Chris H. Bangma

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.)

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.).

Active Surveillance for Low-Risk Prostate Cancer Worldwide: The PRIAS Study

BACKGROUND Overdiagnosis and subsequent overtreatment are important side effects of screening for, and early detection of, prostate cancer (PCa). Active surveillance (AS) is of growing interest as an alternative to radical treatment of low-risk PCa. OBJECTIVE To update our experience in the largest worldwide prospective AS cohort. DESIGN, SETTING, AND PARTICIPANTS Eligible patients had clinical stage T1/T2 PCa, prostate-specific antigen (PSA) ≤ 10 ng/ml, PSA density <0.2 ng/ml per milliliter, one or two positive biopsy cores, and Gleason score ≤ 6. PSA was measured every 3-6 mo, and volume-based repeat biopsies were scheduled after 1, 4, and 7 yr. Reclassification was defined as more than two positive cores or Gleason >6 at repeat biopsy. Recommendation for treatment was triggered in case of PSA doubling time <3 yr or reclassification. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Multivariate regression analysis was used to evaluate predictors for reclassification at repeat biopsy. Active therapy-free survival (ATFS) was assessed with a Kaplan-Meier analysis, and Cox regression was used to evaluate the association of clinical characteristics with active therapy over time. RESULTS AND LIMITATIONS In total, 2494 patients were included and followed for a median of 1.6 yr. One or more repeat biopsies were performed in 1480 men, of whom 415 men (28%) showed reclassification. Compliance with the first repeat biopsy was estimated to be 81%. During follow-up, 527 patients (21.1%) underwent active therapy. ATFS at 2 yr was 77.3%. The strongest predictors for reclassification and switching to deferred treatment were the number of positive cores (two cores compared with one core) and PSA density. The disease-specific survival rate was 100%. Follow-up was too short to draw definitive conclusions about the safety of AS. CONCLUSIONS Our short-term data support AS as a feasible strategy to reduce overtreatment. Clinical characteristics and PSA kinetics during follow-up can be used for risk stratification. Strict monitoring is even more essential in men with high-risk features to enable timely recognition of potentially aggressive disease and offer curative intervention. Limitations of using surrogate end points and markers in AS should be recognized. TRIAL REGISTRATION The current program is registered at the Dutch Trial Register with ID NTR1718 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1718).

Outcomes of Men with Screen-Detected Prostate Cancer Eligible for Active Surveillance Who Were Managed Expectantly

BACKGROUND The incidence of small, localised, well-differentiated prostate cancer (PCa) is increasing, mainly as a result of screening. Many of these cancers will not progress, and radical therapy may lead to substantial overtreatment. Active surveillance (AS) has emerged as an alternative. OBJECTIVE To retrospectively validate the currently used criteria for eligibility for AS. DESIGN, SETTING, AND PARTICIPANTS For this cohort study, data from 616 men who were diagnosed with PCa between 1994 and 2007 at a mean age of 66.3 yr in four centres of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were combined. All patients fit the criteria for AS (prostate-specific antigen [PSA] < or = 10.0 ng/ml, PSA-density < 0.2 ng/ml per ml, stage T1C/T2, Gleason score < or = 3 + 3 = 6, and < or = 2 positive biopsy cores), and initially they were managed expectantly. Median follow-up was 3.91 yr. MEASUREMENTS Disease specific-, overall-, and treatment-free survival were studied. Present PSA characteristics were assessed and also compared between men who were switching to deferred active therapy during follow-up and men remaining untreated. RESULTS AND LIMITATIONS The calculated (Kaplan-Meier) 10-yr PCa-specific survival (21 patients at risk) was 100%, which sharply contrasted with 77% overall survival. Men still alive showed favourable PSA characteristics. Although the calculated 10-yr treatment-free survival was only 43%, objective signs of progression often did not indicate the shift to radical treatment. The cohort consisted of men on AS and those on watchful waiting (WW); information on comorbidity or psychological distress was not available. CONCLUSIONS AS seems justified in selected men with screen-detected PCa. Prospective protocol-based AS programs are necessary to optimise selection criteria and to find the appropriate trigger points for switching to active therapy. Possible negative psychological reactions with AS against improved quality of life by withholding side-effects from radical treatment should be considered.

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.).

A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range

PURPOSE Prostate specific antigen and free prostate specific antigen have limited specificity to detect clinically significant, curable prostate cancer, leading to unnecessary biopsy, and detection and treatment of some indolent tumors. Specificity to detect clinically significant prostate cancer may be improved by [-2]pro-prostate specific antigen. We evaluated [-2]pro-prostate specific antigen, free prostate specific antigen and prostate specific antigen using the formula, ([-2]pro-prostate specific antigen/free prostate specific antigen × prostate specific antigen(1/2)) to enhance specificity to detect overall and high grade prostate cancer. MATERIALS AND METHODS We enrolled 892 men with no history of prostate cancer, normal rectal examination, prostate specific antigen 2 to 10 ng/ml and 6-core or greater prostate biopsy in a prospective multi-institutional trial. We examined the relationship of serum prostate specific antigen, free-to-total prostate specific antigen and the prostate health index with biopsy results. Primary end points were specificity and AUC using the prostate health index to detect overall and Gleason 7 or greater prostate cancer on biopsy compared with those of free-to-total prostate specific antigen. RESULTS In the 2 to 10 ng/ml prostate specific antigen range at 80% to 95% sensitivity the specificity and AUC (0.703) of the prostate health index exceeded those of prostate specific antigen and free-to-total prostate specific antigen. An increasing prostate health index was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to 4 + 3 = 7 disease on biopsy. The AUC of the index exceeded that of free-to-total prostate specific antigen (0.724 vs 0.670) to discriminate prostate cancer with Gleason 4 or greater + 3 from lower grade disease or negative biopsy. Prostate health index results were not associated with age and prostate volume. CONCLUSIONS The prostate health index may be useful in prostate cancer screening to decrease unnecessary biopsy in men 50 years old or older with prostate specific antigen 2 to 10 ng/ml and negative digital rectal examination with minimal loss in sensitivity.

Prostate Cancer Mortality Reduction by Prostate-Specific Antigen-Based Screening Adjusted for Nonattendance and Contamination in the European Randomised Study of Screening for Prostate Cancer (ERSPC)

BACKGROUND Prostate-specific antigen (PSA) based screening for prostate cancer (PCa) has been shown to reduce prostate specific mortality by 20% in an intention to screen (ITS) analysis in a randomised trial (European Randomised Study of Screening for Prostate Cancer [ERSPC]). This effect may be diluted by nonattendance in men randomised to the screening arm and contamination in men randomised to the control arm. OBJECTIVE To assess the magnitude of the PCa-specific mortality reduction after adjustment for nonattendance and contamination. DESIGN, SETTING, AND PARTICIPANTS We analysed the occurrence of PCa deaths during an average follow-up of 9 yr in 162,243 men 55-69 yr of age randomised in seven participating centres of the ERSPC. Centres were also grouped according to the type of randomisation (ie, before or after informed written consent). INTERVENTION Nonattendance was defined as nonattending the initial screening round in ERSPC. The estimate of contamination was based on PSA use in controls in ERSPC Rotterdam. MEASUREMENTS Relative risks (RRs) with 95% confidence intervals (CIs) were compared between an ITS analysis and analyses adjusting for nonattendance and contamination using a statistical method developed for this purpose. RESULTS AND LIMITATIONS In the ITS analysis, the RR of PCa death in men allocated to the intervention arm relative to the control arm was 0.80 (95% CI, 0.68-0.96). Adjustment for nonattendance resulted in a RR of 0.73 (95% CI, 0.58-0.93), and additional adjustment for contamination using two different estimates led to estimated reductions of 0.69 (95% CI, 0.51-0.92) to 0.71 (95% CI, 0.55-0.93), respectively. Contamination data were obtained through extrapolation of single-centre data. No heterogeneity was found between the groups of centres. CONCLUSIONS PSA screening reduces the risk of dying of PCa by up to 31% in men actually screened. This benefit should be weighed against a degree of overdiagnosis and overtreatment inherent in PCa screening.

Evolution of the androgen receptor pathway during progression of prostate cancer

The present work focused on the potential involvement of selective adaptations of the androgen receptor pathway in the initiation and progression of prostate cancer. We defined the androgen receptor pathway by selecting 200 genes that were androgen responsive in prostate cancer cell lines and/or xenografts. This androgen receptor pathway gene signature was then used for profiling prostate cancer xenografts and patient-derived samples. Approximately half of the androgen receptor pathway genes were up-regulated in well-differentiated prostate cancer compared with normal prostate. Functionally distinct parts of the androgen receptor pathway were specifically down-regulated in high-grade cancers. Unexpectedly, metastases have down-regulated the vast majority of androgen receptor pathway genes. The significance of this progressive down-regulation of androgen receptor pathway genes was shown for a few androgen receptor-regulated genes. Lower mRNA expression of HERPUD1, STK39, DHCR24, and SOCS2 in primary prostate tumors was correlated with a higher incidence of metastases after radical prostatectomy. HERPUD1 mRNA expression predicted the occurrence of metastases almost perfectly. In vitro experiments showed that overexpression of the stress response gene HERPUD1 rapidly induces apoptosis. Based on the functions of the genes within the distinct subsets, we propose the following model. Enhanced androgen receptor activity is involved in the early stages of prostate cancer. In well-differentiated prostate cancer, the androgen receptor activates growth-promoting as well as growth-inhibiting and cell differentiation genes resulting in a low growth rate. The progression from low-grade to high-grade prostate carcinoma and metastases is mediated by a selective down-regulation of the androgen receptor target genes that inhibit proliferation, induce differentiation, or mediate apoptosis.

Exosomes as biomarker treasure chests for prostate cancer.

CONTEXT Although progress has been made with regard to types of markers (protein, DNA, RNA, and metabolites) and implementation of improved technologies (mass spectrometry, arrays, and deep sequencing), the discovery of novel biomarkers for prostate cancer (PCa) in complex fluids, such as serum and urine, remains a challenge. Meanwhile, recent studies have reported that many cancer-derived proteins and RNAs are secreted through small vesicles known as exosomes. OBJECTIVE This narrative review describes recent progress in exosome research, focusing on the potential role of exosomes as novel biomarkers for PCa. The purpose of this review is to acquaint clinicians and researchers in the field of urology with the potential role of exosomes as biomarker treasure chests and with their clinical value. EVIDENCE ACQUISITION Medline and Embase entries between 1966 and September 2010 were searched using the keywords exosomes, microvesicles, prostasomes, biomarkers, prostate cancer, and urology. Leading publications and articles constructively contributing to exosome research were selected for this review. EVIDENCE SYNTHESIS Exosomes are small vesicles (50-100 nm) secreted by almost all tissues; they represent their tissue origin. Purification of prostate- and PCa-derived exosomes will allow us to profile exosomes, providing a promising source of protein and RNA biomarkers for PCa. This profiling will contribute to the discovery of novel markers for the early diagnosis and reliable prognosis of PCa. CONCLUSIONS Although the initial results are promising, further investigations are required to assess the clinical value of these exosomes in PCa.

Prostate-Specific Antigen (PSA) Isoform p2PSA in Combination with Total PSA and Free PSA Improves Diagnostic Accuracy in Prostate Cancer Detection

BACKGROUND Novel markers for prostate cancer (PCa) detection are needed. Total prostate-specific antigen (tPSA) and percent free prostate-specific antigen (%fPSA=tPSA/fPSA) lack diagnostic specificity. OBJECTIVE To evaluate the use of prostate-specific antigen (PSA) isoforms p2PSA and benign prostatic hyperplasia-associated PSA (BPHA). DESIGN, SETTING, AND PARTICIPANTS Our study included 405 serum samples from the Rotterdam arm of the European Randomised Study of Screening for Prostate Cancer and 351 samples from the Urology Department of Innsbruck Medical University. MEASUREMENTS BPHA, tPSA, fPSA, and p2PSA levels were measured by Beckman-Coulter Access Immunoassay. In addition, the Beckman Coulter Prostate Health Index was calculated: phi=(p2PSA/fPSA)×√(tPSA). RESULTS AND LIMITATIONS The p2PSA and phi levels differed significantly between men with and without PCa. No difference in BPHA levels was observed. The highest PCa predictive value in both cohorts was achieved by phi with areas under the curve (AUCs) of 0.750 and 0.709, a significant increase compared to tPSA (AUC: 0.585 and 0.534) and %fPSA (AUC: 0.675 and 0.576). Also, %p2PSA (p2PSA/fPSA) showed significantly higher AUCs compared to tPSA and %fPSA (AUC: 0.716 and 0.695, respectively). At 95% and 90% sensitivity, the specificities of phi were 23% and 31% compared to 10% and 8% for tPSA, respectively. In both cohorts, multivariate analysis showed a significant increase in PCa predictive value after addition of p2PSA to a model consisting of tPSA and fPSA (increase in AUC from 0.675 to 0.755 and from 0.581 to 0.697, respectively). Additionally, the specificity at 95% sensitivity increased from 8% to 24% and 7% to 23%, respectively. Furthermore, %p2PSA, phi, and the model consisting of tPSA and fPSA with or without the addition of p2PSA missed the least of the tumours with a biopsy or pathologic Gleason score ≥7 at 95% and 90% sensitivity. CONCLUSIONS This study shows significant increases in PCa predictive value and specificity of phi and %p2PSA compared to tPSA and %fPSA. p2PSA has limited additional value in identifying aggressive PCa (Gleason score ≥7).