Active surveillance of prostate cancer: a questionnaire survey of urologists, clinical oncologists and urology nurse specialists across three cancer networks in the United Kingdom.

BACKGROUND: Active surveillance is considered a mainstream strategy in the management of patients with low-risk prostate cancer. A mission-critical step in implementing a robust active surveillance program and plan its resource and service requirements, is to gauge its current practice across the United Kingdom. Furthermore it is imperative to determine the existing practices in the context of the recommendations suggested by the recent National Institute for Health and Clinical Excellence guidance on active surveillance of prostate cancer. METHODS: An internet questionnaire was circulated to urologists, clinical oncologists and urology nurse specialists across three geographically distinct cancer networks. Twenty five questions across four domains were assessed. (i) hospital resources (staff and clinical areas) utilised for active surveillance (ii) enrolment criteria (iii) follow up (iv) criteria that trigger conversion to active treatment. RESULTS: We received 35 responses, 20 of which were from urologists. The survey data suggests that there is marked heterogeneity in enrolment criteria with patients having features of intermediate-risk prostate cancer often recruited into Active Surveillance programs. Only 60 % of our respondents use multiparametric MRI routinely to assess patient suitability for active surveillance. In addition, marked variation exists in how patients are followed up with regard to PSA testing intervals and timing of repeat biopsies. Only 40 % undertake a repeat biopsy at 12 months. Tumour upgrading on repeat biopsy, an increase in tumour volume or percentage of core biopsies involved would prompt a recommendation for treatment amongst most survey respondents. In addition allocation of resources and services for active surveillance is poor. Currently there are no dedicated active surveillance clinics, which are well-structured, -resourced and -supported for regular patient counselling and follow up. CONCLUSION: This variability in enrolment criteria and follow up is also demonstrated in international and national series of active surveillance. Resources are not currently in place across the UK to support an active surveillance program and a national discussion and debate to plan resources is much required so that it can become a mainstream therapeutic strategy

Multi-transcript profiling in archival diagnostic prostate cancer needle biopsies to evaluate biomarkers in non-surgically treated men.

BACKGROUND: Most biomarkers in prostate cancer have only been evaluated in surgical cohorts. The value of these biomarkers in a different therapy context remains unclear. Our objective was to test a panel of surgical biomarkers for prognostic value in men treated by external beam radiotherapy (EBRT) and primary androgen deprivation therapy (PADT). METHODS: The Fluidigm® PCR array was used for multi-transcript profiling of laser microdissected tumours from archival formalin-fixed diagnostic biopsies of patients treated by EBRT or PADT. Cases were matched for disease characteristics and had known 5 year biochemical relapse outcomes (n = 60). Results were validated by immunohistochemistry in a custom needle biopsy tissue microarray. Six biomarkers previously tested only in surgical cohorts were analysed (PTEN, E-Cadherin, EGFR, EZH2, PSMA, MSMB). Transcript and protein expression was correlated with clinical outcome analysed using Kruskal Wallis, Fisher's test and Cox proportional hazard model. RESULTS: Altered expression of E-Cadherin (p = 0.008) was associated with early relapse after EBRT. In PADT treated men however only altered MSMB transcript was prognostic for early relapse (p = 0.001). The remaining biomarkers however did not demonstrate prognostic ability in either cohort. In a separate tissue array we validated altered E-Cadherin protein as a predictor of early relapse after EBRT (n = 47) (HR 0.34, CI p = 0.02) but not in PADT treated men (n = 63). CONCLUSION: We demonstrate proof of principle of multiple transcript profiling in archival diagnostic biopsies of non-surgically treated men for biomarker discovery. We identify a role for E-Cadherin as a novel biomarker of early relapse following EBRT

Comparative Oncologic and Toxicity Outcomes of Salvage Radical Prostatectomy Versus Nonsurgical Therapies for Radiorecurrent Prostate Cancer: A Meta-Regression Analysis.

CONTEXT: In the absence of randomised controlled trials comparing the oncologic, toxicity, and functional outcomes of salvage radical prostatectomy (SRP), salvage high-intensity focused ultrasound (SHIFU), salvage brachytherapy (SBT), and salvage cryotherapy (SCT), controversy exists as to the optimal salvage modality in radiorecurrent prostate cancer. OBJECTIVE: We carried out a meta-regression analysis to determine whether there is a difference in oncologic, toxicity, and functional outcomes using data from original publications of salvage modalities in the postradiation setting. EVIDENCE ACQUISITION: We performed a systematic review of PubMed/Medline citations according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. We included 63 articles in the analysis (25 on SRP, 8 on SHIFU, 16 on SCT, 14 on SBT). EVIDENCE SYNTHESIS: Median values of the following variables were extracted from each study: patient age, length of follow-up, prostate-specific antigen (PSA) before radiotherapy (RT), PSA before salvage therapy, Gleason score before RT, and time interval between RT and salvage therapy. Functional, toxicity, and oncologic outcomes were measured according to rates of impotence, incontinence, fistula formation, urethral strictures, and biochemical recurrence. Meta-regression adjusting for confounders found no significant difference in oncologic outcomes between SRP and nonsurgical salvage modalities. SBT, SCT, and SHIFU appeared to have better continence outcomes than SRP. No significant difference in toxicity outcomes between modalities was found, although limitations such as reporting, selection, and publication bias and between-study heterogeneity must also be considered with these conclusions. CONCLUSIONS: Oncologic outcomes are comparable for SRP and all three nonsurgical salvage modalities. We found no significant differences in toxicity outcomes among modalities; however, SRP appears to be associated with worse rates of urinary incontinence than SBT, SCT, and SHIFU. PATIENT SUMMARY: We performed a meta-regression analysis to compare oncologic, functional, and toxicity outcomes between salvage radical prostatectomy and nonsurgical salvage modalities. Oncologic and toxicity outcomes appear to be similar; however, all nonsurgical salvage modalities may be associated with better continence outcomes.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.euf.2015.09.00

Understanding of prognosis in non-metastatic prostate cancer: a randomised comparative study of clinician estimates measured against the PREDICT prostate prognostic model

Abstract: PREDICT Prostate is an individualised prognostic model that provides long-term survival estimates for men diagnosed with non-metastatic prostate cancer (www.prostate.predict.nhs.uk). In this study clinician estimates of survival were compared against model predictions and its potential value as a clinical tool was assessed. Prostate cancer (PCa) specialists were invited to participate in the study. 190 clinicians (63% urologists, 17% oncologists, 20% other) were randomised into two groups and shown 12 clinical vignettes through an online portal. Each group viewed opposing vignettes with clinical information alone, or alongside PREDICT Prostate estimates. 15-year clinician survival estimates were compared against model predictions and reported treatment recommendations with and without seeing PREDICT estimates were compared. 155 respondents (81.6%) reported counselling new PCa patients at least weekly. Clinician estimates of PCa-specific mortality exceeded PREDICT estimates in 10/12 vignettes. Their estimates for treatment survival benefit at 15 years were over-optimistic in every vignette, with mean clinician estimates more than 5-fold higher than PREDICT Prostate estimates. Concomitantly seeing PREDICT Prostate estimates led to significantly lower reported likelihoods of recommending radical treatment in 7/12 (58%) vignettes, particularly in older patients. These data suggest clinicians overestimate cancer-related mortality and radical treatment benefit. Using an individualised prognostic tool may help reduce overtreatment

Models predicting survival to guide treatment decision-making in newly diagnosed primary non-metastatic prostate cancer: a systematic review.

OBJECTIVES: Men diagnosed with non-metastatic prostate cancer require standardised and robust long-term prognostic information to help them decide on management. Most currently-used tools use short-term and surrogate outcomes. We explored the evidence base in the literature on available pre-treatment, prognostic models built around long-term survival and assess the accuracy, generalisability and clinical availability of these models. DESIGN: Systematic literature review, pre-specified and registered on PROSPERO (CRD42018086394). DATA SOURCES: MEDLINE, Embase and The Cochrane Library were searched from January 2000 through February 2018, using previously-tested search terms. ELIGIBILITY CRITERIA: Inclusion required a multivariable model prognostic model for non-metastatic prostate cancer, using long-term survival data (defined as ≥5 years), which was not treatment-specific and usable at the point of diagnosis. DATA EXTRACTION AND SYNTHESIS: Title, abstract and full-text screening were sequentially performed by three reviewers. Data extraction was performed for items in the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies checklist. Individual studies were assessed using the new Prediction model Risk Of Bias ASsessment Tool. RESULTS: Database searches yielded 6581 studies after deduplication. Twelve studies were included in the final review. Nine were model development studies using data from over 231 888 men. However, only six of the nine studies included any conservatively managed cases and only three of the nine included treatment as a predictor variable. Every included study had at least one parameter for which there was high risk of bias, with failure to report accuracy, and inadequate reporting of missing data common failings. Three external validation studies were included, reporting two available models: The University of California San Francisco (UCSF) Cancer of the Prostate Risk Assessment score and the Cambridge Prognostic Groups. Neither included treatment effect, and both had potential flaws in design, but represent the most robust and usable prognostic models currently available. CONCLUSION: Few long-term prognostic models exist to inform decision-making at diagnosis of non-metastatic prostate cancer. Improved models are required to inform management and avoid undertreatment and overtreatment of non-metastatic prostate cancer.The Urology Foundation - Research Scholarship

Role and expression of FRS2 and FRS3 in prostate cancer

Background: FGF receptor substrates (FRS2 and FRS3) are key adaptor proteins that mediate FGF-FGFR signalling in benign as well as malignant tissue. Here we investigated FRS2 and FRS3 as a means of disrupting global FGF signalling in prostate cancer.Methods: FRS2 and FRS3 manipulation was investigated in vitro using over-expression, knockdown and functional assays. FRS2 and FRS3 expression was profiled in cell lines and clinical tumors of different grades.Results: In a panel of cell lines we observed ubiquitous FRS2 and FRS3 transcript and protein expression in both benign and malignant cells. We next tested functional redundancy of FRS2 and FRS3 in prostate cancer cells. In DU145 cells, specific FRS2 suppression inhibited FGF induced signalling. This effect was not apparent in cells stably over-expressing FRS3. Indeed FRS3 over-expression resulted in enhanced proliferation (p = 0.005) compared to control cells. Given this functional redundancy, we tested the therapeutic principle of dual targeting of FRS2 and FRS3 in prostate cancer. Co-suppression of FRS2 and FRS3 significantly inhibited ERK activation with a concomitant reduction in cell proliferation (p \u3c 0.05), migration and invasion (p \u3c 0.05). Synchronous knockdown of FRS2 and FRS3 with exposure to cytotoxic irradiation resulted in a significant reduction in prostate cancer cell survival compared to irradiation alone (p \u3c 0.05). Importantly, this synergistic effect was not observed in benign cells. Finally, we investigated expression of FRS2 and FRS3 transcript in a cohort of micro-dissected tumors of different grades as well as by immunohistochemistry in clinical biopsies. Here, we did not observe any difference in expression between benign and malignant biopsies.Conclusions: These results suggest functional overlap of FRS2 and FRS3 in mediating mitogenic FGF signalling in the prostate. FRS2 and FRS3 are not over-expressed in tumours but targeted dual inhibition may selectively adversely affect malignant but not benign prostate cells. © 2011 Valencia et al; licensee BioMed Central Ltd

A novel split mode TFBAR device for quantitative measurements of prostate specific antigen in a small sample of whole blood.

Easy monitoring of prostate specific antigen (PSA) directly from blood samples would present a significant improvement as compared to conventional diagnostic methods. In this work, a split mode thin film bulk acoustic resonator (TFBAR) device was employed for the first time for label-free measurements of PSA concentrations in the whole blood and without sample pre-treatment. The surface of the sensor was covalently modified with anti-PSA antibodies and demonstrated a very high sensitivity of 101 kHz mL ng-1 and low limit of detection (LOD) of 0.34 ng mL-1 in model spiked solutions. It has previously been widely believed that significant pre-processing of blood samples would be required for TFBAR biosensors. Importantly, this work demonstrates that this is not the case, and TFBAR technology provides a cost-effective means for point-of-care (POC) diagnostics and monitoring of PSA in hospitals and in doctors' offices. Additionally, the accuracy of the developed biosensor, with respect to a commercial auto analyser (Beckman Coulter Access), was evaluated to analyse clinical samples, giving well-matched results between the two methods, thus showing a practical application in quantitative monitoring of PSA levels in the whole blood with very good signal recovery

Role and expression of FRS2 and FRS3 in prostate cancer.

BACKGROUND: FGF receptor substrates (FRS2 and FRS3) are key adaptor proteins that mediate FGF-FGFR signalling in benign as well as malignant tissue. Here we investigated FRS2 and FRS3 as a means of disrupting global FGF signalling in prostate cancer. METHODS: FRS2 and FRS3 manipulation was investigated in vitro using over-expression, knockdown and functional assays. FRS2 and FRS3 expression was profiled in cell lines and clinical tumors of different grades. RESULTS: In a panel of cell lines we observed ubiquitous FRS2 and FRS3 transcript and protein expression in both benign and malignant cells. We next tested functional redundancy of FRS2 and FRS3 in prostate cancer cells. In DU145 cells, specific FRS2 suppression inhibited FGF induced signalling. This effect was not apparent in cells stably over-expressing FRS3. Indeed FRS3 over-expression resulted in enhanced proliferation (p = 0.005) compared to control cells. Given this functional redundancy, we tested the therapeutic principle of dual targeting of FRS2 and FRS3 in prostate cancer. Co-suppression of FRS2 and FRS3 significantly inhibited ERK activation with a concomitant reduction in cell proliferation (p < 0.05), migration and invasion (p < 0.05). Synchronous knockdown of FRS2 and FRS3 with exposure to cytotoxic irradiation resulted in a significant reduction in prostate cancer cell survival compared to irradiation alone (p < 0.05). Importantly, this synergistic effect was not observed in benign cells. Finally, we investigated expression of FRS2 and FRS3 transcript in a cohort of micro-dissected tumors of different grades as well as by immunohistochemistry in clinical biopsies. Here, we did not observe any difference in expression between benign and malignant biopsies. CONCLUSIONS: These results suggest functional overlap of FRS2 and FRS3 in mediating mitogenic FGF signalling in the prostate. FRS2 and FRS3 are not over-expressed in tumours but targeted dual inhibition may selectively adversely affect malignant but not benign prostate cells.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Trends and outcome from radical therapy for primary non-metastatic prostate cancer in a UK population.

BACKGROUND: Increasing proportions of men diagnosed with prostate cancer in the UK are presenting with non-metastatic disease. We investigated how treatment trends in this demographic have changed. PATIENT AND METHODS: Non-metastatic cancers diagnosed from 2000-2010 in the UK Anglian Cancer network stratified by age and risk group were analysed [n = 10,365]. Radiotherapy [RT] and prostatectomy [RP] cancer specific survival [CSS] were further compared [n = 4755]. RESULTS: Over the decade we observed a fall in uptake of primary androgen deprivation therapy but a rise in conservative management [CM] and radical therapy [p<0.0001]. CM in particular has become the primary management for low-risk disease by the decade end [p<0.0001]. In high-risk disease however both RP and RT uptake increased significantly but in an age dependent manner [p<0.0001]. Principally, increased RP in younger men and increased RT in men ≥ 70y. In multivariate analysis of radically treated men both high-risk disease [HR 8.0 [2.9-22.2], p<0.0001] and use of RT [HR 1.9 [1.0-3.3], p = 0.024] were significant predictors of a poorer CSM. In age-stratified analysis however, the trend to benefit of RP over RT was seen only in younger men [≤ 60 years] with high-risk disease [p = 0.07]. The numbers needed to treat by RP instead of RT to save one cancer death was 19 for this group but 67 for the overall cohort. CONCLUSION: This study has identified significant shifts in non-metastatic prostate cancer management over the last decade. Low-risk disease is now primarily managed by CM while high-risk disease is increasingly treated radically. Treatment of high-risk younger men by RP is supported by evidence of better CSM but this benefit is not evident in older men

Improving Clinical Risk Stratification at Diagnosis in Primary Prostate Cancer: A Prognostic Modelling Study.

INTRODUCTION: Over 80% of the nearly 1 million men diagnosed with prostate cancer annually worldwide present with localised or locally advanced non-metastatic disease. Risk stratification is the cornerstone for clinical decision making and treatment selection for these men. The most widely applied stratification systems use presenting prostate-specific antigen (PSA) concentration, biopsy Gleason grade, and clinical stage to classify patients as low, intermediate, or high risk. There is, however, significant heterogeneity in outcomes within these standard groupings. The International Society of Urological Pathology (ISUP) has recently adopted a prognosis-based pathological classification that has yet to be included within a risk stratification system. Here we developed and tested a new stratification system based on the number of individual risk factors and incorporating the new ISUP prognostic score. METHODS AND FINDINGS: Diagnostic clinicopathological data from 10,139 men with non-metastatic prostate cancer were available for this study from the Public Health England National Cancer Registration Service Eastern Office. This cohort was divided into a training set (n = 6,026; 1,557 total deaths, with 462 from prostate cancer) and a testing set (n = 4,113; 1,053 total deaths, with 327 from prostate cancer). The median follow-up was 6.9 y, and the primary outcome measure was prostate-cancer-specific mortality (PCSM). An external validation cohort (n = 1,706) was also used. Patients were first categorised as low, intermediate, or high risk using the current three-stratum stratification system endorsed by the National Institute for Health and Care Excellence (NICE) guidelines. The variables used to define the groups (PSA concentration, Gleason grading, and clinical stage) were then used to sub-stratify within each risk category by testing the individual and then combined number of risk factors. In addition, we incorporated the new ISUP prognostic score as a discriminator. Using this approach, a new five-stratum risk stratification system was produced, and its prognostic power was compared against the current system, with PCSM as the outcome. The results were analysed using a Cox hazards model, the log-rank test, Kaplan-Meier curves, competing-risks regression, and concordance indices. In the training set, the new risk stratification system identified distinct subgroups with different risks of PCSM in pair-wise comparison (p < 0.0001). Specifically, the new classification identified a very low-risk group (Group 1), a subgroup of intermediate-risk cancers with a low PCSM risk (Group 2, hazard ratio [HR] 1.62 [95% CI 0.96-2.75]), and a subgroup of intermediate-risk cancers with an increased PCSM risk (Group 3, HR 3.35 [95% CI 2.04-5.49]) (p < 0.0001). High-risk cancers were also sub-classified by the new system into subgroups with lower and higher PCSM risk: Group 4 (HR 5.03 [95% CI 3.25-7.80]) and Group 5 (HR 17.28 [95% CI 11.2-26.67]) (p < 0.0001), respectively. These results were recapitulated in the testing set and remained robust after inclusion of competing risks. In comparison to the current risk stratification system, the new system demonstrated improved prognostic performance, with a concordance index of 0.75 (95% CI 0.72-0.77) versus 0.69 (95% CI 0.66-0.71) (p < 0.0001). In an external cohort, the new system achieved a concordance index of 0.79 (95% CI 0.75-0.84) for predicting PCSM versus 0.66 (95% CI 0.63-0.69) (p < 0.0001) for the current NICE risk stratification system. The main limitations of the study were that it was registry based and that follow-up was relatively short. CONCLUSIONS: A novel and simple five-stratum risk stratification system outperforms the standard three-stratum risk stratification system in predicting the risk of PCSM at diagnosis in men with primary non-metastatic prostate cancer, even when accounting for competing risks. This model also allows delineation of new clinically relevant subgroups of men who might potentially receive more appropriate therapy for their disease. Future research will seek to validate our results in external datasets and will explore the value of including additional variables in the system in order in improve prognostic performance.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pmed.100206