Lucy Simmons

Focal Therapy: Patients, Interventions, and Outcomes—A Report from a Consensus Meeting

Background Focal therapy as a treatment option for localized prostate cancer (PCa) is an increasingly popular and rapidly evolving field. Objective To gather expert opinion on patient selection, interventions, and meaningful outcome measures for focal therapy in clinical practice and trial design. Design, setting, and participants Fifteen experts in focal therapy followed a modified two-stage RAND/University of California, Los Angeles (UCLA) Appropriateness Methodology process. All participants independently scored 246 statements prior to rescoring at a face-to-face meeting. The meeting occurred in June 2013 at the Royal Society of Medicine, London, supported by the Wellcome Trust and the UK Department of Health. Outcome measurements and statistical analysis Agreement, disagreement, or uncertainty were calculated as the median panel score. Consensus was derived from the interpercentile range adjusted for symmetry level. Results and limitations Of 246 statements, 154 (63%) reached consensus. Items of agreement included the following: patients with intermediate risk and patients with unifocal and multifocal PCa are eligible for focal treatment; magnetic resonance imaging–targeted or template-mapping biopsy should be used to plan treatment; planned treatment margins should be 5 mm from the known tumor; prostate volume or age should not be a primary determinant of eligibility; foci of indolent cancer can be left untreated when treating the dominant index lesion; histologic outcomes should be defined by targeted biopsy at 1 yr; residual disease in the treated area of ≤3 mm of Gleason 3 + 3 did not need further treatment; and focal retreatment rates of ≤20% should be considered clinically acceptable but subsequent whole-gland therapy deemed a failure of focal therapy. All statements are expert opinion and therefore constitute level 5 evidence and may not reflect wider clinical consensus. Conclusions The landscape of PCa treatment is rapidly evolving with new treatment technologies. This consensus meeting provides guidance to clinicians on current expert thinking in the field of focal therapy. Patient summary In this report we present expert opinion on patient selection, interventions, and meaningful outcomes for clinicians working in focal therapy for prostate cancer.

Detection, localisation and characterisation of prostate cancer by prostate HistoScanning(™).

Whats known on the subject? and What does the study add?

The PICTURE study — Prostate Imaging (multi-parametric MRI and Prostate HistoScanning™) Compared to Transperineal Ultrasound guided biopsy for significant prostate cancer Risk Evaluation

OBJECTIVE The primary objective of the PICTURE study is to assess the negative predictive value of multi-parametric MRI (mp-MRI) and Prostate HistoScanning™ (PHS) in ruling-out clinically significant prostate cancer. PATIENTS AND METHODS PICTURE is a prospective diagnostic validating cohort study conforming to level 1 evidence. PICTURE will assess the diagnostic performance of multi-parametric Magnetic Resonance Imaging (mp-MRI) and Prostate HistoScanning™ (PHS) ultrasound. PICTURE will involve validating both index tests against a reference test, transperineal Template Prostate Mapping (TPM) biopsies, which can be applied in all men under evaluation. Men will be blinded to the index test results and both index tests will be reported prospectively prior to the biopsies being taken to ensure reporter blinding. Paired analysis of each of the index tests to the reference test will be done at patient level. Those men with an imaging lesion will undergo targeted biopsies to assess the clinical utility of sampling only suspicious areas. The study is powered to assess the negative predictive value of these imaging modalities in ruling-out clinically significant prostate cancer. DISCUSSION The PICTURE study aims to assess the performance characteristics of two imaging modalities (mp-MRI and Prostate HistoScanning) for their utility in the prostate cancer pathway. PICTURE aims to identify if either imaging test may be useful for ruling out clinically significant disease in men under investigation, and also to examine if either imaging modality is useful for the detection of disease. Recruitment is underway and expected to complete in 2014.

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.

Salvage ablative therapy in prostate cancer: International multidisciplinary consensus on trial design

INTRODUCTION Salvage ablative therapy (SAT) has been developed as a form of localized treatment for localized recurrence of prostate cancers following radiation therapy. To better address the utility of SAT, prospective clinical trials must address the aspects of accepted standards in the initial evaluation, treatment, follow-up, and outcomes in the oncology community. We undertook this study to achieve consensus on uniform standardized trial design for SAT trials. METHODS A literature search was performed and an international multidisciplinary group of experts was identified. A questionnaire was constructed and sent out to 71 participants in 3 consecutive rounds according to the Delphi method. The project was concluded with a face-to-face meeting in which the results were reviewed and conclusions were formulated. RESULTS Patients with recurrent disease after radiation therapy were considered candidates for a SAT trial using any ablation scenario performed with cryotherapy or high-intensity focused ultrasound. It is feasible to compare different sources of energy or to compare with historical data on salvage radical prostatectomy outcomes. The primary objective should be to assess the efficacy of the treatment for negative biopsy rate at 12 months. Secondary objectives should include safety parameters and quality-of-life assessment. Exclusion criteria should include evidence of local or distant metastases. The optimal biopsy strategy is image-guided targeted biopsies. Follow-up includes multiparametric magnetic resonance imaging, prostate-specific antigen level, and quality of life for at least 5 years. CONCLUSIONS A multidisciplinary board from international experts reached consensus on trial design for SAT in prostate cancer and provides a standard for designing a feasible SAT trial.

Development and Phantom Validation of a 3-D-Ultrasound-Guided System for Targeting MRI-Visible Lesions During Transrectal Prostate Biopsy

Objective: Three- and four-dimensional transrectal ultrasound transducers are now available from most major ultrasound equipment manufacturers, but currently are incorporated into only one commercial prostate biopsy guidance system. Such transducers offer the benefits of rapid volumetric imaging, but can cause substantial measurement distortion in electromagnetic tracking sensors, which are commonly used to enable 3-D navigation. In this paper, we describe the design, development, and validation of a 3-D-ultrasound-guided transrectal prostate biopsy system that employs high-accuracy optical tracking to localize the ultrasound probe and prostate targets in 3-D physical space. Methods: The accuracy of the system was validated by evaluating the targeted needle placement error after inserting a biopsy needle to sample planned targets in a phantom using standard 2-D ultrasound guidance versus real-time 3-D guidance provided by the new system. Results: The overall mean needle-segment-to-target distance error was 3.6 ± 4.0 mm and mean needle-to-target distance was 3.2 ± 2.4 mm. Conclusion: A significant increase in needle placement accuracy was observed when using the 3-D guidance system compared with visual targeting of invisible (virtual) lesions using a standard B-mode ultrasound-guided biopsy technique.

Characterizing indeterminate (Likert-score 3/5) peripheral zone prostate lesions with PSA density, PI-RADS scoring and qualitative descriptors on multiparametric MRI

OBJECTIVE To determine whether indeterminate (Likert-score 3/5) peripheral zone (PZ) multiparametric MRI (mpMRI) studies are classifiable by prostate-specific antigen (PSA), PSA density (PSAD), Prostate Imaging Reporting And Data System version 2 (PI-RADS_v2) rescoring and morphological MRI features. METHODS Men with maximum Likert-score 3/5 within their PZ were retrospectively selected from 330 patients who prospectively underwent prostate mpMRI (3 T) without an endorectal coil, followed by 20-zone transperineal template prostate mapping biopsies ＋/- focal lesion-targeted biopsy. PSAD was calculated using pre-biopsy PSA and MRI-derived volume. Two readers A and B independently assessed included men with both Likert-assessment and PI-RADS_v2. Both readers then classified mpMRI morphological features in consensus. Men were divided into two groups: significant cancer (≥ Gleason 3 ＋ 4) or insignificant cancer (≤ Gleason 3 ＋ 3)/no cancer. Comparisons between groups were made separately for PSA & PSAD using Mann-Whitney test and morphological descriptors with Fishers exact test. PI-RADS_v2 and Likert-assessment were descriptively compared and percentage inter-reader agreement calculated. RESULTS 76 males were eligible for PSA & PSAD analyses, 71 for PI-RADS scoring, and 67 for morphological assessment (excluding significant image artefacts). Unlike PSA (p = 0.915), PSAD was statistically different (p = 0.004) between the significant [median: 0.19 ng ml-2 (interquartile range: 0.13-0.29)] and non-significant/no cancer [median: 0.13 ng ml-2 (interquartile range: 0.10-0.17)] groups. Presence of mpMRI morphological features was not significantly different between groups. Subjective Likert-assessment discriminated patients with significant cancer better than PI-RADS_v2. Inter-reader percentage agreement was 83% for subjective Likert-assessment and 56% for PI-RADS_v2. CONCLUSION PSAD may categorize presence of significant cancer in patients with Likert-scored 3/5 PZ mpMRI findings. Advances in knowledge: PSAD may be used in indeterminate PZ mpMRI to guide decisions between biopsy vs monitoring.

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

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.

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.