Frank-Jan H. Drost

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

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).

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.

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.

The need for active surveillance for low risk prostate cancer

Prostate cancer is the most common cancer in men worldwide [1], with up to 67% of newly diagnosed cases considered to be low risk [2]. Pure Gleason grade ≤6 prostate cancer has negligible potential to metastasize and patients considered to have localized low-grade prostate cancer have minimal risk of dying of prostate cancer [3,4]. The introduction and continuous use of the prostate-specific antigen (PSA)-test followed by random transrectal ultrasound (TRUS)-guided biopsies above a certain threshold leads to a significant decrease in prostate cancer mortality but unfortunately also to a considerable increase in the detection of low risk cancers [5]. The traditional treatment options for all prostate cancers are invasive and often coincide with harmful side effects. The adverse effects of PSA-testing followed by a prostate biopsy can be reduced by avoiding the diagnosis of low risk prostate cancer, or postponing or averting the invasive treatment of clinically insignificant disease.

How Should Patients on Active Surveillance Be Followed

The key challenge for active surveillance protocols is to accurately identify disease misclassification and disease progression. The aim to delay or avoid radical treatment, and its associated side effects, should be pursued without compromising the safety and the quality of life of the patient. The current available risk assessment methods are used in variable frequencies, with various thresholds and criteria, and result in inconsistent clinical decisions dependent on which protocol is used. In this chapter, we study how, with the currently available tools, men are monitored during active surveillance and discuss what efforts are undertaken to improve the diagnostic accuracy while minimizing the burden of follow-up.

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

MP33-01 SIMILAR HIGH-GRADE PROSTATE CANCER DETECTION BY SEXTANT BIOPSY, 12-CORE TRUS BIOPSY AND MRI-TARGETED BIOPSY IN THE 5TH SCREENING ROUND OF THE ERSPC ROTTERDAM

INTRODUCTION AND OBJECTIVES: In a clinical setting, 12-core TRUS biopsy (12-TRUS-Bx) instead of sextant biopsy (6-TRUS-Bx) increases the low-grade (LG; Gleason 3+3) and highgrade (HG; Gleason >1⁄43+4) prostate cancer (PCa) detection. MRI +/target biopsy (TBx) detects less LG PCa and tends to detect more HG PCa, especially after previous negative biopsy. In this study we compare the performance of 6-TRUS-Bx vs 12-TRUS-Bx vs MRI +/TBx in a pre-screened population-based cohort. METHODS: Men in the 5th screening round of the ERSPC Rotterdam (2013 e 2016) with PSA >1⁄43.0 ng/ml received 6-TRUS-Bx or were included in the MRI side study. Men in the side study received MRI, blinded 12-TRUS-Bx and afterwards fusion target biopsy of PIRADS >1⁄43 lesions if present. The PCa detection rates of the 6-TRUSBx vs 12-TRUS-Bx vs MRI +/TBx strategy were compared after stratification for previous biopsy. RESULTS: A total of 177 men received 6-TRUS-Bx; 158 men received MRI with 12-TRUS-Bx +/TBx. Mean age and mean PSA were resp. 73.2 yrs (SD 1.1) and 5.1 ng/ml (SD 2.8). A total of 78/177 (44%) men who received 6-TRUS-Bx and 74/158 (47%) men who received 12TRUS-Bx +/TBx were biopsy naive. The rate of men with a non-suspicious MRI in the side study was 110/158 (70%).The HG PCa detection rates of 6-TRUS-Bx (17%), 12-TRUS-Bx (20%) and MRI +/TBx (19%) in previously screened but biopsy naive men were comparable. The LG PCa detection rate in biopsy naive men of MRI +/TBx (7%) was significantly lower as compared to 6-TRUS-Bx (23%) and 12-TRUS-Bx (34%). The HG PCa detection rates of 6-TRUS-Bx (5%), 12-TRUS-Bx (5%) and MRI +/TBx (4%) in previously screened and biopsied (>1⁄41 times) men were comparable. The LG PCa detection rate in previously biopsied men of 12-TRUS-Bx (24%) was significantly higher as compared to 6-TRUS-Bx (12%) and MRI +/TBx (7%). CONCLUSIONS: In population-based screening with multiple visits the HG PCa detection rates of 6-TRUS-Bx, 12-TRUS-Bx and MRI +/TBx are comparable, both in biopsy naive and previously biopsied men. Only 5% of previously biopsied men harbor HG PCa at repeat biopsy, confirming the need of better risk-stratification. An MRI +/TBx screening strategy has the potential to reduce biopsy procedures (70%) and overdiagnosis of LG PCa. Source of Funding: none

PD55-04 THE ERSPC VERSUS THE PROTECT STUDY: OUTCOMES AFTER ACTIVE SURVEILLANCE COMPARED TO SURGERY AND RADIOTHERAPY FOR LOCALIZED PROSTATE CANCER.

Health Sciences Centre (n 1⁄41162) of men diagnosed with low-risk prostate cancer between 1990-2016 to identify 432 men under age 60 (n 1⁄4 181, MGH; n 1⁄4 251, Sunnybrook). Clinical outcomes were analyzed, including repeat biopsy data, progression to treatment, and pathologic staging in those who had surgical treatment. Survival estimates were generated by Kaplan-Meier analysis. RESULTS: At diagnosis, median age was 55 years (IQR 53-57) and median PSA was 4.6 ng/mL (IQR 3.1-5.9), with only 11 of 432 men with PSA 10 ng/mL. The vast majority of patients had Gleason 6 (97.7%) and clinical stage T1 (91.9%) disease. With a median follow-up of 5.1 years (range: 0.05-21.7; IQR: 3.1-8.4), 84.3% (364/432) had a repeat biopsy with 62.6% (228/364) showing prostate cancer, 24.5% (89/364) benign, 7.7% (28/364) with PIN, and 5.2% (10/364) with atypia. Kaplan-Meier actuarial freedom-from-treatment was 74.3% at 5 years and 55.4% at 10 years. Of all 432 patients, 131 (30.3%) progressed to treatment for the following reasons: pathologic progression (64.1%), PSA progression (18.3%), patient preference (11.5%), volume progression (3.1%) and other reasons (3.1%). Among the 131 treated patients, 62.6% underwent radical prostatectomy, 13.0% underwent high-intensity focal ultrasound therapy, 12.2% underwent external beam radiation and 10.7% had brachytherapy. On pathologic review after surgery, 88.2% (60/68) were pT2, and 11.8% (8/68) pT3. Five patients developed metastasis (2 with positive lymph nodes at time of radical prostatectomy, 3 with distant metastasis). Metastasis-free survival was 99.7% and 97.5% at 5 and 10 years, respectively. There were no prostate-cancer specific deaths. CONCLUSIONS: Active surveillance is a reasonable option for carefully selected men under 60 with low-risk prostate cancer. However, patients must be surveyed closely and understand the significant risk of ultimately needing treatment.