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.

Positive predictive value of prostate biopsy indicated by prostate-specific-antigen-based prostate cancer screening: trends over time in a European randomized trial*.

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

Increased non-prostate cancer death risk in clinically diagnosed prostate cancer.

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

Outcomes of initially expectantly managed patients with low or intermediate risk screen-detected localized prostate cancer.

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

The Prostate cancer Research International: Active Surveillance study.

PURPOSE OF REVIEW: To inform readers on the ongoing activities of the Prostate cancer Research International: Active Surveillance (PRIAS) study in the light of current findings and research problems on active surveillance worldwide. RECENT FINDINGS: Recent data from the PRIAS study combined with PubMed-based literature from the last 3 years. SUMMARY: The PRIAS study is a rapidly growing registry for active surveillance of low-risk prostate cancer. The study is conducted worldwide, facilitated by an electronic Web-based decision tool with password-restricted access for physicians. Inclusion and monitoring is performed according to protocol. Over 2000 men have been included from over 100 participating centres in 17 countries in four continents. The study was initiated in December 2006. Risk reclassification on repeat biopsy during follow-up has occurred in 27% of biopsied men, although a switch towards active therapy has been performed in 22% of the total cohort.

Identifying and characterizing "escapes"-men who develop metastases or die from prostate cancer despite screening (ERSPC, section Rotterdam).

We aim to identify and characterize "escapes," men who developed metastasis and/or died from prostate cancer (PCa) despite screening, in the framework of the novel international ESCAPE-project. With this knowledge, the ultimate goal is to improve screening strategy. In this article, we focus on the study cohort of the European Randomized Study of Screening for Prostate Cancer (ERSPC), section Rotterdam. In all, 21,210 men were randomized to the screening arm of whom 19,950 were actually screened. The screening interval was 4 years. Men with prostate-specific antigen ≥3.0 ng/ml were recommended to undergo lateralized sextant prostate biopsy. The follow-up was complete until January 1, 2009. Of 19,950 screened men, 2,317 were diagnosed with PCa. Of these cancers 1,946 were detected in a screening round and 371 during an interval. The median follow-up was 11.1 years for the whole cohort and 7.3 years for men diagnosed with PCa. In total, we identified 168 escapes among 2,317 cancers (7.3%) within our screening cohort of 19,950 men (0.8%). More than half of these escapes were found in the initial screening round (94 of 168). Possible mechanisms behind escaping are nonattending, inadequate screening tests, the relative long screening interval, the age cut-off at 75 years, and undertreatment. International cooperation is crucial to compare the escapes of our cohort with other study groups participating in the ESCAPE-project which have different, more aggressive screening strategies. Subsequently, we can achieve improvements of the current screening algorithm, which hopefully will further decrease PCa-specific mortality without increasing overdiagnosis and overtreatment.

Screening for prostate cancer---the controversy continues, but can it be resolved?

BACKGROUND: In 2009, the European Randomized Study of Screening for Prostate Cancer (ERSPC) was one of two studies to report interim data on the effect of screening for prostate cancer (PC) on the disease specific mortality. Contradictory results caused considerable discussion and misunderstanding in secondary literature. METHODS: This document is based on a non systematic review of recent evidence for and against screening for PC, specifically considering three recently published randomized screening trials [ 1-3 ]. RESULTS: The ERSPC data are based on a core age group of 162 387 men, aged 55-69 years, who were identified through population registries in seven European countries. Men were randomized between a screening group that received screening at an average of once every four years and a control group. After a median follow-up of nine years, a reduction in the rate of death from PC by 20% was shown which increased to 31% after adjusting for non-compliance and contamination. Overdetection and subsequent overtreatment (with a number needed to treat (NNT) of 48) are considered to be the major down sides of screening. The recently published 14-year results have shown that these down sides strongly depend on the duration of follow-up. In response to the outcomes of the ERSPC, several points of discussion have been brought up by various authors concerning the usefulness of screening considering benefits, harms and costs, the methodology of the ERSPC and the interpretation of its outcomes. Important issues to address regarding PC screening are addressed. CONCLUSIONS: This paper sheds a light on the controversial points of the ERSPC as well as on the priority issues of PC screening. On July 2, 2010 the Swedish section of ERSPC (Göteborg screening trial) published their results with a median follow-up of 14 years. With longer follow-up the data confirm the trend seen in improvement of PC mortality and suggest much more favorable future outcomes also with respect to the NNT to prevent one PC death.

Updating the prostate cancer risk indicator for contemporary biopsy schemes.

INTRODUCTION AND OBJECTIVE: The prostate cancer risk indicator is a validated tool for predicting the chance of a screen detected prostate cancer to be classified as indolent, partially based on lateralized sextant biopsies. Our objective is to extract correction factors for adjustment of the model, addressing contemporary extended biopsy schemes. MATERIALS AND METHODS: Post-mortem 18-core biopsy results of men who died of unrelated causes, but were diagnosed with prostate cancer post-mortem were used to provide details on prostate biopsies and whole mount specimens. For each of the 18-core biopsies showing cancer, Gleason score, number of positive cores, location in the gland and percentage of cancer involvement were determined and correlated to final pathology. Total length of cancer tissue in a 6-core scheme was related to the length in 12 and 18-core schemes to compute correction factors. Furthermore, upgrading on extended biopsies and final pathology was evaluated. RESULTS: Data from 33 autopsied men were included. The 18 and 12-core biopsies showed 192.72 mm and 143.76 mm of prostate cancer, compared to 70.80 mm with lateralized sextant biopsy, resulting in correction factors of 2.72 and 2.03 for 18 and 12-core schemes respectively. Upgrading in Gleason score on extended biopsy regimens compared to lateralized sextant biopsy occurred in 33% (11/33) of the cases. CONCLUSION: Based on autopsy data, the present correction factors provide a support in the adjustment of the prostate cancer risk indicator towards more extended contemporary biopsy schemes, eventually leading to a more accurate prediction of the probability of indolent cancers and assisting patients and clinicians to make appropriate choices in daily practice.

Critical assessment of prebiopsy parameters for predicting prostate cancer metastasis and mortality.

INTRODUCTION: Value of characteristics assessed prior to diagnosis predicting aggressive prostate cancer, metastases and mortality in men participating in a screening study were identified. MATERIALS AND METHODS: This study included 19950 men, aged 55 to 74 years at first screening, in the European Randomized Study of Screening for Prostate Cancer. Age, Charlson comorbidity, prostate cancer family history, vasectomy status, International Prostate Symptom Score (IPSS) score, digital rectal examination (DRE) status, transrectal ultrasound (TRUS) findings, prostate volume and prostate-specific antigen (PSA) level were assessed. Men were followed for median 11.1 years after first screening visit. Multivariate estimates of the probability of aggressive prostate cancer [stage ≥ T2c, or N1, M1, PSA > 20 ng/mL, or Gleason score ≥ 8], developing distant metastases and dying from prostate cancer stratified for predictors measured before prostate biopsies. Harrell's concordance index (c-index) was used for predictive accuracy. RESULTS: Among 19950 men, 2420 men (12.1%) were diagnosed with prostate cancer, of which 623 men (3.1%) had aggressive prostate cancer, 157 men (0.8%) developed metastases and 104 men (0.5%) died due to a prostate cancer related cause of death. In multivariate analysis, PSA, DRE, TRUS findings and prostate volume had a significant association with detection of aggressive prostate cancer, metastases and prostate cancer mortality. Family history was significantly associated with aggressive prostate cancer. Accuracy for predicting aggressive prostate cancer c-index = 0.90, distant metastases c-index = 0.87, and prostate cancer specific mortality c-index = 0.87. CONCLUSIONS: In a large population of men who were screened for prostate cancer, detection of aggressive prostate cancer, metastases and prostate cancer mortality was predicted based on predictors available before biopsy. These results support the value of a multivariate risk assessment and stratification tools.

[The need for orchiopexy in the case of congenital undescended testis]. / De noodzaak van orchidopexie bij congenitale niet-scrotale testis.

Congenital undescended testis (UDT) is a common congenital anomaly among males. Since ectopic position of the testis is considered a risk factor for the development of testicular cancer and infertility, early diagnosis and treatment are essential. Careful physical examination after birth should indicate those patients with UDT who must be followed up for possible orchiopexy at an early age. Treatment consists of performing orchiopexy at the age of 6-12 months to reduce the risk of malignancy and/or infertility. Despite the necessity of treating UDT, isolated cases of intra-abdominal seminoma are found. In patients with abdominal complaints and UDT, the possibility of problems due to this condition must be considered. In the present case, a patient with an intra-abdominal seminoma in the presence of unilateral UDT is presented.

Value of 3-T multiparametric magnetic resonance imaging and magnetic resonance-guided biopsy for early risk restratification in active surveillance of low-risk prostate cancer: a prospective multicenter cohort study.

OBJECTIVES: The objective of this study was to evaluate the role of 3-T multiparametric magnetic resonance imaging (MP-MRI) and magnetic resonance-guided biopsy (MRGB) in early risk restratification of patients on active surveillance at 3 and 12 months of follow-up. MATERIALS AND METHODS: Within 4 hospitals participating in a large active surveillance trial, a side study was initiated. Pelvic magnetic resonance imaging, prostate MP-MRI, and MRGB were performed at 3 and 12 months (latter prostate MP-MRI and MRGB only) after prostate cancer diagnosis in 1 of the 4 participating hospitals. Cancer-suspicious regions (CSRs) were defined on prostate MP-MRI using Prostate Imaging Reporting And Data System (PI-RADS) scores.Risk restratification criteria for active surveillance discontinuance were (1) histopathologically proven magnetic resonance imaging suspicion of node/bone metastases and/or (2) a Gleason growth pattern (GGP) 4 and/or 5 and/or cancer multifocality (≥3 foci) in MRGB specimens of a CSR on MP-MRI. RESULTS: From 2009 to 2012, a total of 64 of 82 patients were consecutively and prospectively included and underwent MP-MRI and a subsequent MRGB. At 3 and 12 months of follow-up, 14% (9/64) and 10% (3/30) of the patients were risk-restratified on the basis of MP-MRI and MRGB. An overall CSR PI-RADS score of 1 or 2 had a negative predictive value of 84% (38/45) for detection of any prostate cancer and 100% (45/45) for detection of a GGP 4 or 5 containing cancer upon MRGB, respectively. A CSR PI-RADS score of 4 or higher had a sensitivity of 92% (11/12) for detection of a GGP 4 or 5 containing cancer upon MRGB. CONCLUSIONS: Application of MP-MRI and MRGB in active surveillance may contribute in early identification of patients with GGP 4 or 5 containing cancers at 3 months of follow-up. If, during further follow-up, a PI-RADS score of 1 or 2 continues to have a negative predictive value for GGP 4 or 5 containing cancers, a PI-RADS standardized reported MP-MRI may be a promising tool for the selection of prostate cancer patients suitable for active surveillance.

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).

Active surveillance for low-risk prostate cancer.

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

Efficacy versus effectiveness study design within the European screening trial for prostate cancer: consequences for cancer incidence, overall mortality and cancer-specific mortality.

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

Predictors of unfavourable repeat biopsy results in men participating in a prospective active surveillance program.

BACKGROUND: Active surveillance (AS) protocols for low-risk prostate cancer (PCa) generally include repeat prostate biopsies at predefined follow-up intervals. OBJECTIVE: To study the outcome of routinely obtained 1-yr repeat biopsies and factors predicting reclassification to higher risk, to contribute to risk stratification for men on AS. DESIGN, SETTING, AND PARTICIPANTS: We analysed men with low-risk PCa (clinical stage ≤ T2, prostate-specific antigen (PSA) ≤ 10 ng/ml, PSA density <0.2 ng/ml per millilitre, one or two positive biopsy cores, and Gleason score ≤ 6) who had been included in a prospective AS protocol. INTERVENTIONS: PSA was measured 3-monthly and the first volume-dependent repeat biopsy was scheduled 1 yr after diagnosis, independent of PSA doubling time (PSA-DT). Reclassification to higher risk disease on repeat biopsy was defined as Gleason score ≥ 7 or ≥ 3 positive cores. MEASUREMENTS: We analysed whether baseline patient characteristics and PSA-DT were associated with reclassification to more aggressive PCa on repeat biopsy. RESULTS AND LIMITATIONS: A first repeat biopsy was taken in 757 patients after median follow-up of 1.03 yr. The results of repeat biopsies were favourable (no or low-risk PCa) in 594 patients (78.5%) and led to reclassification of risk in 163 (21.5%). Analysis showed that reclassification to higher risk was significantly influenced by the number of initial positive cores (two vs one) (odds ratio [OR]: 1.8; p=0.002) and higher PSA density (OR: 2.1; p=0.003). The outcome was not significantly influenced by age, clinical stage, total number of biopsy cores, or PSA. Adding PSA-DT at time of repeat biopsy to the model showed PSA-DT <3 yr to be significantly associated with reclassification to higher risk (OR: 1.7; p=0.015). Data on tumour involvement per biopsy core were not available. CONCLUSIONS: Clinical features at baseline and during follow-up in our AS cohort are significantly associated with short-term reclassification to higher risk on repeat biopsy. These characteristics can potentially be used for risk stratification of men with PCa who are apparently at favourable risk.

Radical prostatectomy for low-risk prostate cancer following initial active surveillance: results from a prospective observational study.

BACKGROUND: Little is known about the outcome of radical prostatectomy (RP) in men initially followed on active surveillance (AS) for low-risk prostate cancer (PCa). OBJECTIVE: Evaluate pathology findings after RP in our prospective AS cohort. DESIGN, SETTING, AND PARTICIPANTS: All men participated in the Prostate Cancer Research International: Active Surveillance (PRIAS) study. Eligible men were initially diagnosed with low-risk PCa (clinical stage ≤ T2, prostate-specific antigen [PSA] ≤ 10 ng/ml, PSA density <0.2 ng/ml per ml, one or two positive biopsy cores, and Gleason score ≤ 6) and underwent RP between December 2006 and July 2011. The study protocol recommends RP in case of risk reclassification on repeat biopsy (Gleason score >6 and/or more than two positive cores) or a PSA doubling time ≤ 3 yr. MEASUREMENTS: Descriptive statistics were used to report on pathology findings for staging and grading. RESULTS AND LIMITATIONS: Pathology results were available in 167 out of 189 RP cases (88.4%). Median time to RP was 1.3 yr (range: 1.1-1.9). Protocol-based recommendations led to deferred RP in 143 men (75.7%); 24 men (12.7%) switched because of anxiety, and 22 (11.6%) had other reasons. Pathology results showed 134 (80.8%) organ-confined cases and 32 (19.2%) cases with extracapsular extension. Gleason scores ≤ 6, 3+4, 4+3, and 8 were found in 79 (47.3%), 64 (38.3%), 21 (12.6%), and 3 (1.8%) cases, respectively. Unfavourable RP results (pT3-4 and/or Gleason score ≥ 4+3) were found in 49 patients (29%), of whom 33 (67%) had a biopsy-related reason for deferred RP. CONCLUSIONS: RP results in men initially followed on AS show organ-confined disease and favourable Gleason grading in a majority of cases. Most men in our cohort had a protocol-based reason to switch to deferred RP. A main focus for AS protocols should be to improve the selection of patients at the time of inclusion to minimise reclassification of risk and preserve the chance for curative treatment, if indicated.

Towards an optimal interval for prostate cancer screening.

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

Prediction of prostate cancer risk: the role of prostate volume and digital rectal examination in the ERSPC risk calculators.

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

Prostate cancer incidence and disease-specific survival of men with initial prostate-specific antigen less than 3.0 ng/ml who are participating in ERSPC Rotterdam.

BACKGROUND: The European Randomised Study of Screening for Prostate Cancer (ERSPC) applies a prostate-specific antigen (PSA) cut-off value ≥3.0 ng/ml as an indication for lateralised sextant biopsy. OBJECTIVE: To analyse the incidence and disease-specific mortality for prostate cancer (PCa) in men with an initial PSA <3.0 ng/ml. DESIGN, SETTING AND PARTICIPANTS: From November 1993 to December 1999, a total of 42,376 men identified from population registries in the Rotterdam region (55-74 yr of age) were randomised to an intervention or control arm. A total of 19,950 men were screened during the first screening round. INTERVENTION: A PSA <3.0 ng/ml was below the biopsy threshold. PCa cases were identified at rescreens every 4 yr or as interval cancers. MEASUREMENTS: Distribution of incidence, aggressiveness, and disease-specific mortality of PCa per PSA range was measured. Causes of death were evaluated by an independent committee, and follow-up was complete until 31 December 2008. RESULTS AND LIMITATIONS: From 1993 to 2008, 915 PCa cases were diagnosed in 15,758 men (5.8%) with an initial PSA <3.0 ng/ml and a median age of 62.3 yr. Median overall follow-up was 11 yr. PCa incidence increased significantly with higher initial PSA levels. Aggressive PCa (clinical stage ≥T2c, Gleason score ≥8, PSA >20 ng/ml, positive lymph nodes, or metastases at diagnosis) was detected in 66 of 733 screen-detected PCa cases (9.0%) and 72 of 182 interval-detected PCa cases (39.6%). Twenty-three PCa deaths occurred in the total population (0.15%), with an increasing risk of PCa mortality in men with higher initial PSA values. CONCLUSIONS: The risk of PCa, aggressive PCa and PCa mortality in a screening population with initial PSA <3.0 ng/ml increases significantly with higher initial PSA levels. These results contribute to the risk stratification and individual management of men in PSA-based screening programmes.

Disease-specific survival of men with prostate cancer detected during the screening interval: results of the European randomized study of screening for prostate cancer-Rotterdam after 11 years of follow-up.

BACKGROUND: In a screening program, interval cancers are cancers diagnosed between two screening visits. OBJECTIVE: To assess the disease-specific survival (DSS) of men with prostate cancer (PCa) detected during the screening interval. DESIGN, SETTING, AND PARTICIPANTS: Within the European Randomized Study of Screening for Prostate Cancer section Rotterdam, 42 376 men identified from population registries (55-74 yr of age) were randomized to a screening or control arm. The median follow-up was 11 yr. INTERVENTION: Men with prostate-specific antigen ≥ 3.0 ng/ml were recommended to undergo lateralized sextant biopsy. The screening interval was 4 yr. MEASUREMENTS: The disease-specific mortality of men with interval cancers was compared with that of men with PCa in the control arm; the secondary end point was overall mortality. An independent committee determined the causes of death. RESULTS AND LIMITATIONS: In the screening arm, 139 men were diagnosed with interval cancer of whom 8 died of the disease. In the control arm, the corresponding numbers were 1149 and 128, respectively. When comparing men with interval cancer to men with PCa in the control arm, no statistically significant difference in disease-specific mortality (hazard ratio [HR]:1.12; 95% confidence interval [CI], 0.53-2.36; p = 0.77) and overall mortality (HR: 0.98; 95% CI, 0.68-1.38; p = 0.90) was found, adjusted for age, prognostic factors, and treatment modality. The follow-up is too limited to address the difference in DSS stratified for screening interval. CONCLUSIONS: In the setting of population-based PCa screening at 4-yr intervals, the DSS of men with interval cancer seems to be similar to that of men with PCa in the control arm. Given that interval cancers contribute significantly to PCa mortality, further benefit in DSS in the screening arm may be achieved by decreasing the occurrence of interval cancer. However, the balance between mortality reduction and overdiagnosis should be preserved. TRIAL REGISTRATION: ISRCTN49127736.