Simon Bott

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.

The index lesion and focal therapy: an analysis of the pathological characteristics of prostate cancer

To determine the pathological characteristics of radical prostatectomy specimens with respect to index and secondary lesions.

Plexin-B1 mutations in prostate cancer

Semaphorins are a large class of secreted or membrane-associated proteins that act as chemotactic cues for cell movement via their transmembrane receptors, plexins. We hypothesized that the function of the semaphorin signaling pathway in the control of cell migration could be harnessed by cancer cells during invasion and metastasis. We now report 13 somatic missense mutations in the cytoplasmic domain of the Plexin-B1 gene. Mutations were found in 89% (8 of 9) of prostate cancer bone metastases, in 41% (7 of 17) of lymph node metastases, and in 46% (41 of 89) of primary cancers. Forty percent of prostate cancers contained the same mutation. Overexpression of the Plexin-B1 protein was found in the majority of primary tumors. The mutations hinder Rac and R-Ras binding and R-RasGAP activity, resulting in an increase in cell motility, invasion, adhesion, and lamellipodia extension. These results identify a key role for Plexin-B1 and the semaphorin signaling pathway it mediates in prostate cancer.

Determination of optimal drug dose and light dose index to achieve minimally invasive focal ablation of localised prostate cancer using WST11-vascular-targeted photodynamic (VTP) therapy

To determine the optimal drug and light dose for prostate ablation using WST11 (TOOKAD® Soluble) for vascular‐targeted photodynamic (VTP) therapy in men with low‐risk prostate cancer.

Does prostate HistoScanning™ play a role in detecting prostate cancer in routine clinical practice? Results from three independent studies

To evaluate the ability of prostate HistoScanning™ (PHS; Advanced Medical Diagnostics, Waterloo, Belgium) to detect, characterize and locally stage prostate cancer, by comparing it with transrectal ultrasonography (TRUS)‐guided prostate biopsies, transperineal template prostate biopsies (TTBs) and whole‐mount radical prostatectomy specimens.

Utility of tissue microarrays for profiling prognostic biomarkers in clinically localized prostate cancer: the expression of BCL-2, E-cadherin, Ki-67 and p53 as predictors of biochemical failure after radical prostatectomy with nested control for clinical and pathological risk factors

A cure cannot be assured for all men with clinically localized prostate cancer undergoing radical treatment. Molecular markers would be invaluable if they could improve the prediction of occult metastatic disease. This study was carried out to investigate the expression of BCL-2, Ki-67, p53 and E-cadherin in radical prostatectomy specimens. We sought to assess their ability to predict early biochemical relapse in a specific therapeutic setting. Eighty-two patients comprising 41 case pairs were matched for pathological stage, Gleason grade and preoperative prostate-specific antigen (PSA) concentration. One patient in each pair had biochemical recurrence (defined as PSA >or= 0.2 ng mL(-1) within 2 years of surgery) and the other remained biochemically free of disease (defined as undetectable PSA at least 3 years after surgery). Immunohistochemical analysis was performed to assess marker expression on four replicate tissue microarrays constructed with benign and malignant tissue from each radical prostatectomy specimen. Ki-67, p53 and BCL-2, but not E-cadherin, were significantly upregulated in prostate adenocarcinoma compared with benign prostate tissue (P < 0.01). However, no significant differences in expression of any of the markers were observed when comparing patients who developed early biochemical relapse with patients who had no biochemical recurrence. This study showed that expression of p53, BCL-2 and Ki-67 was upregulated in clinically localized prostate cancer compared with benign prostate tissue, with no alteration in E-cadherin expression. Biomarker upregulation had no prognostic value for biochemical recurrence after radical prostatectomy, even after considering pathological stage, whole tumour Gleason grade and preoperative serum PSA level.

The Prevalence of Clinically Significant Prostate Cancer According to Commonly Used Histological Thresholds in Men Undergoing Template Prostate Mapping Biopsies

PURPOSE Transrectal prostate biopsies are inaccurate and, thus, the prevalence of clinically significant prostate cancer in men undergoing biopsy is unknown. We determined the ability of different histological thresholds to denote clinically significant cancer in men undergoing a more accurate biopsy, that of transperineal template prostate mapping. MATERIALS AND METHODS In this multicenter, cross-sectional cohort of men who underwent template prostate mapping biopsies between May 2006 and January 2012, 4 different thresholds of significance combining tumor grade and burden were used to measure the consequent variation with respect to the prevalence of clinically significant disease. RESULTS Of 1,203 men 17% (199) had no previous biopsy, 38% (455) had a prior negative transrectal ultrasound biopsy, 24% (289) were on active surveillance and 21% (260) were seeking risk stratification. Mean patient age was 63.5 years (SD 7.6) and median prostate specific antigen was 7.4 ng/ml (IQR 5.3-10.5). Overall 35% of the patients (424) had no cancer detected. The prevalence of clinically significant cancer varied between 14% and 83% according to the histological threshold used, in particular between 30% and 51% among men who had no previous biopsy, between 14% and 27% among men who had a prior negative biopsy, between 36% and 74% among men on active surveillance, and between 47% and 83% among men seeking risk stratification. CONCLUSIONS According to template prostate mapping biopsy between 1 in 2 and 1 in 3 men have prostate cancer that is histologically defined as clinically significant. This suggests that the commonly used thresholds may be set too low.

Does Prostate HistoScanningTM accurately identify prostate cancer, measure tumour volume and assess pathological stage prior to radical prostatectomy?

Objective The objective of this paper is to assess the ability of Prostate HistoScanning™ (PHS) to accurately identify tumour volume, index lesion characteristics and pathological stage. PHS is a novel technology employing transrectal ultrasound scanning and software analysis of radiofrequency data to produce signatures for benign and cancerous tissues. Recent reports have suggested PHS is capable of characterising the index cancer lesion and disease multifocality and detecting extraprostatic extension (EPE). Materials and methods The index test was preoperative PHS on patients undergoing radical prostatectomy (RP). The reference test was the whole-mount pathological analysis of the RP specimen. PHS analysis estimated total tumour volumes, tumour volumes by prostate sextant, the locations and volumes of index lesions, and the presence and location of EPE. Results There was no correlation between PHS and histology total tumour volume estimates (Pearson coefficient –0.099), despite accounting for specimen fixation shrinkage (Pearson coefficient –0.070), nor among 144 prostate sextants in 24 patients (Pearson coefficient 0.14). Sensitivity and specificity of PHS in detecting foci > 0.2 ml were 63% and 53%, respectively; and 37% and 71%, respectively, for foci > 0.5 ml. Pearson correlation coefficient for index lesion volumes identified at pathology vs PHS was 0.065. PHS failed to locate accurately index lesion and pathological EPE. Conclusions PHS fails to identify total tumour volumes, tumour volumes prostate sextant, index lesion volumes and locations, and presence and location of EPE compared to RP pathology. PHS appears unsuitable for routine diagnostic clinical use in prostate cancer.

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.

Laparoscopic Cytoreductive Nephrectomy: A Three-Center Retrospective Analysis

INTRODUCTION Metastatic renal cell carcinoma is associated with a poor prognosis. Given the current lack of effective systemic therapies and data suggesting a survival benefit from cytoreductive nephrectomy (CRN) before systemic therapy, we have retrospectively analyzed the experience of laparoscopic cytoreductive nephrectomy (LCRN) in three U.K. centers. The focus of this study was to assess the peri- and postoperative safety and hence feasibility of LCRN in the United Kingdom. PATIENTS AND METHODS Twenty-five patients with metastatic renal cell carcinoma deemed suitable for systemic therapy underwent LCRN in three U.K. centers over a 4-year period. RESULTS The tumors ranged from 3.4 cm in diameter to 12 cm. Operating times ranged from 89 (minimum) to 310 minutes (maximum), median 175 minutes. The median amount of blood loss was 150 mL, and hence the transfusion rate was low with only one patient requiring on-table transfusion and two patients requiring additional blood before discharge. Hospital stay ranged between 2.5 and 11 days; median postoperative stay was 3 days. CONCLUSIONS In our initial experience, LCRN seems safe and feasible with low morbidity and a good perioperative outcome.