Jan Verbeek

Improving the Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculator for Initial Prostate Biopsy by Incorporating the 2014 International Society of Urological Pathology Gleason Grading and Cribriform growth

BACKGROUND The survival rate for men with International Society of Urological Pathology (ISUP) grade 2 prostate cancer (PCa) without invasive cribriform (CR) and intraductal carcinoma (IDC) is similar to that for ISUP grade 1. If updated into the European Randomized Study of Screening for Prostate Cancer (ERSPC Rotterdam) risk calculator number 3 (RC3), this may further improve upfront selection of men who need a biopsy. OBJECTIVE To improve the number of possible biopsies avoided, while limiting undiagnosed clinically important PCa by applying the updated RC3 for risk-based patient selection. DESIGN, SETTING, AND PARTICIPANTS The RC3 is based on the first screening round of the ERSPC Rotterdam, which involved 3616 men. In 2015, histopathologic slides for PCa cases (n=885) were re-evaluated. Low-risk (LR) PCa was defined as ISUP grade 1 or 2 without CR/IDC. High-risk (HR) PCa was defined as ISUP grade 2 with CR/IDC and PCa with ISUP grade≥3. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We updated the RC3 using multinomial logistic regression analysis, including data on age, PSA, digital rectal examination, and prostate volume, for predicting LR and HR PCa. Predictive accuracy was quantified using receiver operating characteristic analysis and decision curve analysis. RESULTS AND LIMITATIONS Men without PCa could effectively be distinguished from men with LR PCa and HR PCa (area under the curve 0.70, 95% confidence interval [CI] 0.68-0.72 and 0.92, 95% CI 0.90-0.94). At a 1% risk threshold, the updated calculator would lead to a 34% reduction in unnecessary biopsies, while only 2% of HR PCa cases would be undiagnosed. CONCLUSIONS A relatively simple risk stratification tool augmented with a highly sensitive contemporary pathologic biopsy classification would result in a considerable decrease in unnecessary prostate biopsies and overdiagnosis of potentially indolent disease. PATIENT SUMMARY We improved a well-known prostate risk calculator with a new pathology classification system that better reflects disease burden. This new risk calculator allows individualized prediction of the chance of having (potentially aggressive) biopsy-detectable prostate cancer and can guide shared decision-making when considering prostate biopsy.

Reduction of MRI-targeted biopsies in men with low-risk prostate cancer on active surveillance by stratifying to PI-RADS and PSAdensity, with different thresholds for significant disease

Background The fear of undergrading prostate cancer (PCa) in men on active surveillance (AS) have led to strict criteria for monitoring, which have resulted in good long-term cancer-specific survival, proving the safety of this approach. Reducing undergrading, MRI-targeted biopsies are increasingly used in men with low-risk disease despite their undefined role yet. The objective of this study is to investigate the rate of upgrading using MRI-targeted biopsies in men with low-risk disease on AS, stratified on the basis of PI-RADS and PSA-density, with the aim to reduce potential unnecessary repeat biopsy procedures. Methods A total of 331 men were prospectively enrolled following the MRI-PRIAS protocol. MR imaging was according to Prostate Imaging Reporting and Data System (PI-RADSv2) guidelines. Suspicious MRI lesions (PI-RADS 3–5) were additionally targeted by MRI-TRUS fusion biopsies. Outcome measure was upgrading to Gleason score (GS) ≥3+4 with MRI-targeted biopsies, stratified for PI-RADS and PSA-density. Results In total, 25% (82/331) of men on AS showed upgrading from GS 3+3. Only 3% (11/331) was upgraded to GS ≥8. In 60% (198/331) a suspicious MRI lesion was identified, but in only 41% (82/198) of men upgrading was confirmed. PI-RADS 3, 4 and 5 categorized index lesions, showed upgrading in 30%, 34% and 66% of men, respectively. Stratification to PI-RADS 4–5, instead of PI-RADS 3–5, would have missed a small number of high volume Gleason 4 PCa in PI-RADS 3 category. However, further stratification into PI-RADS 3 lesions and PSA-density <0.15 ng/mL2 could result in a safe targeted biopsy reduction of 36% in this category, without missing any upgrades. Conclusions Stratification with the combination of PI-RADS and PSA-density may reduce unnecessary additional MRI biopsy testing. Overall, the high rate of detected upgrading in men on AS may result in an unintended tightening of continuing in AS. Since patients, included under current AS criteria showed extremely favorable outcome, there might be no need to further restrict continuing on AS with MRI and targeted biopsies.

Head-to-head comparison of prostate cancer risk calculators predicting biopsy outcome

Background Multivariable risk calculators (RCs) predicting prostate cancer (PCa) aim to reduce unnecessary workup (e.g., MRI and biopsy) by selectively identifying those men at risk for PCa or clinically significant PCa (csPCa) (Gleason ≥7). The lack of an adequate comparison makes choosing between RCs difficult for patients, clinicians and guideline developers. We aim to perform a head-to-head comparison of seven well known RCs predicting biopsy outcome. Methods Our study comprised 7,119 men from ten independent contemporary cohorts in Europe and Australia, who underwent prostate biopsy between 2007 and 2015. We evaluated the performance of the ERSPC RPCRC, Finne, Chun, ProstataClass, Karakiewicz, Sunnybrook, and PCPT 2.0 (HG) RCs in predicting the presence of any PCa and csPCa. Performance was assessed by discrimination, calibration and net benefit analyses. Results A total of 3,458 (48%) PCa were detected; 1,784 (25%) men had csPCa. No particular RC stood out predicting any PCa: pooled area under the ROC-curve (AUC) ranged between 0.64 and 0.72. The ERSPC RPCRC had the highest pooled AUC 0.77 (95% CI: 0.73–0.80) when predicting csPCa. Decision curve analysis (DCA) showed limited net benefit in the detection of csPCa, but that can be improved by a simple calibration step. The main limitation is the retrospective design of the study. Conclusions No particular RC stands out when predicting biopsy outcome on the presence of any PCa. The ERSPC RPCRC is superior in identifying those men at risk for csPCa. Net benefit analyses show that a multivariate approach before further workup is advisable.

What is an acceptable false negative rate in the detection of prostate cancer

Background In prostate cancer (PCa) screening men and their physicians aim to rule out the presence of potentially life threatening PCa. To date, prostate specific antigen (PSA) testing and systematic prostate biopsy (Bx)—in case of an elevated PSA—are still the main modes of PCa detection. Often uncertainty remains when a PSA-test is <3.0 ng/mL or a Bx shows a benign result, leading to the continuous repeating of procedures. Here we assess the potential consequences of false negatives by studying follow-up data of a purely PSA-based approach with applying sextant Bx, an approach considered to have a high risk of missing PCa diagnosis. Methods Our study population consisted of 19,970 men from the ERSPC project section Rotterdam, initially screened in 1993–1999. We assessed clinically significant Gleason ≥3+4 PCa (csPCa) diagnosis within the 4-year screening interval and subsequent screening round 4 years later in men having a PSA <3.0 ng/mL at initial screening (no Bx) and men with Bx (PSA >3.0 ng/mL), but no PCa detected at that time. In addition, we addressed PCa mortality and PCa diagnosis for men with a negative PSA test and negative Bx, who were retested every 4 years covering a 15-year follow-up. Results A total of 14,935 men had PSA <3.0 ng/mL in the initial screening round, of whom 75 (0.5%) were diagnosed with csPCa at a subsequent screening examination and 2 (<0.1%) in the 4-year screening interval. For 2,260 men with a previously negative Bx at first screening, the figures were 17 (0.8%) and 2 (0.1%) respectively. Indolent PCa (Gleason ≤3+3) was diagnosed in 312 (2%) men with PSA <3.0 ng/mL initially and 115 (5%) men with initial negative Bx. After a 15-year follow-up, 45 (0.3%) PCa deaths occurred in men with initially low PSA, and 29 men (0.2%) had metastasis. For men with negative Bx, 11 (0.5%) PCa deaths occurred and 4 (0.2%) experienced metastasis. Conclusions The false negative rates for men with PSA <3.0 ng/mL and negative sextant Bx are extremely low but not negligible. Proper risk stratification before deciding to biopsy is expected to hardly miss any clinical significant PCa diagnosis. This is especially relevant with the increased use of the relatively expensive multi-parametric magnetic resonance imaging (mpMRI) guided targeted Bx procedures.

Men on active surveillance without cancer on biopsy are less likely to reclassify

The manuscript of Kearns et al . based on data from the multicenter Canary Prostate Active Surveillance Study (PASS) reports on surveillance biopsies with benign result as prognostic marker for less reclassification to higher risk disease (1). The PASS cohort included men from 2008 with clinically localized low risk prostate cancer (cT1-2c disease, no previous treatment, and Gleason ≤3+4 disease).

MP77-12 HEAD-TO-HEAD COMPARISON OF COMMONLY USED INTERNATIONAL PROSTATE CANCER RISK CALCULATORS FOR PROSTATE BIOPSY

were graded from 0-10 (0: no pain/willing to return for repeat procedure; 10: excruciating pain/not willing to return for repeat procedure). Procedures were performed by a single urologist with a 1% Lidocaine periprostatic nerve block. Pain scores between groups were compared via Mann-Whitney U test. RESULTS: A total of 94 patients were included, with 50 FusionBx+TRUSBx and 44 TRUSBx. For each group, median age was 66.5 (range 47-84) and 68 years (range 44-86), and median number of cores was 14 (range 12-22) and 12 (range 6-14), respectively. Prostate biopsy pain questionnaire scores did not differ significantly for any of the questions (Figure 1). Patients in both groups had mild discomfort overall with the procedure (3 out of 10), the probe insertion (2 out of 10) and the biopsy portion of the exam (3 out of 10). If medically necessary, both groups were very willing to come back for the same procedure again (1 out of 10). CONCLUSIONS: Patients reported no difference in pain or discomfort with added FusionBx relative to TRUSBx alone. Both procedures were mildly painful with patients very willing to return for repeat biopsy if necessary. Patients tolerate the addition of FusionBx to TRUSBx alone. Patients0 pain experience or discomfort does not seem to hinder whether FusionBx of the prostate should be performed, or not.

MP77-13 A PROSPECTIVE EVALUATION ON THE EFFECT OF INTER-OBSERVER VARIABILITY OF DRE ON THE PERFORMANCE OF THE DRE BASED ROTTERDAM PROSTATE CANCER RISK CALCULATOR

were graded from 0-10 (0: no pain/willing to return for repeat procedure; 10: excruciating pain/not willing to return for repeat procedure). Procedures were performed by a single urologist with a 1% Lidocaine periprostatic nerve block. Pain scores between groups were compared via Mann-Whitney U test. RESULTS: A total of 94 patients were included, with 50 FusionBx+TRUSBx and 44 TRUSBx. For each group, median age was 66.5 (range 47-84) and 68 years (range 44-86), and median number of cores was 14 (range 12-22) and 12 (range 6-14), respectively. Prostate biopsy pain questionnaire scores did not differ significantly for any of the questions (Figure 1). Patients in both groups had mild discomfort overall with the procedure (3 out of 10), the probe insertion (2 out of 10) and the biopsy portion of the exam (3 out of 10). If medically necessary, both groups were very willing to come back for the same procedure again (1 out of 10). CONCLUSIONS: Patients reported no difference in pain or discomfort with added FusionBx relative to TRUSBx alone. Both procedures were mildly painful with patients very willing to return for repeat biopsy if necessary. Patients tolerate the addition of FusionBx to TRUSBx alone. Patients0 pain experience or discomfort does not seem to hinder whether FusionBx of the prostate should be performed, or not.

PD03-01 METASTASES AND DEATH AFTER 15 YEAR OF FOLLOW-UP IN MEN WITH SCREEN-DETECTED LOW-RISK PROSTATE CANCER TREATED WITH PROTOCOL BASED ACTIVE SURVEILLANCE, RADICAL PROSTATECTOMY OR RADIOTHERAPY

INTRODUCTION AND OBJECTIVES: The recently published outcomes of the ProtecT trial showed no difference in PCa-specific survival after a median of 10 yr follow-up between surgery (RP), radiotherapy (RT) and active monitoring (AM) in men with screen detected localized prostate cancer (PCa) [1]. However, data also showed a higher rate of metastatic (Mþ) PCa in the AM arm. Caveat of ProtecT are the randomization of PCa cases into the AM arm that are considered high risk and the AM protocol which is substantially different from current Active Surveillance (AS) protocols. METHODS: From men diagnosed with PCa at the 1st and 2nd screening round of ERSPC Rotterdam (1993-2003) considered suitable for AS (i.e Gleason score 3þ3, T2a PCa cases), we calculated PCaspecific survival and rate of Mþ PCa and compared these outcomes between men treated with AS predominantly according to the PRIAS protocol (n1⁄4223), having had a RP (N1⁄4365) or treated with RT (n1⁄4312). RESULTS: Baseline characteristics are listed in Table 1 and reflect the non-randomized setting. However, statistically significant differences do not automatically translate to clinically relevant differences. After a median follow-up of 15-yr (IQR 12-17 yr), 18 men died from PCa. Similar to ProtecT, no significant difference in PC specific survival was found between AS (97.2%; 95% CI: 94.7-99.7), RP (98.5%; 95% CI: 97.2-99.8), and RT (97.5%; 95% CI: 95.5-99.5), logrank p1⁄40.36. However, contrary to ProtecT, Mþ-free survival was also similar with rates of 96.9% (95% CI: 94.4-99.4) for AS, 97.9% (95% CI: 96.3-99.5) for RP and 96.6% (95% CI: 94.4-99.0) for RT, log-rank p1⁄40.42 (Table 2). CONCLUSIONS: The current data support a comparable long-term risk of disease progression of low-risk PCa in men initially treated with AS according to a protocol including regular monitoring with PSA, DRE and prostate biopsy and men opting for immediate active treatment. Personal preferences including considerations on quality of life will become more and more important in the treatment decision of low-risk PCa. 1.Hamdy et al. NEJM. PMID: 27626136 Source of Funding: none