Prostate Radiofrequency Focal Ablation (ProRAFT) Trial: A Prospective Development Study Evaluating a Bipolar Radiofrequency Device to Treat Prostate Cancer.

PURPOSE: We determined the early efficacy of bipolar radiofrequency ablation with a coil design for focal ablation of clinically significant localized prostate cancer visible at multiparametric magnetic resonance imaging. MATERIALS AND METHODS: A prospective IDEAL phase 2 development study (Focal Prostate Radiofrequency Ablation, NCT02294903) recruited treatment-naïve patients with a single focus of significant localized prostate cancer (Gleason 7 or 4 mm or more of Gleason 6) concordant with a lesion visible on multiparametric magnetic resonance imaging. Intervention was a focal ablation with a bipolar radiofrequency system (Encage™) encompassing the lesion and a predefined margin using nonrigid magnetic resonance imaging-ultrasound fusion. Primary outcome was the proportion of men with absence of significant localized disease on biopsy at 6 months. Trial followup consisted of serum prostate specific antigen, multiparametric magnetic resonance imaging at 1 week, and 6 and 12 months post-ablation. Validated patient reported outcome measures for urinary, erectile and bowel functions, and adverse events monitoring system were used. Analyses were done on a per-protocol basis. RESULTS: Of 21 patients recruited 20 received the intervention. Baseline characteristics were median age 66 years (IQR 63-69) and preoperative median prostate specific antigen 7.9 ng/ml (5.3-9.6). A total of 18 patients (90%) had Gleason 7 disease with median maximum cancer 7 mm (IQR 5-10), for a median of 2.8 cc multiparametric magnetic resonance imaging lesions (IQR 1.4-4.8). Targeted biopsy of the treated area (median number of cores 6, IQR 5-8) showed absence of significant localized prostate cancer in 16/20 men (80%), concordant with multiparametric magnetic resonance imaging. There was a low profile of side effects at patient reported outcome measures analysis and there were no serious adverse events. CONCLUSIONS: Focal therapy of significant localized prostate cancer associated with a magnetic resonance imaging lesion using bipolar radiofrequency showed early efficacy to ablate cancer with low rates of genitourinary and rectal side effects.

Focal HIFU therapy for anterior compared to posterior prostate cancer lesions.

OBJECTIVE: To compare cancer control in anterior compared to posterior prostate cancer lesions treated with a focal HIFU therapy approach. MATERIALS AND METHODS: In a prospectively maintained national database, 598 patients underwent focal HIFU (Sonablate®500) (March/2007-November/2016). Follow-up occurred with 3-monthly clinic visits and PSA testing in the first year with PSA, every 6-12 months with mpMRI with biopsy for MRI-suspicion of recurrence. Treatment failure was any secondary treatment (ADT/chemotherapy, cryotherapy, EBRT, RRP, or re-HIFU), tumour recurrence with Gleason ≥ 3 + 4 on prostate biopsy without further treatment or metastases/prostate cancer-related mortality. Cases with anterior cancer were compared to those with posterior disease. RESULTS: 267 patients were analysed following eligibility criteria. 45 had an anterior focal-HIFU and 222 had a posterior focal-HIFU. Median age was 64 years and 66 years, respectively, with similar PSA level of 7.5 ng/ml and 6.92 ng/ml. 84% and 82%, respectively, had Gleason 3 + 4, 16% in both groups had Gleason 4 + 3, 0% and 2% had Gleason 4 + 4. Prostate volume was similar (33 ml vs. 36 ml, p = 0.315); median number of positive cores in biopsies was different in anterior and posterior tumours (7 vs. 5, p = 0.009), while medium cancer core length, and maximal cancer percentage of core were comparable. 17/45 (37.8%) anterior focal-HIFU patients compared to 45/222 (20.3%) posterior focal-HIFU patients required further treatment (p = 0.019). CONCLUSION: Treating anterior prostate cancer lesions with focal HIFU may be less effective compared to posterior tumours.

Evaluating the Trade-Offs Men with Localized Prostate Cancer Make between the Risks and Benefits of Treatments: The COMPARE Study.

PURPOSE: The COMPARE (COMparing treatment options for ProstAte cancer) study aimed to evaluate and quantify the trade-offs patients make between different aspects of active surveillance and definitive therapy. MATERIALS AND METHODS: A discrete choice experiment tool was used to elicit patient preferences for different treatment characteristics in 34 urology departments. Patients with localized prostate cancer completed the discrete choice experiment within 1 week of being diagnosed and before they made treatment decisions. The discrete choice experiment was pretested (5) and piloted (106) with patients. Patients chose their preferred treatment profile based on the 6 characteristics of treatment type (active surveillance, focal therapy, radical therapy), return to normal activities, erectile function, urinary function, not needing more cancer treatment and 10 to 15-year cancer specific survival. Different tools were designed for patients with low-intermediate (468) and high risk (166) disease. An error components conditional logit model was used to estimate preferences and trade-offs between treatment characteristics. RESULTS: Patients with low-intermediate risk disease were willing to trade 6.99% absolute decrease in survival to have active surveillance over definitive therapy. They were willing to trade 0.75%, 0.46% and 0.19% absolute decrease in survival for a 1-month reduction in time to return to normal activities and 1% absolute improvements in urinary and sexual function, respectively. Patients with high risk disease were willing to trade 3.10%, 1.04% and 0.41% absolute decrease in survival for a 1-month reduction in time to return to normal activities and 1% absolute improvements in urinary and sexual function, respectively. CONCLUSIONS: Patients with low-intermediate risk prostate cancer preferred active surveillance to definitive therapy. Patients of all risk levels were willing to trade cancer specific survival for improved quality of life.

Prostate Specific Antigen Criteria to Diagnose Failure of Cancer Control following Focal Therapy of Nonmetastatic Prostate Cancer Using High Intensity Focused Ultrasound.

PURPOSE: We determined whether prostate specific antigen criteria after focal high intensity focused ultrasound to treat prostate cancer could diagnose treatment failure. MATERIALS AND METHODS: A total of 598 patients in a prospectively maintained national database underwent focal high intensity focused ultrasound with a Sonablate® 500 device from March 2007 to November 2016. Followup consisted of 3-month clinic visits and prostate specific antigen testing in year 1 with prostate specific antigen measurement every 6 to 12 months and multiparametric magnetic resonance imaging with biopsy for magnetic resonance imaging suspicious for recurrence. Treatment failure was considered any secondary treatment, tumor recurrence with Gleason 3 + 4 or greater disease on prostate biopsy without further treatment or metastasis and/or prostate cancer related mortality. To diagnose failure we evaluated a series of nadir + x thresholds with x values of 0.1 to 2.0 ng/ml. RESULTS: Median patient age was 65 years (IQR 60-71) and the median Gleason score was 7 (range 6-9). Gleason 3 + 4 or greater disease was present in 80% of cases. Tumors were radiologically staged as T1c-T2c in 522 of the 596 patients (88%) and as T3a/b in 74 (12.4%). Baseline median prostate specific antigen was 7.80 ng/ml (IQR 5.96-10.45) in failed cases and 6.77 ng/ml (IQR 2.65-9.71) in cases without failure. Optimal performance according to the Youden index to indicate the most appropriate nadir + x at all analyzed time points at 3-month intervals showed that nadir + 1.0 ng/ml would have 27.3% to 100% sensitivity and 39.4% to 85.6% specificity depending on the time of evaluation in the first 3 years. Nadir + 1.5 ng/ml showed 18.2% to 100% sensitivity and 60.6% to 91.8% specificity with nadir + 2.0 ng/ml leading to similar sensitivity and specificity ranges. Nadir + 1.0 ng/ml at 12 months and nadir + 1.5 ng/ml at 24 and 36 months had 100% sensitivity and 96.1% to 100% negative predictive value. CONCLUSIONS: Following focal high intensity focused ultrasound a prostate specific antigen nadir of 1.0 ng/ml at 12 months and 1.5 ng/ml at 24 to 36 months might be used to triage men requiring magnetic resonance imaging and biopsy. These data need prospective validation.

Added value of diffusion-weighted images and dynamic contrast enhancement in multiparametric magnetic resonance imaging for the detection of clinically significant prostate cancer in the PICTURE trial.

OBJECTIVE: To determine the additional diagnostic value of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced imaging (DCE) in men requiring a repeat biopsy within the PICTURE study. PATIENTS AND METHODS: PICTURE was a paired-cohort confirmatory study in which 249 men who required further risk stratification after a previous non-magnetic resonance imaging (MRI)-guided transrectal ultrasonography-guided biopsy underwent a 3-Tesla (3T) multiparametic (mp)MRI consisting of T2-weighted imaging (T2W), DWI and DCE, followed by transperineal template prostate mapping biopsy. Each mpMRI was reported using a LIKERT score in a sequential blinded manner to generate scores for T2W, T2W+DWI and T2W+DWI+DCE. Area under the receiver-operating characteristic curve (AUROC) analysis was performed to compare the diagnostic accuracy of each combination. The threshold for a positive mpMRI was set at a LIKERT score ≥3. Clinically significant prostate cancer was analysed across a range of definitions including UCL/Ahmed definition 1 (primary definition), UCL/Ahmed definition 2, any Gleason ≥3 + 4 and any Gleason ≥4 + 3. RESULTS: Of 249 men, sequential MRI reporting was available for 246. There was a higher rate of equivocal lesions (44.6%) using T2W alone compared to the addition of DWI (23.9%) and DCE (19.8%). Using the primary definition of clinically significant disease, there was no significant difference in the overall accuracy between T2W, with an AUROC of 0.74 (95% confidence interval [CI] 0.68-0.80), T2W+DWI at 0.76 (95% CI 0.71-0.82), and T2W+DWI+DCE, with an AUROC of 0.77 (95% CI 0.71-0.82; P = 0.55). The AUROC values remained comparable using other definitions of clinically significant disease including UCL/Ahmed definition 2 (P = 0.79), Gleason ≥3 + 4 (P = 0.53) and Gleason ≥4 + 3 (P = 0.53). CONCLUSIONS: Using 3T MRI, a high level of diagnostic accuracy can be achieved using T2W as a single parameter in men with a prior biopsy; however, such a strategy can lead to a higher rate of equivocal lesions.

Evaluation of functional outcomes after a second focal high-intensity focused ultrasonography (HIFU) procedure in men with primary localized, non-metastatic prostate cancer: results from the HIFU Evaluation and Assessment of Treatment (HEAT) registry.

OBJECTIVES: To assess change in functional outcomes after a second focal high-intensity focused ultrasonography (HIFU) treatment compared with outcomes after one focal HIFU treatment. PATIENTS AND METHODS: In this multicentre study (2005-2016), 821 men underwent focal HIFU for localized non-metastatic prostate cancer. The patient-reported outcome measures of International Prostate Symptom Score (IPSS), pad usage and erectile function (EF) score were prospectively collected for up to 3 years. To be included in the study, completion of at least one follow-up questionnaire was required. The primary outcome was comparison of change in functional outcomes between baseline and follow-up after one focal HIFU procedure vs after a second focal HIFU procedure, using IPSS, Expanded Prostate Cancer Index Composite (EPIC) and International Index of Erectile Function (IIEF) questionnaires. RESULTS: Of 821 men, 654 underwent one focal HIFU procedure and 167 underwent a second focal HIFU procedure. A total of 355 (54.3%) men undergoing one focal HIFU procedure and 65 (38.9%) with a second focal HIFU procedure returned follow-up questionnaires, respectively. The mean age and prostate-specific antigen level were 66.4 and 65.6 years, and 7.9 and 8.4 ng/mL, respectively. After one focal HIFU treatment, the mean change in IPSS was -0.03 (P = 0.02) and in IIEF (EF score) it was -0.4 (P = 0.02) at 1-2 years, with no subsequent decline. Absolute rates of erectile dysfunction increased from 9.9% to 20.8% (P = 0.08), leak-free continence decreased from 77.9% to 72.8% (P = 0.06) and pad-free continence from 98.6% to 94.8% (P = 0.07) at 1-2 years, respectively. IPSS prior to second focal HIFU treatment compared to baseline IPSS prior to first focal HIFU treatment was lower by -1.3 (P = 0.02), but mean IPSS change was +1.4 at 1-2 years (P = 0.03) and +1.2 at 2-3 years (P = 0.003) after the second focal HIFU treatment. The mean change in EF score after the second focal HIFU treatment was -0.2 at 1-2 years (P = 0.60) and -0.5 at 2-3 years (P = 0.10), with 17.8% and 6.2% of men with new erectile dysfunction. The rate of new pad use was 1.8% at 1-2 years and 2.6% at 2-3 years. CONCLUSION: A second focal HIFU procedure causes minor detrimental effects on urinary function and EF. These data can be used to counsel patients with non-metastatic prostate cancer prior to considering HIFU therapy.

Medium-term oncological outcomes in a large cohort of men treated with either focal or hemi-ablation using high-intensity focused ultrasonography for primary localized prostate cancer.

OBJECTIVE: To report medium-term oncological outcomes in men receiving primary focal treatment with high-intensity focused ultrasonography ( HIFU) for prostate cancer (PCa). PATIENTS AND METHODS: Consecutive patients with PCa treated with primary focal HIFU at two centres by six treating clinicians were assessed. Patients were submitted to either focal ablation or hemi-ablation using HIFU (Sonablate 500). The primary objective of the study was to assess medium-term oncological outcomes, defined as overall survival, freedom from biopsy failure, freedom from any further treatment and freedom from radical treatment after focal HIFU. The secondary objective was to evaluate the changes in pathological features among patients treated with focal HIFU over time. We also assessed the relationship between year of surgery and 5-year retreatment probability. RESULTS: A total of 1032 men treated between November 2005 and October 2017 were assessed. The median age was 65 years and median prostate-specific antigen level was 7 ng/mL. The majority of patients had a Gleason score of 3 + 4 or above (80.3%). The median (interquartile range) follow-up was 36 (14-64) months. The overall survival rates at 24, 60 and 96 months were 99%, 97% and 97%, respectively. Freedom from biopsy failure, defined as absence of Gleason 3 + 4 disease, was 84%, 64% and 54% at 24, 60 and 96 months. Freedom from any further treatment was 85%, 59% and 46% at 24, 60 and 96 months, respectively. Approximately 70% of patients who were retreated received a second focal treatment. Freedom from radical treatment was 98%, 91% and 81% at 24, 60 and 96 months. During the study period, we observed an increase in the proportion of patients undergoing focal HIFU with Gleason 3 + 4 disease and with T2 stage disease as defined by multiparametric magnetic resonance imaging. Finally, there was a reduction over time in the proportion of patients undergoing re-treatment within 5 years of first treatment. CONCLUSIONS: Focal HIFU for PCa is a feasible therapeutic strategy, with acceptable survival and oncological results and a reduction in the 5-year retreatment rates over the last decade. Re-do focal treatment is a feasible technique whose functional and oncological outcomes have still to be evaluated.

Immunohistochemical biomarker validation in highly selective needle biopsy microarrays derived from mpMRI-characterized prostates.

INTRODUCTION: Diagnosing prostate cancer routinely involves tissue biopsy and increasingly image guided biopsy using multiparametric MRI (mpMRI). Excess tissue after diagnosis can be used for research to improve the diagnostic pathway and the vertical assembly of prostate needle biopsy cores into tissue microarrays (TMAs) allows the parallel immunohistochemical (IHC) validation of cancer biomarkers in routine diagnostic specimens. However, tissue within a biopsy core is often heterogeneous and cancer is not uniformly present, resulting in needle biopsy TMAs that suffer from highly variable cancer detection rates that complicate parallel biomarker validation. MATERIALS AND METHODS: The prostate cores with the highest tumor burden (in terms of Gleason score and/or maximum cancer core length) were obtained from 249 patients in the PICTURE trial who underwent transperineal template prostate mapping (TPM) biopsy at 5 mm intervals preceded by mpMRI. From each core, 2 mm segments containing tumor or benign tissue (as assessed on H&E pathology) were selected, excised and embedded vertically into a new TMA block. TMA sections were then IHC-stained for the routinely used prostate cancer biomarkers PSA, PSMA, AMACR, p63, and MSMB and assessed using the h-score method. H-scores in patient matched malignant and benign tissue were correlated with the Gleason grade of the original core and the MRI Likert score for the sampled prostate area. RESULTS: A total of 2240 TMA cores were stained and IHC h-scores were assigned to 1790. There was a statistically significant difference in h-scores between patient matched malignant and adjacent benign tissue that is independent of Likert score. There was no association between the h-scores and Gleason grade or Likert score within each of the benign or malignant groups. CONCLUSION: The construction of highly selective TMAs from prostate needle biopsy cores is possible. IHC data obtained through this method are highly reliable and can be correlated with imaging. IHC expression patterns for PSA, PSMA, AMACR, p63, and MSMB are distinct in malignant and adjacent benign tissue but did not correlate with mpMRI Likert score.

Accuracy of Transperineal Targeted Prostate Biopsies, Visual Estimation and Image Fusion in Men Needing Repeat Biopsy in the PICTURE Trial.

PURPOSE: We evaluated the detection of clinically significant prostate cancer using magnetic resonance imaging targeted biopsies and compared visual estimation to image fusion targeting in patients requiring repeat prostate biopsies. MATERIALS AND METHODS: The prospective, ethics committee approved PICTURE trial (ClinicalTrials.gov NCT01492270) enrolled 249 consecutive patients from January 11, 2012 to January 29, 2014. Men underwent multiparametric magnetic resonance imaging and were blinded to the results. All underwent transperineal template prostate mapping biopsies. In 200 men with a lesion this was preceded by visual estimation and image fusion targeted biopsies. As the primary study end point clinically significant prostate cancer was defined as Gleason 4 + 3 or greater and/or any grade of cancer with a length of 6 mm or greater. Other definitions of clinically significant prostate cancer were also evaluated. RESULTS: Mean ± SD patient age was 62.6 ± 7 years, median prostate specific antigen was 7.17 ng/ml (IQR 5.25-10.09), mean primary lesion size was 0.37 ± 1.52 cc with a mean of 4.3 ± 2.3 targeted cores per lesion on visual estimation and image fusion combined, and a mean of 48.7 ± 12.3 transperineal template prostate mapping biopsy cores. Transperineal template prostate mapping biopsies detected 97 clinically significant prostate cancers (48.5%) and 85 insignificant cancers (42.5%). Overall multiparametric magnetic resonance imaging targeted biopsies detected 81 clinically significant prostate cancers (40.5%) and 63 insignificant cancers (31.5%). In the 18 cases (9%) of clinically significant prostate cancer on magnetic resonance imaging targeted biopsies were benign or clinically insignificant on transperineal template prostate mapping biopsy. Clinically significant prostate cancer was detected in 34 cases (17%) on transperineal template prostate mapping biopsy but not on magnetic resonance imaging targeted biopsies and approximately half was present in nontargeted areas. Clinically significant prostate cancer was found on visual estimation and image fusion in 53 (31.3%) and 48 (28.4%) of the 169 patients (McNemar test p = 0.5322). Visual estimation missed 23 clinically significant prostate cancers (13.6%) detected by image fusion. Image fusion missed 18 clinically significant prostate cancers (10.8%) detected by visual estimation. CONCLUSIONS: Magnetic resonance imaging targeted biopsies are accurate for detecting clinically significant prostate cancer and reducing the over diagnosis of insignificant cancers. To maximize detection visual estimation as well as image fusion targeted biopsies are required.

Patient Reported Outcome Measures for Transperineal Template Prostate Mapping Biopsies in the PICTURE Study.

PURPOSE: Transperineal template prostate mapping biopsy is an increasingly used method of procuring tissue from men with suspected prostate cancer. We report patient related outcome measures and adverse events in men in the PICTURE trial (ClinicalTrials.gov NCT01492270) who underwent this diagnostic test. MATERIALS AND METHODS: A total of 249 men underwent multiparametric magnetic resonance imaging followed by transperineal template prostate mapping biopsy as a validation study. Functional outcomes before and after transperineal template prostate mapping were prospectively collected and recorded with questionnaires, including the I-PSS (International Prostate Symptom Score), the I-PSS-QoL (Quality of Life), the IIEF-15 (International Index of Erectile Function-15) and the EPIC (Expanded Prostate Cancer Index Composite) urinary function. RESULTS: Mean age was 62 years, median prostate specific antigen was 6.8 ng/ml and median gland size was 37 ml. At transperineal template prostate mapping biopsy a median of 49 cores (IQR 40-55) were taken. Mean time to complete the post-procedure patient related outcome measure questionnaires was 46 days. Adverse events included post-procedure acute urinary retention in 24% of patients, rectal pain in 26% and perineal pain in 41%. Transperineal template prostate mapping biopsy resulted in a statistically significant increase in scores on the I-PSS from 10.9 to 11.8 (p = 0.024) and the I-PSS-QoL from 1.57 to 1.76 (p = 0.03). The IIEF-15 erectile function score decreased by 23.2% from 47.7 to 38.7 (p <0.001). Significant deterioration was noted in all 5 of IIEF-15 functional domains, including erectile and orgasmic function, sexual desire, and intercourse and overall satisfaction (p <0.001). EPIC urinary scores showed no overall change from baseline. CONCLUSIONS: Transperineal template prostate mapping biopsy causes a high urinary retention rate and a detrimental impact on genitourinary functional outcomes, including deterioration in urinary flow and sexual function. Our findings can be used to ensure adequate counseling about transperineal template prostate mapping biopsies. The results point to a need for strategies such as multiparametric magnetic resonance imaging and targeted biopsies to minimize the harms of transperineal template prostate mapping biopsy.

Prostate cancer detection using quantitative T2 and T2 -weighted imaging: The effects of 5-alpha-reductase inhibitors in men on active surveillance.

BACKGROUND: T2 -weighted imaging (T2 -WI) information has been used in a qualitative manner in the assessment of prostate cancer. Quantitative derivatives (T2 relaxation time) can be generated from T2 -WI. These outputs may be useful in helping to discriminate clinically significant prostate cancer from background signal. PURPOSE/HYPOTHESIS: To investigate changes in quantitative T2 parameters in lesions and noncancerous tissue of men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo daily for 6 months. STUDY TYPE: Retrospective. POPULATION/SUBJECTS: Forty men randomized to 6 months of daily dutasteride (n = 20) or placebo (n = 20). FIELD STRENGTH/SEQUENCE: Multiparametric 3T MRI at baseline and 6 months. This included a multiecho MR sequence for quantification of the T2 relaxation times, in three regions of interest (index lesion, noncancerous peripheral [PZ] and transitional [TZ] zones). A synthetic signal contrast (T2 Q contrast) between lesion and noncancerous tissue was assessed using quantitative T2 values. Signal contrast was calculated using the T2 -weighted sequence (T2 W contrast). ASSESSMENT: Two radiologists reviewed the scans in consensus according to Prostate Imaging Reporting and Data System (PI-RADS v. 2) guidelines. STATISTICAL TESTS: Wilcoxon and Mann-Whitney U-tests, Spearman's correlation. RESULTS: When compared to noncancerous tissue, shorter T2 values were observed within lesions at baseline (83.5 and 80.5 msec) and 6 months (81.5 and 81.9 msec) in the placebo and dutasteride arm, respectively. No significant differences for T2 W contrast at baseline and after 6 months were observed, both in the placebo (0.40 [0.29-0.49] vs. 0.43 [0.25-0.49]; P = 0.881) and dutasteride arm (0.35 [0.24-0.47] vs. 0.37 [0.22-0.44]; P = 0.668). There was a significant, positive correlation between the T2 Q contrast and the T2 W contrast values (r = 0.786; P < 0.001). DATA CONCLUSION: The exposure to antiandrogen therapy did not significantly influence the T2 contrast or the T2 relaxation values in men on active surveillance for prostate cancer. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1646-1653.

The PICTURE study: diagnostic accuracy of multiparametric MRI in men requiring a repeat prostate biopsy.

BACKGROUND: Transrectal prostate biopsy has limited diagnostic accuracy. Prostate Imaging Compared to Transperineal Ultrasound-guided biopsy for significant prostate cancer Risk Evaluation (PICTURE) was a paired-cohort confirmatory study designed to assess diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI) in men requiring a repeat biopsy. METHODS: All underwent 3 T mpMRI and transperineal template prostate mapping biopsies (TTPM biopsies). Multiparametric MRI was reported using Likert scores and radiologists were blinded to initial biopsies. Men were blinded to mpMRI results. Clinically significant prostate cancer was defined as Gleason ⩾4+3 and/or cancer core length ⩾6 mm. RESULTS: Two hundred and forty-nine had both tests with mean (s.d.) age was 62 (7) years, median (IQR) PSA 6.8 ng ml (4.98-9.50), median (IQR) number of previous biopsies 1 (1-2) and mean (s.d.) gland size 37 ml (15.5). On TTPM biopsies, 103 (41%) had clinically significant prostate cancer. Two hundred and fourteen (86%) had a positive prostate mpMRI using Likert score ⩾3; sensitivity was 97.1% (95% confidence interval (CI): 92-99), specificity 21.9% (15.5-29.5), negative predictive value (NPV) 91.4% (76.9-98.1) and positive predictive value (PPV) 46.7% (35.2-47.8). One hundred and twenty-nine (51.8%) had a positive mpMRI using Likert score ⩾4; sensitivity was 80.6% (71.6-87.7), specificity 68.5% (60.3-75.9), NPV 83.3% (75.4-89.5) and PPV 64.3% (55.4-72.6). CONCLUSIONS: In men advised to have a repeat prostate biopsy, prostate mpMRI could be used to safely avoid a repeat biopsy with high sensitivity for clinically significant cancers. However, such a strategy can miss some significant cancers and overdiagnose insignificant cancers depending on the mpMRI score threshold used to define which men should be biopsied.

Nanoknife Electroporation Ablation Trial: A Prospective Development Study Investigating Focal Irreversible Electroporation for Localized Prostate Cancer.

PURPOSE: Irreversible electroporation has attractive attributes for focal ablation, namely nonthermal effect, precise demarcation of treatment and tissue selectivity. We report a prospective development study investigating focal irreversible electroporation. MATERIALS AND METHODS: A total of 20 men with certain characteristics were recruited for study, including a visible index lesion on anterior magnetic resonance imaging that was concordant with transperineal targeted and template prostate mapping biopsy, absent clinically significant disease noted elsewhere (University College London definition 2) and prostate specific antigen 15 ng/ml or less. Our primary objective was to determine the side effect profile at 12 months. Secondary objectives included the domain specific toxicity profile using patient reported outcomes and early disease control using magnetic resonance imaging targeted biopsy. RESULTS: A total of 19 patients with median age of 60 years (IQR 53-66) and median prostate specific antigen 7.75 ng/ml (IQR 5.5-10.03) were treated. Of the patients 16 were available for estimating the first outcome as 1 was lost to followup and 2 had received another form of treatment by study end. All 16 men had pad-free/leak-free continence at 12 months. The proportion of men with erection sufficient for penetration decreased from 12 of 16 (75%) to 11 of 16 (69%). No serious adverse events were recorded. There was a statistically significant improvement in urinary symptoms according to changes in UCLA-EPIC (UCLA Expanded Prostate Cancer Index Composite) and I-PSS (International Prostate Symptom Score) (p = 0.039 and 0.001, respectively). Erectile function remained stable according to the change in IIEF-15 (15-Item International Index of Erectile Function) (p = 0.572). Median prostate specific antigen significantly decreased to 1.71 ng/ml (p = 0.001). One man refused followup biopsy. No residual disease was found in 11 patients (61.1%). One man (5.6%) harbored clinically insignificant disease and the remaining 6 (33.3%) harbored clinically significant disease. CONCLUSIONS: Focal irreversible electroporation has low genitourinary toxicity. Additional studies are needed to optimize patient selection and treatment parameters.

The Effect of Dutasteride on Magnetic Resonance Imaging Defined Prostate Cancer: MAPPED-A Randomized, Placebo Controlled, Double-Blind Clinical Trial.

PURPOSE: Dutasteride, which is licensed for symptomatic benign prostatic hyperplasia, has been associated with a lower progression rate of low risk prostate cancer. We evaluated the effect of dutasteride on prostate cancer volume as assessed by T2-weighted magnetic resonance imaging. MATERIALS AND METHODS: In this randomized, double-blind, placebo controlled trial, men with biopsy proven, low-intermediate risk prostate cancer (up to Gleason 3 + 4 and PSA up to 15 ng/ml) who had visible lesion of 0.2 ml or greater on T2-weighted magnetic resonance imaging sequences were randomized to daily dutasteride 0.5 mg or placebo for 6 months. Lesion volume was assessed at baseline, and 3 and 6 months with image guided biopsy to the lesion at study exit. The primary end point was the percent reduction in lesion volume over 6 months. This trial was registered with the European Clinical Trials register (EudraCT 2009-102405-18). RESULTS: A total of 42 men were recruited between June 2010 and January 2012. In the dutasteride group, the average volumes at baseline and 6 months were 0.55 and 0.38 ml, respectively and the average reduction was 36%. In the placebo group, the average volumes at baseline and 6 months were 0.65 and 0.76 ml, respectively, and the average reduction was -12%. The difference in percent reductions between the groups was 48% (95% CI 27.4-68.3, p <0.0001). The most common adverse event was deterioration in erectile function, which was 25% in men randomized to dutasteride and 16% in men randomized to placebo. CONCLUSIONS: Dutasteride was associated with a significant reduction in prostate cancer volume on T2-weighted magnetic resonance imaging compared to placebo.

Focal salvage high-intensity focused ultrasound in radiorecurrent prostate cancer.

OBJECTIVE: To assess short- to medium-term cancer control rates and side effects of focal salvage high- intensity focused ultrasound (HIFU). MATERIALS AND METHODS: A retrospective registry analysis identified 150 men who underwent focal salvage HIFU (FS-HIFU) (Sonablate 500) between November 2006 and August 2015. Metastatic disease was excluded by nodal assessment on the pelvic MRI, a radioisotope bone scan and positron-emission tomography (PET) imaging (choline-18F-fluorodeoxyglucose PET or choline PET-CT). In our current clinical practice, metastatic disease must be excluded by both choline PET and bone scan. Localization of cancer was carried out using multiparametric MRI of the prostate (T2-weighted, diffusion-weighted and dynamic contrast-enhanced imaging) with systematic or template prostate mapping biopsies. The primary outcome was a composite failure incorporating biochemical failure (BCF) and/or positive localized or distant imaging results and/or positive biopsy and/or systemic therapy and/or metastases/prostate cancer-specific death. The secondary outcome was BCF using the Phoenix-ASTRO definition (prostate-specific antigen [PSA] nadir + 2 ng/mL). We used Kaplan-Meier analysis and Cox proportional hazards regression to quantify the effect of the determinants on the endpoints. RESULTS: The mean (standard deviation [sd]) patient age at focal salvage HIFU was 69.8 (6.1) years and the median (interquartile range [IQR]) PSA pre-focal salvage HIFU was 5.5 (3.6-7.9) ng/mL. The median (IQR) follow-up was 35 (22-52) months. Patients were classified as having low- 2.7% (4/150), intermediate- 39.3% (59/150) and high-risk disease 41.3% (62/150) according to D'Amico classification, prior to focal salvage HIFU. Composite failure occurred in 61% of patients (91/150) and BCF occurred in 51.3% (77/150). The Kaplan-Meier composite endpoint-free survival (CEFS) rate at 3 years was 40% (95% confidence interval [CI] 31-50) for the entire group. Kaplan-Meier estimates of CEFS were 100%, 49% and 24% at 3 years in the low-, intermediate- and high-risk groups pre-salvage HIFU, respectively. The Kaplan-Meier biochemical disease-free survival (BDFS) rate at 3 years was 48% (95% CI 39-59) for the entire group. Kaplan-Meier estimates of BDFS were 100%, 61% and 32% at 3 years in the low-, intermediate- and high-risk groups pre-salvage HIFU, respectively. Complications included urinary tract infection (11.3%; 17/150), bladder neck stricture (8%; 12/150), recto-urethral fistula after one HIFU procedure (2%; 3/150) and osteitis pubis (0.7%; 1/150). CONCLUSION: Focal salvage HIFU conferred a relatively low complication and side effect rate. CEFS and biochemical control in the short to medium term were reasonable, especially in this relatively high-risk cohort, but still low compared with current whole-gland salvage therapies. Focal salvage therapy may offer disease control in men at high risk whilst minimizing additional treatment morbidities.

MRI findings in men on active surveillance for prostate cancer: does dutasteride make MRI visible lesions less conspicuous? Results from a placebo-controlled, randomised clinical trial.

OBJECTIVES: To investigate changes in the Apparent Diffusion Coefficient (ADC) using diffusion-weighted imaging (DWI) in men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo. METHODS: We analysed 37 men, randomised to 6 months of daily dutasteride (n = 18) or placebo (n = 19), undergoing 3T multi-parametric Magnetic Resonance Imaging (mpMRI) scans at baseline and 6 months. Images were reviewed blind to treatment allocation and clinical information. Mean ADC of peripheral (PZ) and transition (TZ) zones, and MR-suspicious lesions were compared between groups over 6 months. Conspicuity was defined as the PZ divided by tumour ADC, and its change over 6 months was assessed. RESULTS: A decrease in mean conspicuity in the dutasteride group (but not the controls) was seen over 6 months (1.54 vs 1.38; p = 0.025). Absolute changes in ADC and conspicuity were significantly different between placebo and dutasteride groups at 6 months: (-0.03 vs 0.08, p = 0.033) and (0.11 vs -0.16, p = 0.012), as were percentage changes in the same parameters: (-2.27% vs 8.56% p = 0.048) and (9.25% vs -9.89% p = 0.013). CONCLUSIONS: Dutasteride was associated with increased tumour ADC and reduced conspicuity. A lower threshold for triggering biopsy might be considered in men on dutasteride undergoing mpMRI for prostate cancer. KEY POINTS: • Dutasteride increases ADC and reduces conspicuity in small mpMRI-visible prostate cancers. • Knowledge of dutasteride exposure is important in the interpretation of prostate mpMRI. • A lower threshold for triggering biopsy may be appropriate on dutasteride.

Morbidity associated with primary high intensity focused ultrasound and redo high intensity focused ultrasound for localized prostate cancer.

PURPOSE: High intensity focused ultrasound may have a role as an alternative to standard radical therapies for localized prostate cancer. An attribute of high intensity focused ultrasound is that it can be repeated. We determined morbidity after primary and redo high intensity focused ultrasound. MATERIALS AND METHODS: We performed an academic lead analysis of United Kingdom registry data on high intensity focused ultrasound treatments at 3 centers using patient reported continence and sexual function outcomes. Validated questionnaires were completed before and after each ultrasound treatment. RESULTS: A total of 359 patients received 1 whole gland high intensity focused ultrasound treatment for localized prostate cancer from October 2004 to June 2012, of whom 130 (36.2%) received re-treatment. Median followup was 27 months (range 3 to 81) after re-treatment. When analyzing adverse events, 10.8% of patients experienced urinary tract infection after the first treatment compared to 3.9% after re-treatment (p=0.009). Urethral dilatation was required in 13.8% and 14.0% of patients after first and redo ultrasound treatments (p=0.7), and bladder neck incision was required in 9.2% and 11.6%, respectively (p=0.2). Before and after re-treatment 73.3% and 55.1% of patients had no leak, and 2.7% and 9.0% used daily pads (p<0.001 and p=0.07, respectively). Analysis of erectile function showed that 56.2% and 56.0% of patients were potent before and after re-treatment, respectively (p=0.9). CONCLUSIONS: Redo high intensity focused ultrasound is associated with an increase in urinary side effects but sexual side effects do not appear to be significantly increased. The number of adverse events seems to be equivalent after first and redo treatments. Meticulous patient selection is of paramount importance when selecting men for redo high intensity focused ultrasound.

Urinary and Sexual Impact of Robotic Radical Prostatectomy: Reporting of Patient-reported Outcome Measures in the First Year after Radical Prostatectomy in a Contemporary Multicentre Cohort in the United Kingdom.

Background and objective: Radical prostatectomy (RP) is an established treatment for localised prostate cancer that can have a significant impact on urinary and sexual function, with recovery over time. Our aim was to describe functional recovery in the first year after RP, reporting descriptive outcomes alongside validated patient-reported outcome measure scores (Expanded Prostate Cancer Index Composite, EPIC-26). Methods: Men undergoing RP between September 2015 and November 2019 completed EPIC-26 at baseline and 1, 3, 6, and 12 mo. Key findings and limitations: Overall, 2030 men consented to participation, underwent RP, and completed EPIC-26. At baseline, 97% were pad-free (1928/1996; 95% confidence interval [CI] 96-97%) and 77% were leak-free and pad-free (1529/1996; 95% CI 75-78), with a median EPIC-26 incontinence domain score of 100 (interquartile range [IQR] 86-100). At 12 mo, 65% were pad-free (904/1388; 95% CI 63-68%) and 42% were leak-free and pad-free (583/1388; 95% CI 39-45%), with a median EPIC-26 score of 76 (IQR 61-100). While one in three men reported wearing a pad at 12 mo, fewer than one in ten men needed more than 1 pad/d. At baseline, 1.9% reported a "moderate or big problem" with urine leakage, which increased to 9.7% at 12 mo. At baseline, the median sexual domain score among 1880 men was 74 (IQR 43-92) and 52% had erections sufficient for intercourse without medication (975/1880; 95% CI 50-54%). Among these 975 men, 630 responded at 12 mo, of whom 17% reported sufficient erections for intercourse (105/630; 95% CI 14-20%), without medication in 6% (37/630; 95% CI 4-8%) and needing medication in 11% (68/630; 95% CI 9-13%); the median EPIC-26 domain score was 26 (IQR 13-57). Conclusions and clinical implications: Reporting of functional outcomes after RP in terms of easily understood concepts such as pad-free and leak-free status, and erections with and with medication, alongside the classical report using EPIC-26 domain scores, increases the understanding of RP recovery patterns over the first year. Patient summary: At 12 months after surgery for prostate cancer, one in ten men reported a moderate or big problem with urine leakage and one in five men reported sufficient erections.

Focal salvage therapy for localized prostate cancer recurrence after external beam radiotherapy: a pilot study.

BACKGROUND: The objective of this study was to evaluate the safety, feasibility, side-effect profile, and proof of concept for focal salvage therapy using high-intensity focused ultrasound (HIFU). METHODS: A registry-based analysis was conducted between 2004 and 2009 of 430 patients who underwent HIFU. Thirty-nine patients received focal salvage therapy for localized recurrence after external beam radiotherapy. Multiparametric magnetic resonance imaging studies combined with transperineal template prostate mapping biopsies or transrectal biopsies were used to localize disease. Validated questionnaires were used to assess functional outcomes. Biochemical failure was defined by using both Phoenix criteria (prostate-specific antigen [PSA] nadir plus 2 ng/mL) and Stuttgart criteria (PSA nadir plus 1.2 ng/mL). RESULTS: The mean pre-HIFU PSA level was 4.6 ng/mL. The median follow-up was 17 months (interquartile range, 10-29 months). International Index of Erectile Function-5 scores decreased from a median ± standard deviation (SD) of 18 ± 16 to 13 ± 21 at 6 months, demonstrating worsening function. Scores on the University of California Los Angeles-Expanded Prostate Cancer Index Composite Urinary domain indicate that pad-free, leak-free continence status was 64%, and the pad-free rate was 87.2% at last follow-up. One rectourethral fistula occurred and spontaneously resolved with urinary and bowel diversion. The actuarial progression-free survival rate (including PSA nonresponders) was 69% at 1 year and 49% at 2 years according to Phoenix criteria. Excluding PSA nonresponders, these rates were 74% and 58%, respectively (Phoenix criteria). CONCLUSIONS: The results from this study indicated that focal salvage therapy is a potential strategy for localized recurrence after radiotherapy that may reduce the harms resulting from whole-gland salvage therapies.

Whole-gland salvage high-intensity focused ultrasound therapy for localized prostate cancer recurrence after external beam radiation therapy.

BACKGROUND: Whole-gland high-intensity focused ultrasound (HIFU) has been used as salvage therapy for local recurrence following external beam radiation therapy for decades. This article describes the use of the Sonablate 500 HIFU system in the salvage setting. METHODS: An evaluation was performed of a consecutive group of men with biochemical failure after external beam radiation therapy with histologically proven local recurrence and bone-scan and pelvic magnetic resonance imaging to exclude macroscopic metastases, and who chose to have whole-gland salvage HIFU (Sonablate 500) at 2 centers (3 expert HIFU surgeons at each center). The modified Clavien system was used to categorize adverse events and validated questionnaires for functional outcomes. Progression following HIFU treatment was defined as ASTRO-Phoenix criteria (prostate serum antigen [PSA] >nadir+2 ng/mL) and/or a positive biopsy and/or start of hormone therapy. RESULTS: Eighty-four men underwent whole-gland salvage HIFU (2004-2009). Median age, pretreatment serum PSA, and biopsy Gleason score was 68 years (range, 64-72 years), 4.3 ng/mL (range, 1.9-7.9 ng/mL), and 7 (range, 6-7), respectively. Mean follow-up was 19.8 months (range, 3.0-35.1 months). After salvage HIFU, 62% of the men were pad-free and leak-free. Mean International Index of Erectile Function-5 point score fell from 8.8 to 4.7 (P < .001). International Prostate Symptoms Score and RAND-SF36 scores were not affected. Two men developed rectourethral fistulae after 1 salvage procedure. A further 2 fistulae occurred in the 6 men undergoing a second salvage HIFU. Intervention for bladder outlet obstruction was needed in 20% (17 of 84 patients). If PSA nonresponders were included, 1- and 2-year progression-free survival rates were 59% (50 of 84 patients) and 43% (36 of 84 patients), respectively. If PSA nonresponders were excluded, 1- and 2-year progression-free survival rates were 62% (48 of 77 patients) and 48% (37 of 77 patients), respectively. CONCLUSIONS: Salvage whole-gland HIFU is a high-risk procedure. Although its use in early cancer control is promising, strategies to better identify metastatic disease prior to salvage therapy and reduce local toxicity are needed to improve on this.