A Prospective Multicenter Comparison Study of Risk-adapted Ultrasound-directed and Magnetic Resonance Imaging-directed Diagnostic Pathways for Suspected Prostate Cancer in Biopsy-naïve Men.

BACKGROUND: European Association of Urology guidelines recommend a risk-adjusted biopsy strategy for early detection of prostate cancer in biopsy-naïve men. It remains unclear which strategy is most effective. Therefore, we evaluated two risk assessment pathways commonly used in clinical practice. OBJECTIVE: To compare the diagnostic performance of a risk-based ultrasound (US)-directed pathway (Rotterdam Prostate Cancer Risk Calculator [RPCRC] #3; US volume assessment) and a magnetic resonance imaging (MRI)-directed pathway. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective multicenter study (MR-PROPER) with 1:1 allocation among 21 centers (US arm in 11 centers, MRI arm in ten). Biopsy-naïve men with suspicion of prostate cancer (age ≥50 yr, prostate-specific antigen 3.0-50 ng/ml, ± abnormal digital rectal examination) were included. INTERVENTION: Biopsy-naïve men with elevated risk of prostate cancer, determined using RPCRC#3 in the US arm and Prostate Imaging Reporting and Data System scores of 3-5 in the MRI arm, underwent systematic biopsies (US arm) or targeted biopsies (MRI arm). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the proportion of men with grade group (GG) ≥2 cancer. Secondary outcomes were the proportions of biopsies avoided and GG 1 cancers detected. Categorical (nonparametric) data were assessed using the Mann-Whitney U test and χ2 tests. RESULTS AND LIMITATIONS: A total of 1965 men were included in the intention-to-treat population (US arm n = 950, MRI arm n = 1015). The US and MRI pathways detected GG ≥2 cancers equally well (235/950, 25% vs 239/1015, 24%; difference 1.2%, 95% confidence interval [CI] -2.6% to 5.0%; p = 0.5). The US pathway detected more GG 1 cancers than the MRI pathway (121/950, 13% vs 84/1015, 8.3%; difference 4.5%, 95% CI 1.8-7.2%; p < 0.01). The US pathway avoided fewer biopsies than the MRI pathway (403/950, 42% vs 559/1015, 55%; difference -13%, 95% CI -17% to -8.3%; p < 0.01). Among men with elevated risk, more GG ≥2 cancers were detected in the MRI group than in the US group (52% vs 43%; difference 9.2%, 95% CI 3.0-15%; p < 0.01). CONCLUSIONS: Risk-adapted US-directed and MRI-directed pathways detected GG ≥2 cancers equally well. The risk-adapted US-directed pathway performs well for prostate cancer diagnosis if prostate MRI capacity and expertise are not available. If prostate MRI availability is sufficient, risk assessment should preferably be performed using MRI, as this avoids more biopsies and detects fewer cases of GG 1 cancer. PATIENT SUMMARY: Among men with suspected prostate cancer, relevant cancers were equally well detected by risk-based pathways using either ultrasound or magnetic resonance imaging (MRI) to guide biopsy of the prostate. If prostate MRI availability is sufficient, risk assessment should be performed with MRI to reduce unnecessary biopsies and detect fewer irrelevant cancers.

The value of MRI in the detection of prostate cancer in a peripheral center.

INTRODUCTION: This study evaluated the value of pre-biopsy MRI and target biopsy in detection of significant prostate cancer in a peripheral center. METHODS: A retrospective study included all patients of whom a MRI of the prostate was performed before biopsy, initial and repeated biopsy, between June 2016 and May 2017. Patients underwent transrectal ultrasound guided 8-12 cores prostate biopsy and cognitive fusion target biopsy was performed if a suspicious lesion was seen on MRI. The prostate cancer detection was compared between the MRI cognitive target biopsy and standard random biopsy. RESULTS: In a total of 265 patients a MRI was performed of whom 115 underwent prostate biopsy, 96 patients underwent MRI before initial biopsies and 19 patients had previous negative biopsies. In the initial biopsy group 83 MRI's were abnormal and only 7 (8.4%) target biopsies had an additional value in detecting or upstaging prostate cancer. Prostate cancer was found in 4 of 13 (30.8%) normal MRI's. In the prior negative biopsy group, 4 of 18 abnormal MRI's had an additional value in upstaging or detecting prostate cancer. CONCLUSION: In this study the pre-biopsy MRI had a limited additional value compared to standard biopsy in detecting or upstaging prostate cancer.

Prostate cancer antigen 3: diagnostic outcomes in men presenting with urinary prostate cancer antigen 3 scores ≥100.

OBJECTIVE: To describe the results of 3 rounds of diagnostic testing and linkage to the Dutch Cancer Registry for men with an initial prostate cancer antigen 3 (PCA3) score ≥100. METHODS: Within an earlier reported comparative study of PCA3 vs prostate-specific antigen in a prescreened population, 90 men with a PCA3 score ≥100 were identified and underwent biopsy, 28 prostate cancers (PCs) were found, 62 men remained at risk of a diagnosis of PC. All men were offered repeat testing; 6 PCs were found in 20 men at rebiopsy. Men with at least 1 negative biopsy (n = 56) were invited to undergo magnetic resonance imaging (MRI) studies and MRI-guided biopsies if indicated. Linkage to the Dutch Cancer Registry after 2.8 years of follow-up was performed for men with negative biopsies. RESULTS: Of the 56 men at risk, 28 agreed to participate in further testing. They were offered MRI studies; only 7 men agreed, and in 2, suspicious lesions were found and biopsies carried out. Only 1 PC was diagnosed and classified as T1c, Gleason 3 + 3 = 6. The overall findings of 3 rounds of testing and of linkage to the cancer registry show that eventually 35 PCs were detected in 90 men with PCA3 scores ≥100 (positive predictive value 38.9%). CONCLUSION: Finding no PC despite extended diagnostic efforts in many men with initial PCA3 scores ≥100 is unexpected and might be clinically relevant.

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.

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.

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

OBJECTIVES: • To investigate whether cysteine-rich secretory protein 3 (CRISP-3) and/or ß-microseminoprotein (ß-MSP) expression in diagnostic prostate needle biopsies have predictive value for prostate cancer (PC) on radical prostatecomy (RP). • To evaluate their potential clinical implementation in a preoperative setting. PATIENTS AND METHODS: • In total, 174 participants from the European Randomized Study of Screening for Prostate Cancer, Rotterdam section, treated by RP for PC were included in the present study. • CRISP-3 and ß-MSP immunohistochemistry was performed on corresponding diagnostic needle biopsies. • Outcome was correlated with clinicopathological parameters (prostate-specific-antigen, PSA; number of positive biopsies; Gleason score, GS; pT-stage; surgical margins at RP) and significant PC at RP (pT3/4, or GS > 6, or tumour volume ≥ 0.5 mL) in the total cohort (n= 174) and in a subgroup with low-risk features at biopsy (PSA ≤ 10 ng/ml, cT ≤ 2, PSA density <0.20 ng/mL/g, GS < 7 and ≤ 2 positive biopsy cores; n= 87). RESULTS: • ß-MSP and CRISP-3 expression in PC tissue was heterogeneous, with variable staining intensities occurring in the same tissue specimen. • High expression of ß-MSP significantly correlated with GS < 7 at RP; it was not a predictor for significant PC at RP neither in the total group (n= 174; odds ratio, OR, 0.319; 95% confidence interval, CI, 0.060-1.695; P= 0.180), nor in the low-risk group (n= 87; OR, 0.227; 95% CI, 0.040-1.274; P= 0.092). • CRISP-3 expression was not related to clinicopathological parameters, and did not predict significant PC at RP in the total group (n= 174; OR, 1.056; 95% CI, 0.438-2.545; P= 0.904) or the low-risk group (n= 87; OR, 1.856; 95% CI, 0.626-5.506; P= 0.265). CONCLUSIONS: • High ß-MSP expression correlated with low GS in subsequent RP specimens, supporting the view that ß-MSP exerts a tumour-suppressive effect. • No significant prognostic value of ß-MSP or CRISP-3 in prostate needle biopsies for significant PC at RP was found. • ß-MSP or CRISP-3 do not have additional value in the therapeutic stratification of patients with PC.

A critical analysis of the tumor volume threshold for clinically insignificant prostate cancer using a data set of a randomized screening trial.

PURPOSE: The identification of clinically insignificant prostate cancer could help avoid overtreatment. Current criteria for insignificant prostate cancer use a tumor volume threshold of less than 0.5 ml for the index tumor. In this study we reassess this tumor volume threshold for clinically insignificant prostate cancer using an independent data set. MATERIALS AND METHODS: The rate of insignificant prostate cancer was calculated by modeling lifetime risk estimates of prostate cancer diagnosis in screened and nonscreened participants in a randomized prostate cancer screening trial. Using lifetime risk estimates 50.8% of screen detected prostate cancer was calculated to be clinically insignificant and the 49.2% largest tumor volume of 325 prostatectomy specimens was used to determine the threshold tumor volume for insignificant prostate cancer. Because stage and grade represent the strongest determinants of cancer aggressiveness, we also calculated the tumor volume threshold for insignificant cancer after the selection of patients with organ confined prostate cancer without Gleason pattern 4/5. The analyses were performed for total tumor volume and for index tumor volume. RESULTS: The minimum threshold tumor volume of the index tumor and total tumor was 0.55 and 0.70 ml, respectively. After accounting for tumor stage and grade we obtained a threshold volume for the index tumor and total tumor of 1.3 and 2.5 ml, respectively. CONCLUSIONS: We confirmed the original value of the index tumor volume threshold of 0.5 ml for insignificant prostate cancer, and we demonstrated that clinically insignificant prostate cancer may include index Gleason score 6, pT2 tumors with volumes up to at least 1.3 ml. These results suggest a reconsideration of current methods and nomograms used for pretreatment risk assessment.

Performance of prostate cancer antigen 3 (PCA3) and prostate-specific antigen in Prescreened men: reproducibility and detection characteristics for prostate cancer patients with high PCA3 scores (≥ 100).

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

Prostate specific antigen velocity does not aid prostate cancer detection in men with prior negative biopsy.

PURPOSE: Prostate specific antigen velocity has been proposed as a marker to aid in prostate cancer detection. We determined whether prostate specific antigen velocity could predict repeat biopsy results in men with persistently increased prostate specific antigen after initial negative biopsy. MATERIALS AND METHODS: We identified 1,837 men who participated in the Göteborg or Rotterdam section of the European Randomized Screening study of Prostate Cancer and who underwent 1 or more subsequent prostate biopsies after an initial negative finding. We evaluated whether prostate specific antigen velocity improved predictive accuracy beyond that of prostate specific antigen alone. RESULTS: Of the 2,579 repeat biopsies 363 (14%) were positive for prostate cancer, of which 44 (1.7%) were high grade (Gleason score 7 or greater). Prostate specific antigen velocity was statistically associated with cancer risk but had low predictive accuracy (AUC 0.55, p <0.001). There was some evidence that prostate specific antigen velocity improved AUC compared to prostate specific antigen for high grade cancer. However, the small increase in risk associated with high prostate specific antigen velocity (from 1.7% to 2.8% as velocity increased from 0 to 1 ng/ml per year) had questionable clinical relevance. CONCLUSIONS: Men with prior negative biopsy are at lower risk for prostate cancer at subsequent biopsies with high grade disease particularly rare. We found little evidence to support prostate specific antigen velocity to aid in decisions about repeat biopsy for prostate cancer.

Performance of the prostate cancer antigen 3 (PCA3) gene and prostate-specific antigen in prescreened men: exploring the value of PCA3 for a first-line diagnostic test.

BACKGROUND: The performance characteristics of serum prostate-specific antigen (PSA) as a diagnostic test for prostate cancer (PCa) are poor. The performance of the PCa antigen 3 (PCA3) gene as a primary diagnostic is unknown. OBJECTIVE: Assess the value of PCA3 as a first-line diagnostic test. DESIGN, SETTING AND PARTICIPANTS: Participants included men aged 63-75 who were invited for rescreening in the period from September 2007 to February 2009 within the European Randomised Study of Screening for Prostate Cancer, Rotterdam section. INTERVENTIONS: Lateral sextant biopsies were performed if the serum PSA value was > or =3.0 ng/ml and/or the PCA3 score was > or =10. MEASUREMENTS: Measurements included distribution and correlation of PSA value and PCA3 score and their relation to the number of cases and the characteristics of PCa detected. Additional value of PCA3 was included in men with previous negative biopsy and/or PSA <3.0 ng/ml. RESULTS AND LIMITATIONS: In 721 men, all biopsied, 122 PCa cases (16.9%) were detected. Correlation between PSA and PCA3 is poor (Spearman rank correlation: ρ=0.14; p<0.0001). A PSA > or =3.0 ng/ml misses 64.7% of the total PCa that can be detected with the sextant biopsy technique and 57.9% of serious PCa (T2a or higher and/or Gleason grade > or =4, n=19), and 68.2% of biopsies could have been avoided; the respective data for PCA3 > or =35 are 32%, 26.3%, and 51.7%. Performance of PCA3 in men with low PSA (area under the curve [AUC]: 0.63) and/or previous negative biopsy (AUC: 0.68) is unclear but has limited reliability due to small numbers. CONCLUSIONS: PCA3 as a first-line screening test shows improvement of the performance characteristics and identification of serious disease compared with PSA in this prescreened population.

Is delayed radical prostatectomy in men with low-risk screen-detected prostate cancer associated with a higher risk of unfavorable outcomes?

BACKGROUND: Strategies of active surveillance (AS) of low-risk screen-detected prostate cancer have emerged, because the balance between survival outcomes and quality of life issues when radically treating these malignancies is disputable. Delay before radical treatment caused by active surveillance may be associated with an impaired chance of curability. METHODS: Men diagnosed with low-risk (T1c/T2; prostate-specific antigen [PSA] = <10.0; PSA density, <0.2 ng/mL; Gleason score, 3 + 3=6; 1-2 positive biopsies) prostate cancer in the Swedish section of the European Randomized Study of Screening for Prostate Cancer who received radical prostatectomy (RP) were studied. One group received immediate RP, whereas another group received delayed RP after an initial period of expectant management. These groups were compared regarding histopathological and biochemical outcomes, correcting for baseline differences. RESULTS: Mean follow-up after diagnosis was 5.7 years (standard deviation [SD], 3.2). The immediate RP group (n = 158) received RP a mean of 0.5 (SD, 0.2) years after diagnosis; the delayed RP group (n = 69) received RP after 2.6 (SD, 2.0) years (P < .001). After adjustment for small baseline dissimilarities, no differences in RP frequencies of Gleason score >6 (odds ratio [OR], 1.54; P = .221), capsular penetration (OR, 2.45; P = .091), positive margins (OR, 1.34; P = .445), RP tumor volume (difference, 0.099; P = .155), or biochemical progression rates (P = .185, P = .689) were found between groups, although all data were in favor of immediate RP. CONCLUSIONS: With limited patient numbers available for analysis, differences in intermediate outcomes between immediate RP and delayed RP were nonsignificant. The delayed RP group may be subject to a selection bias. Prospective evaluation of active surveillance protocols is essential.

Eleven-year outcome of patients with prostate cancers diagnosed during screening after initial negative sextant biopsies.

BACKGROUND: The appropriate way of biopsying a prostate remains controversial. Is sextant biopsy still adequate with repeat screening? OBJECTIVE: Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), lateralized sextant biopsies were applied. In this analysis we use distant end points to study the fate of prostate cancers (PCa) potentially missed by initial biopsies. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study included 19 970 men ages 55-74 identified from the Rotterdam population registry and screened repeatedly for PCa between 1993 and 2005. PCa detected later in men with initially negative biopsies were considered as missed. Rescreening every 4 yr and a complete follow-up of 11 yr allowed an inventory of progressive and deadly disease in these men. INTERVENTION: Sextant biopsies initially, later lateralized, in screen-positive men. MEASUREMENTS: The fate of PCa potentially missed by initial sextant biopsies in terms of progression-free and PCa-specific survival were the main outcome measures. Kaplan-Meier analysis was used to evaluate differences between subgroups. RESULTS AND LIMITATIONS: In 3056 men with negative biopsies at the first screen, 287 PCa were subsequently detected. Of these 287 cases, 26 developed progressive disease and 7 died of PCa. Poor outcomes were encountered mainly in 20 interval cases. The seven PCa deaths in men with initially negative biopsies amounted to only 0.03% compared to the 0.35% PCa death rate in the whole population of 19 970 men. Limitations include the retrospective character of this analysis. CONCLUSIONS: The number of potentially missed cancers with a poor outcome in terms of progression-free survival and deaths from PCa is very low. Despite some limitations, our data show that lateralized sextant biopsy is not obsolete if repeated screening is applied.

False-negative prostate needle biopsies: frequency, histopathologic features, and follow-up.

Little is known about the frequency, histopathologic characteristics, and clinical consequences of false-negative prostate biopsies, that is, biopsies classified as benign but containing adenocarcinoma or atypical suspicious glands [atypical small acinar proliferations (ASAP)]. Objective of this study was to evaluate false-negative prostate biopsy in a prostate cancer screening setting. Prostate biopsy sets of 196 participants of a screening trial, which had been reported as "benign" at initial diagnosis, followed by a diagnosis of adenocarcinoma in a subsequent screening round were reviewed by 2 urologic pathologists. Adenocarcinoma was identified in 19 biopsy cores corresponding to 16 (8.2%) patients and ASAP in 24 cores, corresponding to 19 patients (9.7%). All missed prostate cancers were Gleason score 6 (3+3). After correction for patient selection, the overall false-negative biopsy rate was estimated to be 2.4%; 1.1% for prostate cancer; and 1.3% for ASAP. Clinicopathologic features at the time of initial biopsy and of subsequent prostate cancer diagnosis did not differ between patients with a false-negative or true benign biopsy. Relatively low number of atypical glands (<10 glands), intense intermingling with preexistent glands or lack of architectural disorganization were the most prominent risk factors for a false-negative diagnosis. Another potential pitfall was the presence of prostate cancer variants, as 1 adenocarcinoma was of foamy gland type and 3 of pseudohyperplastic type. Routine examination of at least 1 level of prostate biopsy sets at high magnification and awareness of histologic prostate cancer variants might reduce the risk of missing or misinterpreting a relevant lesion at prostate biopsy evaluation.

The effect of study arm on prostate cancer treatment in the large screening trial ERSPC.

Prostate cancer (PC) mortality is the most valid end-point in screening trials, but could be influenced by the choice of initial treatment if treatment has an effect on mortality. In this study, PC treatment was compared between the screening and control arms in a screening trial. Data were collected from the European Randomized Study of Screening for Prostate Cancer (ERSPC). The characteristics and initial treatment of PC cases detected in the screening and the control arm were compared. Polytomous logistic regression analysis was used to assess the influence of study arm on treatment, adjusting for potential confounders and with statistical imputation of missing values. A total of 8,389 PC cases were detected, 5,422 in the screening arm and 3,145 in the control arm. Polytomous regression showed that trial arm was associated with treatment choice after correction for missing values, especially in men with high-risk PC. A control subject with high-risk PC was more likely than a screen subject to receive radiotherapy (OR: 1.43, 95% CI: 1.01-2.05, p = 0.047), expectant management (OR: 2.92, 95% CI: 1.33-6.42, p = 0.007) or hormonal treatment (OR: 1.77, 95% CI: 1.07-2.94, p = 0.026) instead of radical prostatectomy. However, trial arm had only a minor role in treatment choice compared to other variables. In conclusion, a small effect of trial arm on treatment choice was seen, particularly in men with high-risk PC. Therefore, differences in treatment between arms are unlikely to play a major role in the interpretation of the results of the ERSPC.

Should pathologists routinely report prostate tumour volume? The prognostic value of tumour volume in prostate cancer.

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

The value of EZH2, p27(kip1), BMI-1 and MIB-1 on biopsy specimens with low-risk prostate cancer in selecting men with significant prostate cancer at prostatectomy.

OBJECTIVE: To assess the additional prognostic value of the molecular markers EZH2, MIB-1, p27(kip1) and BMI-1 on needle biopsies from men with low-risk prostate cancer, as this disease in needle biopsies shows a heterogeneous clinical outcome, and while it is known that the expression of these tissue markers is predictive of the clinical outcome after radical prostatectomy (RP) their value in prostate biopsies is largely unknown. PATIENTS AND METHODS: The study included men participating in a screening study, diagnosed with low-risk prostate cancer and subsequently treated with RP. Immunohistochemical staining for EZH2, MIB-1, p27(kip1) and BMI-1 on the needle biopsies were (semi)quantitatively scored and expression levels were related to significant disease at RP. Clinical low-risk prostate cancer was defined as a prostate-specific antigen (PSA) level of < or =10 ng/mL, clinical T-stage < or =2, biopsy Gleason score < or =6, a PSA density of <0.20 ng/mL/g and two or fewer positive cores. Significant PC at RP was defined as presence of any of extracapsular extension, Gleason pattern 4/5, or tumour volume > or =0.5 mL. RESULTS: In all, 86 biopsy specimens were included; there was high EZH2 expression (>1.0%) in 42% and a low p27(kip) expression (<90%) in 63%. Significant disease was present in 44 (51%) RP specimens. A high EZH2 (odds ratio 3.19, P = 0.043) and a low p27(kip1) (4.69, P = 0.036) were independent predictors for significant prostate cancer at RP. CONCLUSIONS: The determination of EZH2 and p27(kip1) on diagnostic needle biopsies supports the selection of men with indolent prostate cancer at RP. Especially p27(kip1) could improve the pretreatment risk assessment of patients with low-risk prostate cancer.

A risk-based strategy improves prostate-specific antigen-driven detection of prostate cancer.

BACKGROUND: Screening for prostate cancer (PC) is controversial due to uncertainties about its efficiency. OBJECTIVE: We aimed to develop strategies to reduce the number of unnecessary biopsies while still detecting most clinically important PC cases. DESIGN, SETTING, AND PARTICIPANTS: In 1850 men initially screened and biopsied (prostate-specific antigen [PSA] value > or =3.0 ng/ml) in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, we calculated both the probability of having a positive lateralized sextant biopsy [P(biop+)] and the probability of having an indolent cancer [P(ind)] if PC was detected at biopsy (n=541). Analyses of repeat screening included 225 cancers in 1201 men. INTERVENTIONS: The P(biop+) was based on applying a logistic regression model that included ultrasound volume, digital rectal exam, and transrectal ultrasound in addition to the PSA value. The P(ind) was based on a recently validated nomogram. MEASUREMENTS AND LIMITATIONS: At initial screening the fraction of positive biopsies was 29% (541 of 1850). Applying an additional P(biop+) cut-off of 12.5% implied that 613 of the 1850 men (33%) would not have been biopsied. This would result in an increase in the positive predictive value (PPV) to 38% (468 of 1237). At repeat screening a similar P(biop+) cut-off would result in an increase in the PPV from 19% (225 of 1201) to 25% (188 of 760). Thirteen percent of PC cases would not have been diagnosed, of which 70% (initial screening) and 81% (repeat screening) could be considered as potentially indolent. None of the deadly PC cases would have been missed. A PSA cut-off of > or =4.0 ng/ml resulted in similar numbers of biopsied cases saved but considerably higher numbers of missed diagnoses. CONCLUSIONS: An individualized screening algorithm using other available prebiopsy information in addition to PSA level can result in a considerable reduction of unnecessary biopsies. Very few important PC cases, for which diagnosis at a subsequent screening visit might be too late for treatment with curative intent, would be missed.

Prostate-specific antigen velocity for early detection of prostate cancer: result from a large, representative, population-based cohort.

BACKGROUND: It has been suggested that changes in prostate-specific antigen (PSA) over time (ie, PSA velocity [PSAV]) aid prostate cancer detection. Some guidelines do incorporate PSAV cut points as an indication for biopsy. OBJECTIVE: To evaluate whether PSAV enhances prediction of biopsy outcome in a large, representative, population-based cohort. DESIGN, SETTING, AND PARTICIPANTS: There were 2742 screening-arm participants with PSA <3 ng/ml at initial screening in the European Randomized Study of Screening for Prostate Cancer in Rotterdam, Netherlands, or Göteborg, Sweden, and who were subsequently biopsied during rounds 2-6 due to elevated PSA. MEASUREMENTS: Total, free, and intact PSA and human kallikrein 2 were measured for 1-6 screening rounds at intervals of 2 or 4 yr. We created logistic regression models to predict prostate cancer based on age and PSA, with or without free-to-total PSA ratio (%fPSA). PSAV was added to each model and any enhancement in predictive accuracy assessed by area under the curve (AUC). RESULTS AND LIMITATIONS: PSAV led to small enhancements in predictive accuracy (AUC of 0.569 vs 0.531; 0.626 vs 0.609 if %fPSA was included), although not for high-grade disease. The enhancement depended on modeling a nonlinear relationship between PSAV and cancer. There was no benefit if we excluded men with higher velocities, which were associated with lower risk. These results apply to men in a screening program with elevated PSA; men with prior negative biopsy were not evaluated in this study. CONCLUSIONS: In men with PSA of about ≥3 ng/ml, we found little justification for formal calculation of PSAV or for use of PSAV cut points to determine biopsy. Informal assessment of PSAV will likely aid clinical judgment, such as a sudden rise in PSA suggesting prostatitis, which could be further evaluated before biopsy.

Anxiety and distress during active surveillance for early prostate cancer.

BACKGROUND: Patients on active surveillance (AS) for early prostate cancer (PC) may experience feelings of anxiety and distress while living with "untreated" cancer. In this study, these feelings were quantified, and their associations with various psychologic, medical, demographic, and decision-related factors were assessed. METHODS: Men with recently diagnosed PC who participated in a prospective protocol-based AS program (the Prostate Cancer Research International: Active Surveillance study [PRAIS]) received a questionnaire (N = 150). Scores concerning decisional conflict (the Decisional Conflict Scale), depression (the Center for Epidemiologic Studies Depression Scale), generic anxiety (the abridged State-Trait Anxiety Inventory), and PC-specific anxiety (the Memorial Anxiety Scale for Prostate Cancer) were compared with reference values and the literature. Associations with scores on physical health (the Medical Outcomes Study 12-item short-form Physical Component Summary), personality (the Eysenck Personality Questionnaire), shared decision-making, knowledge of PC, and demographic and medical parameters were determined with univariate and multivariate linear regression analyses. RESULTS: The questionnaire response rate was 86% (129 of 150 men). Of all respondents, 81%, 92%, 83%, and 93% scored better than reference values for clinically significant uncertainty regarding the treatment decision, depression, generic anxiety, and PC-specific anxiety, respectively. Scores were comparable to or more favorable than those of men (reported in literature) who underwent other treatments for localized PC. In multivariate analysis, the following associations emerged: a perceived important role of the physician in shared decision-making was associated with higher decisional conflict, better physical health was associated with lower depression, neurotic personality was associated with higher depression and with generic and PC-specific anxiety, and higher prostate-specific antigen level was associated with higher PC-specific anxiety. CONCLUSIONS: Men on protocol-based AS mainly reported favorable levels of anxiety and distress. A neurotic personality score was associated with unfavorable effects. These findings may help to optimize patient selection for AS or to select men for supportive measures.

Screening: should more biopsies be taken in larger prostates?

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