Overall survival benefit of androgen suppression in addition to dose-escalated external beam radiotherapy for high-risk prostate cancer: Nationwide real-world data indicates a shift in men that benefit.

OBJECTIVE: To evaluate the real-world added value of androgen deprivation therapy (ADT) in addition to external beam radiotherapy (EBRT) in men with high-risk non-metastatic prostate cancer, in view of advances in radiotherapy and diagnostics. METHODS: All Dutch men diagnosed with high-risk non-metastatic prostate cancer (defined as: ≥cT2c-T3b N0M0, PSA ≥20-50 ng/ml, and/or Gleason score ≥8 (International Society of Urological Pathology [ISUP] grade ≥4)) from 2009 through 2019 and treated with EBRT with or without ADT were identified in the population-based Netherlands Cancer Registry. Propensity scores were used to match (1:1) men that received ADT to men that did not receive ADT. Subsequently, OS was compared. Analyses were also stratified by number of high-risk features, 1 (either ≥cT2c, PSA >20 ng/ml or Gleason score ≥8) versus ≥2 (out of ≥cT2c, PSA >20 ng/ml and Gleason score ≥8). RESULTS: A total of 14,773 men with high-risk non-metastatic prostate cancer were identified, 3,958 (27%) of which received EBRT alone. After matching, 3,427 men remained in both groups and baseline characteristics were well-balanced. After a median follow-up of 92 months, OS was better in men treated with EBRT and ADT compared to men treated with EBRT alone (10-year OS: 66.4% versus 61.8%; HR 0.88 [95%CI: 0.80-0.96]). There was no statistically significant difference in OS in the subgroup of men with only 1 high-risk feature (10-year OS 67.7% versus 64.9%; HR 0.95 [95%CI: 0.85-1.07]). CONCLUSIONS: In a contemporary cohort of men treated for high-risk non-metastatic prostate cancer with EBRT, an OS benefit of adding ADT was only observed in men with at least 2 high-risk features. These results suggest that improvements in diagnostics and treatment in recent decades have resulted in a stage shift of men benefiting from the addition of ADT to EBRT.

Prostate cancer risk assessment by the primary care physician and urologist: transabdominal- versus transrectal ultrasound prostate volume-based use of the Rotterdam Prostate Cancer Risk Calculator.

Background: Our objective was to assess the accuracy of transabdominal ultrasound (TAUS) measured prostate volume in the primary care setting with transrectal ultrasound (TRUS) measured prostate volume by the urologist as the reference test. Furthermore, our objective was to assess whether risk-stratification using TAUS prostate volume by the primary care physician could reduce unnecessary referrals to the urologist. Methods: Men in two Dutch primary care offices with a prostate cancer (PCa) screening request received a digital rectal examination (DRE), prostate specific-antigen (PSA), and TAUS prostate volume measurement by the general practitioner, followed by Rotterdam Prostate Cancer Risk Calculator (RPCRC) risk assessment. The examination was repeated by a urologist using TRUS. A prostate biopsy was performed in case of a RPCRC positive biopsy advice. A non-inferiority analysis was performed comparing TAUS and TRUS prostate volume differences. A risk-based referral strategy using TAUS and the RPCRC in the primary care setting was compared with the standard referral strategy based on PSA (≥3 ng/mL) and DRE. Results: A total of 105 men were included with a median PSA of 1.9 ng/mL. The mean prostate volumes measured by TAUS and TRUS were 55 and 45 mL, respectively. The mean overestimation of the prostate volume by TAUS as compared to the reference test was 9.9 mL (95% CI: 5.9-13.8). According to Dutch standard practice, 41 out of 105 (39%) men would have been referred to the urologist. Stratification in primary care based on the RPCRC using TAUS prostate volume would have avoided 29 out of the 41 (71%) referrals, at the expense of non-referral of 5 out of 11 (45%) men with a biopsy indication, according to the urologist. Conclusions: RPCRC-based risk stratification in primary care using TAUS prostate volume measurement is feasible and may prevent unnecessary referrals to the urologist and reduce costs. The accuracy of the risk assessment with TAUS might be improved by sufficient training and centralization to achieve a higher volume of consultations in primary care facilities.

Value of Serial Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging-guided Biopsies in Men with Low-risk Prostate Cancer on Active Surveillance After 1 Yr Follow-up.

BACKGROUND: Active surveillance (AS) aims to reduce overtreatment of low-risk prostate cancer (PC). Incorporating multiparametric magnetic resonance imaging (mp-MRI) and MR-guided biopsy (MRGB) in an AS protocol might contribute to more accurate identification of AS candidates. OBJECTIVE: To evaluate the value of 3T mp-MRI and MRGB in PC patients on AS at inclusion and after 12-mo follow-up. DESIGN, SETTING, AND PARTICIPANTS: Patients with cT1c-cT2 PC, prostate-specific antigen (PSA) ≤10ng/ml, PSA density <0.2ng/ml/ml, and Gleason scores (GSs) of ≤6 and ≤2 positive biopsy cores were included and followed in an AS protocol including mp-MRI and MRGB. The mp-MRI and MRGB were performed at <3 and 12 mo after diagnosis. Reclassification was defined as GS >6, >2 positive cores at repeat transrectal ultrasound-guided biopsy (TRUSGB), presence of PC in >3 separate cancer foci upon both MRGB and TRUSGB, or cT3 tumor on mp-MRI. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Reclassification rates, treatment after discontinuation, and outcome on radical prostatectomy after discontinuing AS were reported. Uni- and multivariate analyses were performed to identify predictors of reclassification after 1 yr. RESULTS AND LIMITATIONS: From 2009 to 2013, a total of 111 of 158 patients were consecutively and prospectively included. Around initial diagnosis, 36 patients were excluded from the study protocol; mp-MRI+MRGB reclassified 25/111 (23%) patients, and 11 patients were excluded at own request. Reasons for reclassification were as follows: GS upgrade (15/25, 60%); cT3 disease (3/25, 12%); suspicion of bone metastases (1/25, 4%); and multifocal disease upon MRGB (6/25, 24%). Repeat examinations after 1 yr showed reclassification in 33/75 patients (44%). Reasons were the following: GS upgrade upon TRUSGB (9/33, 27%); volume progression upon TRUSGB (9/33, 27%); cT3 disease upon mp-MRI (1/33, 3%); GS upgrade upon MRGB (1/33, 3%); volume progression upon MRGB (1/33, 3%); multifocal disease upon MRGB (2/33, 6%); and upgrade or upstage upon both TRUSGB and MRGB (10/33, 30%). On logistic regression analysis, the presence of cancer at initial mp-MRI and MRGB examinations was the only predictor of reclassification after 1 yr (odds ratio 5.9, 95% confidence interval 2.0-17.6). CONCLUSIONS: Although mp-MRI and MRGB are of additional value in the evaluation of PC patients on AS, the value of mp-MRI after 1 yr was limited. As a considerable percentage of GS ≥7 PC after 1 yr was detected only by TRUSGB, TRUSGB cannot be omitted yet. PATIENT SUMMARY: More aggressive tumors are detected if low-risk prostate cancer patients are additionally monitored by magnetic resonance imaging. However, some high-grade tumors are detected only by transrectal ultrasound-guided biopsy.

Characteristics of Prostate Cancer Found at Fifth Screening in the European Randomized Study of Screening for Prostate Cancer Rotterdam: Can We Selectively Detect High-grade Prostate Cancer with Upfront Multivariable Risk Stratification and Magnetic Resonance Imaging?

BACKGROUND: The harm of screening (unnecessary biopsies and overdiagnosis) generally outweighs the benefit of reducing prostate cancer (PCa) mortality in men aged ≥70 yr. Patient selection for biopsy using risk stratification and magnetic resonance imaging (MRI) may improve this benefit-to-harm ratio. OBJECTIVE: To assess the potential of a risk-based strategy including MRI to selectively identify men aged ≥70 yr with high-grade PCa. DESIGN, SETTING, AND PARTICIPANTS: Three hundred and thirty-seven men with prostate-specific antigen ≥3.0 ng/ml at a fifth screening (71-75 yr) in the European Randomized study of Screening for Prostate Cancer Rotterdam were biopsied. One hundred and seventy-nine men received six-core transrectal ultrasound biopsy (TRUS-Bx), while 158 men received MRI, 12-core TRUS-Bx, and fusion TBx in case of Prostate Imaging Reporting and Data System ≥3 lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the overall, low-grade (Gleason Score 3+3) and high-grade (Gleason Score ≥ 3+4) PCa rate. Secondary outcome was the low- and high-grade PCa rate detected by six-core TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx. Tertiary outcome was the reduction of biopsies and low-grade PCa detection by upfront risk stratification with the Rotterdam Prostate Cancer Risk Calculator 4. RESULTS AND LIMITATIONS: Fifty-five percent of men were previously biopsied. The overall, low-grade, and high-grade PCa rates in biopsy naïve men were 48%, 27%, and 22%, respectively. In previously biopsied men these PCa rates were 25%, 20%, and 5%. Sextant TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx had a similar high-grade PCa rate (11%, 12%, and 11%) but a significantly different low-grade PCa rate (17%, 28%, and 7%). Rotterdam Prostate Cancer Risk Calculator 4-based stratification combined with 12-core TRUS-Bx ± MRI-TBx would have avoided 65% of biopsies and 68% of low-grade PCa while detecting an equal percentage of high-grade PCa (83%) compared with a TRUS-Bx all men approach (79%). CONCLUSIONS: After four repeated screens and ≥1 previous biopsies in half of men, a significant proportion of men aged ≥70 yr still harbor high-grade PCa. Upfront risk stratification and the combination of MRI and TRUS-Bx would have avoided two-thirds of biopsies and low-grade PCa diagnoses in our cohort, while maintaining the high-grade PCa detection of a TRUS-Bx all men approach. Further studies are needed to verify these results. PATIENT SUMMARY: Prostate cancer screening reduces mortality but is accompanied by unnecessary biopsies and overdiagnosis of nonaggressive tumors, especially in repeatedly screened elderly men. To tackle these drawbacks screening should consist of an upfront risk-assessment followed by magnetic resonance imaging and transrectal ultrasound-guided biopsy.

Effect of pathologic revision and Ki67 and ERG immunohistochemistry on predicting radical prostatectomy outcome in men initially on active surveillance.

OBJECTIVE: To investigate if pathologic biopsy reevaluation and implementation of immunohistochemical biomarkers could improve prediction of radical prostatectomy outcome in men initially on active surveillance. METHODS: Biopsy specimens from diagnosis until switching to radical prostatectomy in men initially on active surveillance in the Dutch part of the Prostate cancer Research International Active Surveillance (PRIAS) study were collected and revised by a single pathologist. Original and revised biopsy Gleason score were compared and correlated with radical prostatectomy Gleason score. Biopsy specimens were immunohistochemically stained for Ki67 and ERG. Predictive ability of clinical characteristics and biomarkers on Gleason ≥7 or ≥pT3 on radical prostatectomy was tested using logistic regression and ROC curve analysis. RESULTS: A total of 150 biopsies in 95 men were revised. In 13% of diagnostic or second-to-last biopsies and 20% of the last biopsies on active surveillance revision of Gleason score resulted in change of recommendation (ie, active treatment or active surveillance). Concordance with Gleason score on radical prostatectomy was however similar for both the revised and original Gleason on biopsy. Ki67 and ERG were not statistically significant predictors of Gleason ≥7 or ≥pT3 on radical prostatectomy. CONCLUSIONS: Although interobserver differences in pathology reporting on biopsy could result in a change of management strategy in approximately 13-20% of men on active surveillance, both pathological revision and tested biomarkers (Ki67 and ERG) did not improve prediction of outcome on radical prostatectomy. Undersampling of most aggressive tumor remains the main focus in order to increase accurate grading at time of treatment decision making.

Risk-stratification based on magnetic resonance imaging and prostate-specific antigen density may reduce unnecessary follow-up biopsy procedures in men on active surveillance for low-risk prostate cancer.

OBJECTIVES: To assess the value of risk-stratification based on magnetic resonance imaging (MRI) and prostate-specific antigen density (PSA-D) in reducing unnecessary biopsies without missing Gleason pattern 4 prostate cancer in men on active surveillance (AS). PATIENTS AND METHODS: In all, 210 men on AS with Gleason score 3 + 3 prostate cancer received a first MRI and if indicated [Prostate Imaging Reporting and Data System (PI-RADS) score ≥3] targeted biopsy (TBx) using MRI-transrectal ultrasonography (TRUS) fusion. The MRI was performed 3 months after diagnosis (group A: n = 97), at confirmatory biopsy (group B: n = 39) or at surveillance biopsy after one or more repeat TRUS-guided systematic biopsies (TRUS-Bx) (group C: n = 74). The primary outcome was upgrading to Gleason score ≥3 + 4 prostate cancer based on MRI ± TBx in groups A, B and C. Biopsy outcomes were stratified for the overall PI-RADS score and PSA-D to identify a subgroup of men in whom a biopsy could have been avoided as no Gleason score upgrading was detected. RESULTS: In all, 134/210 (64%) men had a positive MRI and 51/210 (24%) men had Gleason score upgrading based on MRI-TBx. The percentage of Gleason score upgrading based on MRI-TBx was 23% (22/97), 23% (9/39) and 27% (20/74) in respectively groups A, B and C. Additional Gleason score upgrading detected by TRUS-Bx occurred in 8% (3/39) of men in group B and 6% (1/17) of men who received TRUS-Bx in group C. No Gleason score upgrading was detected by MRI-TBx in men with a PI-RADS score of 3 and a PSA-D of <0.15 ng/mL2 (n = 15), nor by TRUS-Bx in men with a PI-RADS score of 1-3 and a PSA-D of <0.15 ng/mL2 (n = 15). CONCLUSION: At least one out of five men on AS with Gleason score 3 + 3 prostate cancer at diagnostic TRUS-Bx show Gleason score upgrading based on first MRI ± TBx at baseline, confirmatory or surveillance biopsy. Men with a PI-RADS score of 1-3 and PSA-D of <0.15 ng/mL2 did not show Gleason score upgrading at MRI ± TBx or TRUS-Bx at each time point of surveillance. Thus risk-stratification based on PI-RADS and PSA-D may reduce unnecessary follow-up biopsy procedures in men on AS.

Long-term follow-up after active surveillance or curative treatment: quality-of-life outcomes of men with low-risk prostate cancer.

PURPOSE: To compare long-term (4-10 years) quality of life (QoL) of men with low-risk prostate cancer (PCa) treated by different modalities and a reference group without PCa. METHODS: In this cross-sectional study, four groups were sent a one-time QoL-questionnaire; PCa patients (1) following the structured Prostate cancer Research International Active Surveillance protocol, (2) who underwent radical prostatectomy (RP) in the context of the European Randomized study of Screening for Prostate Cancer-section Rotterdam, (3) who underwent radiotherapy (RT) at an academic hospital in The Netherlands, and (4) an age-matched reference group of men without PCa. The QoL-questionnaire addressed prostate-specific health (EPIC), generic health (SF-12), and anxiety (STAI-6). Statistical significance (p ≤ 0.05) and clinical relevance (≥0.5 SD) of differences between groups were assessed. RESULTS: The AS, RP, RT, and reference group response rates amounted to 74% (122/165), 66% (70/106), 66% (221/335), and 75% (205/273), respectively. At a mean of 6.6 years of follow-up, active surveillance (AS)-men reported better urinary function [M = 93.0 (SD = 10.6) vs. 80.0 (SD = 19.1), p ≤ 0.001], less urinary incontinence [M = 90.0 (SD = 14.6) vs. 70.1 (SD = 28.8), p ≤ 0.001], and better sexual function [M = 40.9 (SD = 24.6) vs. 14.8 (17.7), p ≤ 0.001, clinically relevant] than RP-men. Compared to RT, AS-men reported better sexual function [M = 40.9 (SD = 24.6) vs. 25.8 (SD = 25.0), p = 0.069]. The four groups reported similarly low anxiety levels; the number of highly anxious men (STAI ≥ 44) ranged from 8 to 13%. For all QoL domains, men on AS and men without PCa reported very similar scores. CONCLUSIONS: Prostate-specific function of AS-men was significantly better than that of RP-men. When comparing AS to RT, a borderline significant difference in sexual function was seen. Men who followed an AS strategy for a long-term period were not anxious and accepted it well, suggesting that AS may be a good treatment option for men with low-risk PCa.

Biopsy undergrading in men with Gleason score 6 and fatal prostate cancer in the European Randomized study of Screening for Prostate Cancer Rotterdam.

OBJECTIVES: A total of 15 men who died of prostate cancer had cT1/2 biopsy Gleason score ≤6 prostate cancer at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam. Our objective was to explain (part of) these prostate cancer deaths by undergrading with the classical Gleason score. METHODS: Biopsy specimens of 98 men with classical Gleason score ≤6 or 3 + 4 = 7 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam were retrospectively reviewed by two pathologists using the International Society of Urological Pathology 2014 modified Gleason score. These 98 men included 15 men with cT1/2 classical Gleason score ≤6 who died of prostate cancer (cases) and 83 randomly selected men with classical Gleason score ≤6 or 3 + 4 = 7 (controls). The primary outcome was the reclassification rate from classical Gleason score ≤6 to modified classical Gleason score 3 + 4 = 7 (grade group 2) stratified for prostate cancer death. The secondary outcome was the rate of cribriform/intraductal carcinoma in Gleason score-reclassified men stratified for prostate cancer death. RESULTS: A total of 79 out of 98 men had classical Gleason score ≤6 prostate cancer. A total of eight out of 15 (53%) prostate cancer deaths with classical Gleason score ≤6 were reclassified to modified Gleason score 3 + 4 = 7, compared with 16 out of 64 (25%) men with non-fatal prostate cancer (P = 0.017). A total of five out of eight (63%) Gleason score-reclassified men with fatal prostate cancer had cribriform/intraductal carcinoma, compared with two out of 16 (13%) Gleason score-reclassified men with non-fatal prostate cancer (P = 0.011). CONCLUSIONS: Part of the prostate cancer deaths with Gleason score ≤6 at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam could be explained by biopsy undergrading. The present study confirms that the International Society of Urological Pathology 2014 modified Gleason score is more accurate for prognostic assessment based on prostate biopsy than the classical Gleason score.

A Decade of Active Surveillance in the PRIAS Study: An Update and Evaluation of the Criteria Used to Recommend a Switch to Active Treatment.

BACKGROUND: The Prostate Cancer Research International Active Surveillance (PRIAS) study was initiated a decade ago to study the most optimal selection and follow-up of men on active surveillance (AS). OBJECTIVE: We report on 10 yr of follow-up of men on AS in the PRIAS study and evaluate if criteria used to recommend a switch to active treatment truly predict unfavorable outcome on subsequent radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: Men with low-risk prostate cancer were included and followed prospectively on AS. Follow-up consisted of regular prostate-specific antigen (PSA) tests, digital rectal examinations, and biopsies. Men with Gleason >3+3, more than two positive biopsy cores, or stage higher than cT2 were advised to switch to active treatment (until 2014, a PSA doubling time [PSA DT] of 0-3 yr was also used). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Reclassification rates, treatment after discontinuation, and outcome on RP after discontinuing AS were reported. Regression analysis on the outcome of RP was used to evaluate the predictive value of criteria currently used to recommend a switch to active treatment. Kaplan-Meier and competing risk analysis were used to report discontinuation rates over time and long-term oncologic end points. RESULTS AND LIMITATIONS: A total of 5302 men were included in PRIAS across 18 countries. Reclassification rates remained stable on all subsequent biopsies, with 22-33% of men having either Gleason >3+3 or more than two positive cores on any repeat biopsy. At 5 and 10 yr of follow-up, 52% and 73% of men, respectively, had discontinued AS, most of them because of protocol-based reclassification. A third of men undergoing subsequent RP had favorable pathologic tumor features (Gleason 3+3 and pT2). Of the criteria used to recommend a switch to active treatment, more than two positive cores and a PSA DT of 0-3 yr were not predictive of unfavorable pathologic outcome on RP. CONCLUSIONS: A substantial group of men discontinued AS without subsequent unfavorable tumor features on RP; therefore, we propose Gleason upgrading and cT3 as the only indicators for an immediate switch to active treatment. Surrogate indicators (eg, more than two positive cores and a fast-rising PSA) should not trigger immediate active treatment but rather further investigation to confirm the suspicion of higher risk disease. PATIENT SUMMARY: We confirmed the safety of active surveillance as a treatment option for men with low-risk prostate cancer; however, some changes could be made to the follow-up protocol to safely increase the number of men who remain on active surveillance.

Active surveillance for prostate cancer: a narrative review of clinical guidelines.

In the past decade active surveillance (AS) of men with localized prostate cancer has become an increasingly popular management option, and a range of clinical guidelines have been published on this topic. Existing guidelines regarding AS for prostate cancer vary widely, but predominantly state that the most suitable patients for AS are those with pretreatment clinical stage T1c or T2 tumours, serum PSA levels <10 ng/ml, biopsy Gleason scores of 6 or less, a maximum of one or two tumour-positive biopsy core samples and/or a maximum of 50% of cancer per core sample. Following initiation of an AS programme, most guidelines recommend serial serum PSA measurements, digital rectal examinations and surveillance biopsies to check for and identify pathological indications of tumour progression. Definitions of disease reclassification and progression differ among guidelines and multiple criteria for initiation of definitive treatment are proposed. The variety of descriptions of criteria for clinically insignificant prostate cancer indicates a lack of consensus on optimal AS and intervention thresholds. A single set of guidelines are needed in order to reduce variations in clinical practice and to optimize clinical decision-making. To enable truly evidence-based guidelines, further research that combines existing evidence, while also gathering information from more long-term studies is needed.

Complications after prostate biopsies in men on active surveillance and its effects on receiving further biopsies in the Prostate cancer Research International: Active Surveillance (PRIAS) study.

OBJECTIVE: To study the risk of serial prostate biopsies on complications in men on active surveillance (AS) and determine the effect of complications on receiving further biopsies. PATIENTS AND METHODS: In the global Prostate cancer Research International: Active Surveillance (PRIAS) study, men are prospectively followed on AS and repeat prostate biopsies are scheduled at 1, 4, and 7 years after the diagnostic biopsy, or once yearly if prostate-specific antigen-doubling time is <10 years. Data on complications after biopsy, including infection, haematuria, haematospermia, and pain, were retrospectively collected for all biopsies taken during follow-up in men from several large participating centres. Generalised estimating equations were used to test predictors of infection after biopsy. Competing risk analysis was used to compare the rates of men receiving further biopsies between men with and without previous complications. RESULTS: In all, 2 184 biopsies were taken in 1 164 men. Infection was reported after 55 biopsies (2.5%), and one in five men reported any form of complication. At multivariable analysis, the number of previous biopsies was not a significant predictor of infection (odds ratio 1.04, 95% confidence interval 0.76-1.43). The only significant predictor for infection was the type of prophylaxis used. Of all men with a complication at the diagnostic or first repeat biopsy, 21% did not have a repeat biopsy at the time a repeat biopsy was scheduled according to protocol, vs 12% for men without a previous biopsy complication. CONCLUSION: In our present cohort of men on AS, we found no evidence that repeat prostate biopsy in itself posed a risk of infection. However, complications after biopsy were not uncommon and after a complication men were less likely to have further biopsies. We should aim to safely reduce the amount of repeat biopsies in men on AS.

Risk-based Patient Selection for Magnetic Resonance Imaging-targeted Prostate Biopsy after Negative Transrectal Ultrasound-guided Random Biopsy Avoids Unnecessary Magnetic Resonance Imaging Scans.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) is increasingly used in men with suspicion of prostate cancer (PCa) after negative transrectal ultrasound (TRUS)-guided random biopsy. Risk-based patient selection for mpMRI could help to avoid unnecessary mpMRIs. OBJECTIVE: To study the rate of potentially avoided mpMRIs after negative TRUS-guided random biopsy by risk-based patient selection using the Rotterdam Prostate Cancer Risk Calculator (RPCRC). DESIGN, SETTING, AND PARTICIPANTS: One hundred and twenty two consecutive men received a mpMRI scan and subsequent MRI-TRUS fusion targeted biopsy in case of suspicious lesion(s) (Prostate Imaging Reporting and Data System ≥ 3) after negative TRUS-guided random biopsy. Men were retrospectively stratified according to the RPCRC biopsy advice to compare targeted biopsy outcomes after risk-based patient selection with standard (prostate specific antigen and/or digital rectal examination-driven) patient selection. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The rate of potentially avoided mpMRIs by RPCRC-based patient selection in relation to the rate of missed high-grade (Gleason ≥ 3+4) PCa. Receiver operating characteristic curve analysis was performed to determine the area under the curve of the RPCRC for (high-grade) PCa. RESULTS AND LIMITATIONS: Of the 60 men with a positive biopsy advice, six (10%) had low-grade PCa and 28 (47%) had high-grade PCa in targeted biopsy. Of the 62 men with a negative advice, two (3%) had low-grade PCa and three (5%) had high-grade PCa. Upfront RPCRC-based patient selection would have avoided 62 (51%) of 122 mpMRIs and two (25%) of eight low-grade PCa diagnoses, missing three (10%) of 31 high-grade PCa. The area under the curve of the RPCRC for PCa and high-grade PCa was respectively 0.76 (95% confidence interval 0.67-0.85) and 0.84 (95% confidence interval 0.76-0.93). CONCLUSIONS: Risk-based patient selection with the RPCRC can avoid half of mpMRIs after a negative prostate specific antigen and/or digital rectal examination-driven TRUS-guided random biopsy. Further improvement in risk-based patient selection for mpMRI could be made by adjusting the RPCRC for MRI-targeted biopsy outcome prediction. PATIENT SUMMARY: The suspicion of prostate cancer remains in many men after a negative ultrasound-guided prostate biopsy. These men increasingly receive an often unnecessary magnetic resonance imaging (MRI) scan. We found that patient selection for MRI based on the Rotterdam Prostate Cancer Risk Calculator biopsy advice could avoid half of the MRIs.

Rule-based versus probabilistic selection for active surveillance using three definitions of insignificant prostate cancer.

PURPOSE: To study whether probabilistic selection by the use of a nomogram could improve patient selection for active surveillance (AS) compared to the various sets of rule-based AS inclusion criteria currently used. METHODS: We studied Dutch and Swedish patients participating in the European Randomized study of Screening for Prostate Cancer (ERSPC). We explored which men who were initially diagnosed with cT1-2, Gleason 6 (Gleason pattern ≤3 + 3) had histopathological indolent PCa at RP [defined as pT2, Gleason pattern ≤3 and tumour volume (TV) ≤0.5 or TV ≤ 1.3 ml, and TV no part of criteria (NoTV)]. Rule-based selection was according to the Prostate cancer Research International: Active Surveillance (PRIAS), Klotz, and Johns Hopkins criteria. An existing nomogram to define probability-based selection for AS was refitted for the TV1.3 and NoTV indolent PCa definitions. RESULTS: 619 of 864 men undergoing RP had cT1-2, Gleason 6 disease at diagnosis and were analysed. Median follow-up was 8.9 years. 229 (37%), 356 (58%), and 410 (66%) fulfilled the TV0.5, TV1.3, and NoTV indolent PCa criteria at RP. Discriminating between indolent and significant disease according to area under the curve (AUC) was: TV0.5: 0.658 (PRIAS), 0.523 (Klotz), 0.642 (Hopkins), 0.685 (nomogram). TV1.3: 0.630 (PRIAS), 0.550 (Klotz), 0.615 (Hopkins), 0.646 (nomogram). NoTV: 0.603 (PRIAS), 0.530 (Klotz), 0.589 (Hopkins), 0.608 (nomogram). CONCLUSIONS: The performance of a nomogram, the Johns Hopkins, and PRIAS rule-based criteria are comparable. Because the nomogram allows individual trade-offs, it could be a good alternative to rigid rule-based criteria.

Ethnicity and prostate cancer: the way to solve the screening problem?

In their analysis in BMC Medicine, Lloyd et al. provide individual patient lifetime risks of prostate cancer diagnosis and prostate cancer death stratified by ethnicity. This easy to understand information is helpful for men to decide whether to start prostate-specific antigen testing (i.e. screening). A higher lifetime risk of prostate cancer death in some ethnic groups is not automatically a license to start screening. The potential benefit in the form of reducing metastases and death should still be weighed against the potential risk of over diagnosis. In case of ethnicity, this harm-to-benefit ratio does not differ between groups. Stratifying men for screening based on ethnicity is therefore not optimal and will not solve the current screening problem. Other methods for risk-stratifying men have been proven to produce a more optimal harm-to-benefit ratio. Please see related article: http://www.biomedcentral.com/1741-7015/13/171.

Compliance Rates with the Prostate Cancer Research International Active Surveillance (PRIAS) Protocol and Disease Reclassification in Noncompliers.

BACKGROUND: Men with prostate cancer on active surveillance (AS) are advised to follow strict follow-up schedules and switch to definitive treatment on risk reclassification. However, some men might not adhere to these strict protocols. OBJECTIVE: To determine the number of noncompliers and disease reclassification rates in men not complying with the follow-up protocol of the Prostate Cancer Research International Active Surveillance (PRIAS) study. DESIGN, SETTING, AND PARTICIPANTS: A total of 4547 men with low-risk prostate cancer were included and prospectively followed on AS. Men were regularly examined using prostate-specific antigen (PSA), digital rectal examination, and repeat biopsies, and were advised to switch to definitive treatment on disease reclassification (>cT2c, Gleason score > 3+3, >2 cores positive, or PSA doubling time [PSA-DT] 0-3 yr). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Rates of men not complying with follow-up visits or a recommendation to discontinue AS are reported. Biopsy outcome (Gleason ≥7 or >2 cores positive) was compared between compliers and noncompliers using Cox proportional hazards analysis. RESULTS AND LIMITATIONS: The compliance rate for PSA visits was 91%. By contrast, the compliance rate for standard repeat biopsies decreased over time (81%, 60%, 53%, and 33% at 1, 4, 7, and 10 yr after diagnosis, respectively). Yearly repeat biopsies in men with faster rising PSA (PSA-DT 3-10 yr) was low at <30%, although these men had higher upgrading rates at repeat biopsy (25-30% vs 16%). PSA-DT of 0-3 yr was the most common recommendation for discontinuation, but 71% continued on AS. Men with PSA-DT of 0-3 yr were at higher risk of upgrading on repeat biopsy (hazard ratio 2.02, 95% confidence interval 1.36-3.00) compared to men without fast rising PSA. CONCLUSION: Some men and their physicians do not comply with AS follow-up protocols. In particular, yearly repeat biopsies in men with fast rising PSA are often ignored, as is the recommendation to discontinue AS because of very fast rising PSA. Although these men are at greater risk of higher Gleason scores on repeat biopsy, the majority still exhibit favorable tumor characteristics. Fast rising PSA should therefore not trigger a recommendation to receive active treatment, but should rather serve as a criterion for stricter follow-up. In addition, we should aim to find ways of safely reducing the number of biopsies to increase adherence to AS protocols. PATIENT SUMMARY: We looked at compliance with an active surveillance protocol for low-risk prostate cancer in a large active surveillance study. We observed reluctance to undergo yearly biopsies because of fast rising prostate-specific antigen, despite a higher risk of disease progression. Further research should aim to safely reduce the number of repeat biopsies in men on active surveillance to increase protocol adherence.

[Guidelines on the early detection of prostate cancer]. / Richtlijnen voor vroegdiagnostiek van prostaatkanker.

The early diagnosis of prostate cancer presents certain dilemmas, and various prostate cancer guidelines have been developed to support clinicians in decision making. However, these guidelines often give contradictory advice and should be appraised critically. We will discuss how the general practitioner (GP) should deal with the frequently used, often contradictory guidelines on this topic. A number of dilemmas concerning the early diagnosis of prostate cancer are discussed in this clinical lesson, based on a single case in the GP's practice; this concerns a 49-year-old male who approached his GP for prostate cancer screening. After the process of shared decision making, the patient was screened and diagnosed with a low-grade prostate carcinoma for which active surveillance was initiated.

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

PURPOSE: We assessed differences in treatment between the screening and control arms of ERSPC Rotterdam and studied whether possible treatment differences could explain the positive study outcome. MATERIALS AND METHODS: In ERSPC Rotterdam men 55 to 74 years old were randomized to a screening arm of 21,210 and a control arm of 21,166. Treatment after diagnosis was at the discretion of the care provider chosen by the patient. Initial treatment was compared in 4 risk groups. The relation between prostate cancer incidence and prostate cancer mortality was assessed by risk group by correlating the incidence RR and the mortality RR. A direct relation would have supported a stage shift as the main cause of changes in prostate cancer mortality. RESULTS: Initial treatment differed between the arms in the low, intermediate and high risk groups but not in the metastatic group. The RRs of prostate cancer incidence and mortality per risk group were related 1:1 (regression line slope 1.00, 95% CI 0.30-1.74). Of changes in prostate cancer mortality 94% could be explained by changes in prostate cancer incidence. This made treatment differences unlikely as the reason for the observed decrease in prostate cancer mortality. CONCLUSIONS: Differences in treatment between the ERSPC Rotterdam screening and control arms were unlikely to explain the differences in prostate cancer mortality. Results are instead consistent with a decrease in prostate cancer mortality as the result of a favorable stage through screening.

Differences in Treatment and Outcome After Treatment with Curative Intent in the Screening and Control Arms of the ERSPC Rotterdam.

UNLABELLED: Screening for prostate cancer (PCa) results in a favorable stage shift. However, even if screening did not result in a clinically apparent lower stage or grade, it might still lead to less disease recurrence after treatment with curative intent (radical prostatectomy [RP] and radiation therapy [RT]) because the tumor had less time to develop outside the prostate. The outcome after treatment could also differ because of variations in treatment quality (eg, radiation dosage/adjuvant hormonal therapy). To test these hypotheses, we compared differences in the treatment quality of the screening and control arms of the European Randomized Study of Screening for Prostate Cancer (ERSPC) Rotterdam and disease-free survival (DFS) after curative treatment in PCa patients with similar stage and grade. A total of 2595 men were initially treated with RP or RT. In the control arm, RT was more often combined with hormonal therapy; treatment dosage was often ≥69Gy. This most likely resulted from changes over time in treatment that coincided with the later detection in the control arm. DFS was higher in the screening arm in all risk groups. After correction for lead time, these differences were minimal, however. We concluded that treatment quality differed between the screening and control arms of the ERSPC Rotterdam. RT quality was especially superior in the control arm with higher dosages and more often RT in combination with hormonal therapy. Despite these differences favoring the control arm, DFS differences were minimal. PATIENT SUMMARY: We looked at differences in prostate cancer (PCa) treatment and outcome after PCa treatment in men diagnosed after screening and men diagnosed after normal clinical practice. Treatment differed with superior treatment given to men diagnosed in normal clinical practice. We propose a likely explanation for this apparently counterintuitive finding (progressive insight combined with, on average, a later detection of tumors in unscreened men). Although unscreened men received better treatment, this advantage seemed to be outweighed by the advantage associated with the earlier detection, on average, of the tumor in screened men. TRIAL REGISTRATION: ISRCTN49127736.