Leonard P. Bokhorst

Magnetic Resonance Imaging in Active Surveillance of Prostate Cancer: A Systematic Review

CONTEXTnThere is great interest in using magnetic resonance imaging (MRI) for men on active surveillance for prostate cancer.nnnOBJECTIVEnTo systematically review evidence regarding the use of MRI in men with low- or intermediate-risk prostate cancer suitable for active surveillance.nnnEVIDENCE ACQUISITIONnOvid Medline and Embase databases were searched for active surveillance, prostate cancer, and MRI from inception until April 25, 2014 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses process. Identified reports were critically appraised according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria.nnnEVIDENCE SYNTHESISnA lesion on MRI suspicious for prostate cancer (positive MRI) is seen in two-thirds of men otherwise suitable for active surveillance. A positive MRI makes the identification of clinically significant disease at repeat biopsy more likely, especially when biopsies are targeted to suspicious MRI lesions. Radical prostatectomy data show that positive MRI is more likely to be associated with upgrading (Gleason score>3+3) than a negative MRI (43% vs 27%). A positive MRI is not significantly more likely to be associated with upstaging at radical prostatectomy (>T2) than a negative MRI (10% vs 8%). Although MRI is of interest in the monitoring of men on active surveillance, robust data on the use of repeat MRI in active surveillance are lacking. Prospective studies with clear definitions of radiological significance and progression are needed before this approach can be adopted.nnnCONCLUSIONSnMRI is useful for detection of clinically significant disease at initial assessment of men considering active surveillance. To use MRI as a monitoring tool in surveillance, it will be necessary to define both radiological significance and radiological progression.nnnPATIENT SUMMARYnThis review assesses evidence for the use of magnetic resonance imaging (MRI) in men on active surveillance for prostate cancer. MRI at the start of surveillance can detect clinically significant disease in one-third to half of men. There are few data to assess the use of MRI as a monitoring tool during surveillance, so there is a need to define significant disease on MRI and significant changes over time.

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.

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

BACKGROUNDnMultiparametric 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.nnnOBJECTIVEnTo 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).nnnDESIGN, SETTING, AND PARTICIPANTSnOne 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.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnThe 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.nnnRESULTS AND LIMITATIONSnOf 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).nnnCONCLUSIONSnRisk-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.nnnPATIENT SUMMARYnThe 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.

Active surveillance: Oncologic outcome

Purpose of review To give insight into recent literature (during the past 12–18 months) reporting on oncologic outcomes of men on active surveillance. Recent findings From recent published trials comparing radical prostatectomy vs. watchful waiting, we learn that radical treatment only benefits a small proportion of men and that a substantial part of men is overtreated. Therefore, active surveillance should aim at postponing treatment for most, but still generate the same disease-specific mortality as radical prostatectomy by treating only those who benefit. In this review some recent published data on prostate cancer-specific mortality under active surveillance as well as intermediate outcomes are described. Summary Prostate cancer-specific mortality under active surveillance is very low; however, longer follow-up is warranted. When deferred radical treatment and immediate radical treatment are compared, results seem to be quite similar, suggesting that postponing treatment does not affect the outcomes of men under active surveillance. Furthermore, in the majority of men active treatment could be avoided completely, without compromising oncologic outcome.

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

BACKGROUNDnActive 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.nnnOBJECTIVEnTo evaluate the value of 3T mp-MRI and MRGB in PC patients on AS at inclusion and after 12-mo follow-up.nnnDESIGN, SETTING, AND PARTICIPANTSnPatients 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.nnnOUTCOME MEASUREMENTS AND STATISTICAL ANALYSISnReclassification 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.nnnRESULTS AND LIMITATIONSnFrom 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).nnnCONCLUSIONSnAlthough 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.nnnPATIENT SUMMARYnMore 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.

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

PURPOSEnWe 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.nnnMATERIALS AND METHODSnIn 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.nnnRESULTSnInitial 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.nnnCONCLUSIONSnDifferences 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.

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

MP62-10 OUTCOME IN MEN CONTINUING ACTIVE SURVEILLANCE DESPITE PROTOCOL ADVICE TO DISCONTINUE

INTRODUCTION AND OBJECTIVES: Active surveillance (AS) is an increasingly accepted strategy for patients with low risk, low grade prostate cancer (PCa). Although differences in inclusion criteria exist, high volume Gleason 6 and higher grade of disease are commonly excluded. Yet, no consensus has been established concerning indicators of progression and uncertainties as to when patients should seek more aggressive treatment persist. Some postulate that Gleason 6 PCa has an indolent course and that only Gleason 7 should be considered a histologic trigger to treat. We aimed to elucidate the outcomes of patients who developed increased volume of Gleason 6 PCa ( 4 cores or 50% of core involved) while on AS and compared their risk of later grade progression to those who did not experience volume progression. METHODS: A prospectively maintained database was utilized to identify a total of 555 patients, median age 62.4, who were on AS with Gleason 6 disease between 2008 and 2013. Patients who demonstrated volume progression only at biopsy 2 (B2), biopsy 3 (B3), or biopsy 4+ (B4+) were studied. Univariate statistics were used for comparison. For the purposes of the current work, the endpoint of study was the development of grade progression whether it be grade only or grade + volume at the event biopsy. RESULTS: A total of 70 patients demonstrated volume progression at or after their second or confirmatory biopsy (B2). Mean follow-up was 3.67 years. In comparison to those never experiencing volume or grade progression, the mean age was 62.9 years vs. 62.1(p-value1⁄40.33), respectively. Mean PSA at diagnosis was not significantly different (p-value1⁄40.84), but median prostate volume was significantly smaller in patients who demonstrated volume progression (p-value <0.001). Incidence of pure volume progression was 6.8% at B2, 6.1% at B3 and 7.8% at B4. A Chi-square comparison between patients who upgraded to Gleason 7 (at B3) with or without volume progression (on previous biopsy, B2) revealed a significant difference in proportions 33.3% to 12.7% (P1⁄40.003), respectively. CONCLUSIONS: Although Gleason 6 PCa has a favourable natural history, it appears that patients who develop volume progression during AS are at a substantially higher risk of concomitant grade progression. Thus if these individuals choose to remain on AS their followup should be adjusted accordingly. If a patient demonstrates tumour volume progression early in their AS journey they are more likely to have pathological grade progression and should seek treatment.