ERG rearrangement as detected by in-situ hybridization or polymerase chain reaction have resulted in varying outcomes. The objective of this study was to correlate immunohistochemical ERG protein expression with clinico-pathological parameters at radical prostatectomy specimens, and to determine its predictive value for postoperative disease recurrence and progression in a prostate cancer screening cohort. Since androgen receptor is downregulated by ERG in cell lines, we also compared the expression of respective proteins. We selected 481 participants from the European Randomized Study of Screening for Prostate Cancer treated by radical prostatectomy for prostate adenocarcinoma. A tissue microarray was constructed containing representative cores of all prostate cancer specimens as well as 22 xenografts and seven cell lines. Immunohistochemical expression of ERG and androgen receptor was correlated with prostate-specific antigen (PSA), Gleason sum, pT-stage, surgical margins, biochemical recurrence, local recurrence, overall death and disease-specific death. ERG expression was detected in 284 patients (65%). Expression occurred significantly more frequent in patients with PSA ≤10 ng/ml (P=0.024). There was no significant association between ERG and Gleason sum, pT-stage or surgical margin status. PSA (P=0.011), Gleason sum (P=0.003), pT-stage (P=0.001) and surgical margin status (P<0.001) all had independent value for postoperative biochemical recurrence, while positive surgical margin (P=0.021) was the only independent predictor for local recurrence. ERG protein expression did not have prognostic value for the clinical end points in uni- and multivariate analyses. A positive correlation existed between ERG and androgen receptor expression in single tissue cores (P<0.001). In conclusion, immunohistochemical ERG expression has no predictive value for prostate cancer recurrence or progression after radical prostatectomy. Increasing ERG levels are associated with the upregulation of androgen receptor expression in clinical specimens.