Comparison of Multiparametric MRI-targeted and Systematic Biopsies for Detection of Cribriform and Intraductal Carcinoma Prostate Cancer.

Background Intraductal carcinoma (IDC) and invasive cribriform (Cr) subtypes of prostate cancer (PCa) are an indication of aggressiveness, but the evidence regarding whether MRI can be used to detect Cr/IDC-pattern PCa is contradictory. Purpose To compare the detection of Cr/IDC-pattern PCa at multiparametric MRI (mpMRI)-targeted biopsy versus systematic biopsy in biopsy-naive men at risk for PCa. Materials and Methods This study was a secondary analysis of a prospective randomized controlled trial that recruited participants with a clinical suspicion of PCa between April 2017 and November 2019 at five centers. Participants were randomized 1:1 to either the MRI arm or the systematic biopsy arm. Targeted biopsy was performed in participants with a Prostate Imaging Reporting and Data System score of at least 3. MRI features were recorded, and biopsy slides and prostatectomy specimens were reviewed for the presence or absence of Cr/IDC histologic patterns. Comparison of Cr/IDC patterns was performed using generalized linear mixed modeling. Results A total of 453 participants were enrolled, with 226 in the systematic biopsy arm (median age, 65 years [IQR, 59-70 years]; 196 biopsies available for assessment) and 227 in the mpMRI-targeted biopsy arm (median age, 67 years [IQR, 60-72 years]; 132 biopsies available for assessment). Identification of Cr/IDC PCa was lower in the systematic biopsy arm compared with the mpMRI arm (31 of 196 biopsies [16%] vs 33 of 132 biopsies [25%]; P = .01). No evidence of a difference in mean cancer core length (CCL) (11.3 mm ± 4.4 vs 9.7 mm ± 4.5; P = .09), apparent diffusion coefficient (685 µm2/sec ± 178 vs 746 µm2/sec ± 245; P = .52), or dynamic contrast-enhanced positivity (27 [82%] vs 37 [90%]; P = .33) for clinically significant PCa (csPCa) was observed between participants with or without Cr/IDC disease in the MRI arm. Cr/IDC-positive histologic patterns overall had a higher mean CCL compared with Cr/IDC-negative csPCa (11.1 mm ± 4.4 vs 9.2 mm ± 4.1; P = .009). Conclusion MRI-targeted biopsy showed increased detection of Cr/IDC histologic patterns compared with systematic biopsy. Clinical trial registration no. NCT02936258 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Scialpi and Martorana in this issue.

'Spin' in urology non-randomised studies comparing therapeutic interventions: a temporal analysis.

OBJECTIVE: To determine the prevalence of 'spin' (i.e., reporting practices that distort the interpretation of results by positively reflecting negative findings or downplaying potential harms) strategies and level of spin in urological observational studies and whether the use of spin has changed over time. MATERIALS AND METHODS: MEDLINE and Embase were searched to identify observational studies comparing therapeutic interventions in the top five urology journals and major urological subspecialty journals, published between 2000 and 2001, 2010 and 2011, and 2020 and 2021. RESULTS: A total of 235 studies were included. Spin was identified in 81% of studies, with a median of two strategies per study. The most commonly used strategies were inadequate implication for clinical practice (30%), causal language or causal claim (29%), and use of linguistic spin (29%). Moderate to high levels of spin were found in 55% of conclusions. From 2000 to 2020, the average number of strategies used has significantly decreased each decade (H = 27.459, P < 0.001), and the median level of spin in conclusions was significantly lower in studies published in the 2020s and 2010s than in the 2000s (H = 11.649, P = 0.003). CONCLUSIONS: Our results suggest that 81% of urological observational studies comparing therapeutic interventions contained spin. Over the past two decades, the use of spin has significantly declined, but this remains an area for improvement, with 70% of included studies published in the 2020s employing spin. Medical writing should scrupulously avoid words or phrases that are not supported by data in the manuscript.

Assessing "Spin" in Urology Randomized Controlled Trials With Statistically Nonsignificant Primary Outcomes.

PURPOSE: "Spin" refers to a form of language manipulation that positively reflects negative findings or downplays potential harms. Spin has been reported in randomized controlled trials of other surgical specialties, which can lead to the recommendation of subpar or ineffective treatments. The goal of this study was to characterize spin strategies and severity in statistically nonsignificant urology randomized controlled trials. MATERIALS AND METHODS: A comprehensive search of MEDLINE and Embase for the top 5 urology journals, major urology subspecialty journals, and high-impact nonurology journals from 2019 to 2021 was conducted. Statistically nonsignificant randomized controlled trials with a defined primary outcome were included. Screening, data extraction, and spin assessment were performed in duplicate by 2 independent reviewers. RESULTS: From the database search of 4,339 studies, 46 trials were included for analysis. Spin was identified in 35 studies (76%), with the majority of abstracts (n = 26, 57%) and main texts (n = 35, 76%) containing some level of spin. "Obscuring the statistical nonsignificance of the primary outcome and focusing on statistically significant secondary results" was the most frequently used strategy in abstracts, while "other" strategies not previously defined were the most commonly used strategies in main texts. Moderate or high spin severity was identified in 21 (46%) abstract and 22 (48%) main text conclusions. CONCLUSIONS: Overall, our results suggest that 76% of statistically nonsignificant urology randomized controlled trials contained some level of spin. Readers and writers should be aware of common spin strategies when interpreting nonsignificant results and critically appraise the significance of results when making decisions for clinical practice.

Focal Therapy for Prostate Cancer: Evolutionary Parallels to Breast Cancer Treatment.

PURPOSE: Our goal was to review the history of the adoption of focal therapy for breast and prostate cancer and review common barriers to implementation. MATERIALS AND METHODS: A narrative review of the literature was performed of English-language MEDLINE indexed articles of breast-conservation therapy and prostate cancer focal therapy. RESULTS: The introduction of focal therapy in breast cancer began with pioneering case series, and multiple randomized trials were performed prior to widespread adoption. Focal therapy for prostate cancer has just started the process of clinical trials with a single published randomized controlled trial. Commonly cited barriers to the adoption of prostate focal therapy include historical views of Halstedian tumor biology, tumor multifocality, over-detection, limitations in prostate imaging, and trial design end points. CONCLUSIONS: The adoption of breast-conserving therapy evolved over decades and used data from multiple large, randomized, clinical trials. Barriers to the adoption of prostate cancer local therapy are similar to those faced by breast cancer clinical trials. Completion of well-designed trials in prostate cancer focal therapy is essential for its evidence-based adoption.

Effect of 18F-DCFPyL PET/CT on the Management of Patients with Recurrent Prostate Cancer: Results of a Prospective Multicenter Registry Trial.

Background The high positivity rate of prostate-specific membrane antigen (PSMA) PET in the setting of biochemical failure (BCF), even when conventional imaging is negative, is promising. Purpose To assess the disease detection rate of PSMA-based PET/CT with fluorine 18-DCFPyL as a radiotracer and the PET-directed management change in men with suspected limited recurrent prostate cancer. Materials and Methods This prospective multicenter registry (Ontario PSMA-PET Registry for Recurrent Prostate Cancer, or PREP) enrolled men with BCF after primary therapy (radical prostatectomy plus or minus salvage radiation therapy or primary radiation therapy) and zero to four disease sites at conventional imaging (CT and bone scintigraphy). The positivity rate of PSMA PET according to serum prostate-specific antigen (PSA) level; frequency of local-egional, oligometastatic, and extensive metastatic recurrence; and rate of change in management after PET findings were recorded. The nonparametric Mood median test was used to assess the association between serum PSA level and change in management. Results A total of 1289 men (median age, 71 years [interquartile range, 65-75 years]) were evaluated. PSMA PET helped detect disease in 841 of 1289 men (65%) and in 615 of 999 men (62%) with negative conventional imaging. The recurrence detection rates according to serum PSA level at enrollment were 38% (160 of 424 men), 63% (107 of 171 men), and 83% (573 of 692 men) for PSA under 0.5 ng/mL, 0.5-1.0 ng/mL, and above 1.0 ng/mL, respectively. At PSMA PET, 399 of 1289 men (31%) had local-regional recurrence, 314 (24%) had oligometastatic disease, and 128 (10%) had extensive metastases. Following PET examination, a change in planned management was recorded in 748 of 1289 men (58%), and in 371 of 1250 men (30%), there was a change in management intent, more commonly from palliative to potentially curative intent (255 of 1289 men [20%]). Conclusion Prostate-specific membrane antigen PET helped detect additional sites of disease compared with conventional imaging in approximately 60% of men with biochemical failure and suspected low-volume metastatic disease, resulting in frequent change in management, including a change from palliative to curative or radical intent therapy in 20% of men. Long-term follow-up is needed to determine whether this impacts disease control. Clinical trial registration no. NCT03718260 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Civelek in this issue.

Low Serum Testosterone in Men with Newly Diagnosed Androgen-Deprivation Therapy-Naïve Prostate Cancer and Its Relationship to Cardiovascular Risk Factors: A RADICAL-PC Substudy.

PURPOSE: Cardiovascular disease is a common cause of death in prostate cancer patients. Low testosterone is associated with increased cardiovascular risk in the general male population. We investigated the relationship between serum testosterone, cardiovascular disease and risk factors in androgen-deprivation therapy-naïve prostate cancer patients. MATERIALS AND METHODS: We performed a cross-sectional analysis of a subgroup of 1,326 androgen-deprivation therapy-naïve men from RADICAL-PC (Role of Androgen-Deprivation Therapy In CArdiovascular Disease-A Longitudinal Prostate Cancer study) in whom serum testosterone was measured at baseline. RADICAL-PC is a prospective multicenter cohort study of men (2,565) enrolled within 1 year of prostate cancer diagnosis, or within 6 months of commencing androgen-deprivation therapy for the first time. Cardiovascular risk factors, cancer characteristics and total serum testosterone were collected at baseline. Low testosterone was defined as total serum testosterone <11 nmol/L (<320 ng/dL). A Framingham cardiovascular risk score ≥15 was considered high risk for future cardiovascular events. We performed logistic regression to calculate odds ratios for the association between testosterone and cardiovascular risk. RESULTS: Among 1,326 participants (median age 67 years, range 45-93), 553 (42%) had low testosterone. Low testosterone was associated with existing cardiovascular disease, diabetes, elevated hemoglobin A1c, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hypertension and Framingham score >15. Among patients with low testosterone, the odds ratio for high cardiovascular risk was 1.33 (1.02-1.73) after adjusting for ethnicity, education, alcohol use, cancer characteristics, physical activity and body mass index. CONCLUSIONS: Among androgen-deprivation therapy-naïve prostate cancer patients, low testosterone is common and associated with increased cardiovascular risk factors.

Overdiagnosis in urologic cancer : For World Journal of Urology Symposium on active surveillance in prostate and renal cancer.

BACKGROUND: Cancer, which historically was diagnosed at late and incurable stages, has expanded to a heterogeneous group of conditions that vary from clinically insignificant to rapidly aggressive and lethal. This evolution is due to the widespread use of screening tests for early detection of cancer, both directed (i.e., PSA, mammography, colonoscopy) and undirected (abdominal imaging). The use of these tests has resulted in both benefits and harms. The benefits are a reduction in survival and mortality, due to significant cancers being diagnosed at a more curable stage. The harms are an increase, in some cases dramatic, in the diagnosis of clinically insignificant disease. These are called 'cancer' but not destined to affect the patient's life, even in the absence of treatment. METHODS: Non-explicit summary of the literature on overdiagnosis of cancer. RESULTS: The phenomenon of overdiagnosis requires two factors: the presence of a common reservoir of microfocal disease and a screening test to find it. These factors exist for breast, prostate, skin, renal, and thyroid cancers, and to a lesser degree for lung cancer. The problem of cancer overdiagnosis and overtreatment is complex, with numerous etiologies and many tradeoffs. It is a particular problem in prostate cancer but is a major issue in many other cancer sites. Screening for prostate cancer based on the best data from prospective randomized trials significantly reduces cancer mortality. However, reducing overtreatment in patients diagnosed with indolent disease is critical to the success of screening. CONCLUSION: Active surveillance, the focus of this series of articles, is an important strategy to reduce overtreatment. This article reviews the pathological, clinical, social, and psychological aspects of overdiagnosis in cancer.

Focal therapy: definition and rationale.

PURPOSE OF REVIEW: The role of focal therapy for the treatment of prostate cancer is expanding in clinical practice. The aim of this review is to introduce readers to controversies in the use of focal therapy and its rationale. RECENT FINDINGS: There is a growing body of literature regarding the short-term and medium-term cancer control parameters and quality of life outcomes. These are mostly observational studies without a comparative arm. There is a need for high-quality randomize control trials comparing these treatments to definitive standard of care interventions (e.g. surgery or radiotherapy) in appropriate patient populations. SUMMARY: Focal therapy for prostate cancer has become an established therapeutic strategy. Evidence continues to accrue regarding its effectiveness. It is a useful treatment option for the appropriately selected patient, with the appeal of improved quality of life compared with standard therapies.

MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography-guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited. METHODS: In a multicenter, randomized, noninferiority trial, we assigned men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard transrectal ultrasonography-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of prostate cancer; men whose MRI results were not suggestive of prostate cancer were not offered biopsy. Standard biopsy was a 10-to-12-core, transrectal ultrasonography-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant cancer. Secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. RESULTS: A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28%) had MRI results that were not suggestive of prostate cancer, so they did not undergo biopsy. Clinically significant cancer was detected in 95 men (38%) in the MRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (adjusted difference, 12 percentage points; 95% confidence interval [CI], 4 to 20; P=0.005). MRI, with or without targeted biopsy, was noninferior to standard biopsy, and the 95% confidence interval indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of clinically insignificant cancer (adjusted difference, -13 percentage points; 95% CI, -19 to -7; P<0.001). CONCLUSIONS: The use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard transrectal ultrasonography-guided biopsy in men at clinical risk for prostate cancer who had not undergone biopsy previously. (Funded by the National Institute for Health Research and the European Association of Urology Research Foundation; PRECISION ClinicalTrials.gov number, NCT02380027 .).

Interpreting Testosterone and Concomitant Prostate Specific Antigen Values during Androgen Deprivation Therapy for Recurrent Prostate Cancer.

PURPOSE: Measurement of testosterone levels during androgen deprivation therapy (ADT) is broadly recommended, but how therapy should be altered in response to testosterone values during ADT remains controversial. Our objective was therefore to evaluate the relation between testosterone and concomitant prostate specific antigen (PSA) levels during ADT on clinical outcomes. MATERIALS AND METHODS: Patients from the continuous androgen deprivation arm of the PR.7 trial of intermittent ADT for biochemically recurrent prostate cancer following radiotherapy were included. Statistical analyses evaluated the prognostic importance of testosterone levels during ADT relative to concomitant PSA levels. We similarly evaluated whether the number of testosterone breakthroughs >1.7 nmol/l predicted the time to castrate-resistant prostate cancer (CRPC), cancer specific survival (CSS) or overall survival (OS) with Kaplan-Meier and Cox regression analyses. RESULTS: Overall, the prognostic importance of testosterone on outcomes was eclipsed by the prognostic value of concomitant PSA values. The occurrence of testosterone values >0.7 nmol/l in the first year of therapy was associated with subsequent rises >1.7 nmol/l, but the number of testosterone breakthroughs per patient had no relationship to the risk of CRPC, CSS or OS. A time-dependent adjusted analysis indicated as expected that PSA values were prognostic, but there was no association of relative cumulative testosterone exposure with outcomes. CONCLUSIONS: In this large-scale trial with long followup, breakthrough testosterone was unrelated to time to CRPC, CSS or OS. Castrate testosterone values during ADT for recurrent prostate cancer provides prognostic information that must be considered alongside the time since ADT initiation and concomitant PSA values.

Magnetic Resonance Imaging-Guided Transurethral Ultrasound Ablation of Prostate Cancer.

PURPOSE: Magnetic resonance imaging-guided transurethral ultrasound ablation uses directional thermal ultrasound under magnetic resonance imaging thermometry feedback control for prostatic ablation. We report 12-month outcomes from a prospective multicenter trial (TACT). MATERIALS AND METHODS: A total of 115 men with favorable to intermediate risk prostate cancer across 13 centers were treated with whole gland ablation sparing the urethra and apical sphincter. The co-primary 12-month endpoints were safety and efficacy. RESULTS: In all, 72 (63%) had grade group 2 and 77 (67%) had NCCN® intermediate risk disease. Median treatment delivery time was 51 minutes with 98% (IQR 95-99) thermal coverage of target volume and spatial ablation precision of ±1.4 mm on magnetic resonance imaging thermometry. Grade 3 adverse events occurred in 9 (8%) men. The primary endpoint (U.S. Food and Drug Administration mandated) of prostate specific antigen reduction ≥75% was achieved in 110 of 115 (96%) with median prostate specific antigen reduction of 95% and nadir of 0.34 ng/ml. Median prostate volume decreased from 37 to 3 cc. Among 68 men with pretreatment grade group 2 disease, 52 (79%) were free of grade group 2 disease on 12-month biopsy. Of 111 men with 12-month biopsy data, 72 (65%) had no evidence of cancer. Erections (International Index of Erectile Function question 2 score 2 or greater) were maintained/regained in 69 of 92 (75%). Multivariate predictors of persistent grade group 2 at 12 months included intraprostatic calcifications at screening, suboptimal magnetic resonance imaging thermal coverage of target volume and a PI-RADS™ 3 or greater lesion at 12-month magnetic resonance imaging (p <0.05). CONCLUSIONS: The TACT study of magnetic resonance imaging-guided transurethral ultrasound whole gland ablation in men with localized prostate cancer demonstrated effective tissue ablation and prostate specific antigen reduction with low rates of toxicity and residual disease.

Scoping review: hotspots for COVID-19 urological research: what is being published and from where?

PURPOSE: Contemporary, original research should be utilised to inform guidelines in urology relating to the COVID-19 pandemic. This comprehensive review aimed to: identify all up-to-date original publications relating to urology and COVID-19, characterise where publications were from, and outline what topics were investigated. METHODS: This review utilised a search strategy that assessed five electronic databases, additional grey literature, and global trial registries. All current published, in-press, and pre-print manuscripts were included. Eligible studies were required to be original research articles of any study design, reporting on COVID-19 or urology, in any of study population, intervention, comparison, or outcomes. Included studies were reported in a narrative synthesis format. Data were summarised according to primary reported outcome topic. A world heatmap was generated to represent where included studies originated from. RESULTS: Of the 6617 search results, 48 studies met final inclusion criteria, including 8 pre-prints and 7 ongoing studies from online registries. These studies originated from ten countries according to first author affiliation. Most studies originated from China (n = 13), followed by Italy (n = 12) and USA (n = 11). Topics of the study included pathophysiological, administrative, and clinical fields: translational (n = 14), COVID-19-related outcomes (n = 5), urology training (n = 4), telemedicine (n = 7), equipment and safety (n = 2), urology in general (n = 4), uro-oncology (n = 3), urolithiasis (n = 1), and kidney transplantation (n = 8). CONCLUSION: This review has outlined available original research relevant to COVID-19 and urology from the international community. This summary may serve as a guide for future research priorities in this area.

Moving away from systematic biopsies: image-guided prostate biopsy (in-bore biopsy, cognitive fusion biopsy, MRUS fusion biopsy) -literature review.

OBJECTIVE: To compare the detection rate of clinically significant cancer (CSCa) by magnetic resonance imaging-targeted biopsy (MRI-TB) with that by standard systematic biopsy (SB) and to evaluate the role of MRI-TB as a replacement from SB in men at clinical risk of prostate cancer. METHODS: The non-systematic literature was searched for peer-reviewed English-language articles using PubMed, including the prospective paired studies, where the index test was MRI-TB and the comparator text was SB. Also the randomized clinical trials (RCTs) are included if one arm was MRI-TB and another arm was SB. RESULTS: Eighteen prospective studies used both MRI-TB and TRUS-SB, and eight RCT received one of the tests for prostate cancer detection. In most prospective trials to compare MRI-TB vs. SB, there was no significant difference in any cancer detection rate; however, MRI-TB detected more men with CSCa and fewer men with CISCa than SB. CONCLUSION: MRI-TB is superior to SB in detection of CSCa. Since some significant cancer was detected by SB only, a combination of SB with the TB technique would avoid the underdiagnosis of CSCa.

Impact of COVID-19 on medical education: introducing homo digitalis.

PURPOSE: To determine how members of the Société Internationale d'Urologie (SIU) are continuing their education in the time of COVID-19. METHODS: A survey was disseminated amongst SIU members worldwide by email. Results were analyzed to examine the influence of age, practice region and settings on continuing medical education (CME) of the respondents. RESULTS: In total, 2494 respondents completed the survey. Internet searching was the most common method of CME (76%; all ps < 0.001), followed by searching journals and textbook including the online versions (62%; all ps < 0.001). Overall, 6% of the respondents reported no time/interest for CME during the pandemic. Although most urologists report using only one platform for their CME (26.6%), the majority reported using ≥ 2 platforms, with approximately 10% of the respondents using up to 5 different platforms. Urologists < 40 years old were more likely to use online literature (69%), podcasts/AV media (38%), online CME courses/webinars (40%), and social media (39%). There were regional variations in the CME modality used but no significant difference in the number of methods by region. There was no significant difference in responses between urologists in academic/public hospitals or private practice. CONCLUSION: During COVID-19, urologists have used web-based learning for their CME. Internet learning and literature were the top frequently cited learning methods. Younger urologists are more likely to use all forms of digital learning methods, while older urologists prefer fewer methods.

Current evidence for focal therapy and partial gland ablation for organ-confined prostate cancer: systematic review of literature published in the last 2 years.

PURPOSE OF REVIEW: The shift in the diagnostic algorithm for prostate cancer to early imaging with mpMRI has resulted in many patients being diagnosed with small volume, apparently unilateral, clinically significant cancers. In these patients, a minimally invasive, nonmorbid intervention is appealing. The aim of this study was to review data reported within the last 2 years on focal therapy and partial gland ablation for organ-confined prostate cancer. RECENT FINDINGS: High-intensity focal ultrasound, focal cryotherapy, photodynamic therapy, irreversible electroporation and focal laser ablation, have been used as treatment modalities for localized prostate cancer treatment. The reported oncologic outcomes vary widely and makes comparisons challenging. All the focal therapies report low rates of complications, and high rates of continence and erectile function preservation. The most common adverse events are hematuria, urinary retention and urinary tract infections. During this period, the initial results of several new technologies including MRI-guided transurethral ultrasound ablation were published. SUMMARY: Focal therapy and partial gland ablation for organ-confined prostate cancer is an option for patients with intermediate-risk disease because of its low complication profile and preservation of QOL. Trials comparing the outcome of different focal therapy technologies have not been carried out, and the existing evidence does not point to one approach being clearly superior to others. Long-term oncologic outcome is lacking. Despite this, for men with unilateral intermediate-risk prostate cancer whose disease is often relatively indolent, focal therapy is an appealing option.

Prostate cancer mortality and metastasis under different biopsy frequencies in North American active surveillance cohorts.

BACKGROUND: Active surveillance (AS) is an accepted means of managing low-risk prostate cancer. Because of the rarity of downstream events, data from existing AS cohorts cannot yet address how differences in surveillance intensity affect metastasis and mortality. This study projected the comparative benefits of different AS schedules in men diagnosed with prostate cancer who had Gleason score (GS) ≤6 disease and risk profiles similar to those in North American AS cohorts. METHODS: Times of GS upgrading were simulated based on AS data from the University of Toronto, Johns Hopkins University, the University of California at San Francisco, and the Canary Pass Active Surveillance Cohort. Times to metastasis and prostate cancer death, informed by models from the Scandinavian Prostate Cancer Group 4 trial, were projected under biopsy surveillance schedules ranging from watchful waiting to annual biopsies. Outcomes included the risk of metastasis, the risk of death, remaining life-years (LYs), and quality-adjusted LYs. RESULTS: Compared with watchful waiting, AS biopsies reduced the risk of prostate cancer metastasis and prostate cancer death at 20 years by 1.4% to 3.3% and 1.0% to 2.4%, respectively; and 5-year biopsies reduced the risk of metastasis and prostate cancer death by 1.0% to 2.4% and 0.6% to 1.6%, respectively. There was little difference between annual and 5-year biopsy schedules in terms of LYs (range of differences, 0.04-0.16 LYs) and quality-adjusted LYs (range of differences, -0.02 to 0.09 quality-adjusted LYs). CONCLUSIONS: Among men diagnosed with GS ≤6 prostate cancer, obtaining a biopsy every 3 or 4 years appears to be an acceptable alternative to more frequent biopsies. Reducing surveillance intensity for those who have a low risk of progression reduces the number of biopsies while preserving the benefit of more frequent schedules.

Testosterone Breakthrough Rates during Androgen Deprivation Therapy for Castration Sensitive Prostate Cancer.

PURPOSE: Androgen deprivation therapy is an established therapy for castration sensitive prostate cancer and recent studies have observed that patients whose testosterone levels are suppressed below 0.7 nmol/l have improved outcomes. Testosterone breakthrough, or a rise in testosterone above a target threshold after the first month of androgen deprivation therapy, is generally associated with treatment deficiency. The purpose of this review is to summarize breakthrough rate data and explore the relationship to clinical outcomes in patients with castration sensitive prostate cancer receiving androgen deprivation therapy. MATERIALS AND METHODS: Our systematic search identified 45 studies with a total of 52 cohorts representing 6,047 total patients reporting testosterone breakthrough rates or derivative measures above the thresholds of 1.7 nmol/l (51 cohorts, 6,015 patients) or 0.7 nmol/l (15 cohorts, 2,495 patients). RESULTS: Significantly higher weighted mean breakthrough rates were seen for the 0.7 nmol/l threshold compared to 1.7 nmol/l (41.3% vs 6.9%, p <0.0001). A significant association between breakthrough rates and worse clinical outcomes overall was not found, although when larger trials (sample size greater than 100) and higher event rates (greater than 50%) were considered for the lowest threshold, significant associations between breakthrough rates and clinical outcomes were observed. Clinical factors such as administration and monitoring frequency, type of testosterone assay and type of androgen deprivation therapy did not significantly affect breakthrough rates, although nonvalidated assays were associated with a large degree of variability. CONCLUSIONS: Results from our analysis indicate that testosterone breakthroughs likely result in worse clinical outcomes and should be avoided. Moreover, there is a need to standardize assessment of testosterone levels both clinically and in the research context to better inform treatment decisions and improve the reliability and comparability of results across studies.

Impact of Biopsy Compliance on Outcomes for Patients on Active Surveillance for Prostate Cancer.

PURPOSE: Active surveillance for prostate cancer relies on regular prostate specific antigen tests and surveillance biopsies. Compliance rates with biopsies vary but the subsequent impact on oncologic outcomes is not known. The objective of this study was to determine whether noncompliance with the confirmatory biopsy negatively impacts prostate cancer specific outcomes. MATERIALS AND METHODS: A retrospective analysis was performed on a prospective single-arm cohort of men enrolled in active surveillance for prostate cancer between 1995 and 2018 with a median followup of 9.1 years. A total of 1,275 patients were enrolled and 1,043 had a minimum of 3 years of followup and were included in the analysis. Patients were stratified by compliance with a confirmatory biopsy within 24 months of enrollment in active surveillance. The primary outcome was recurrence-free survival. Secondary outcomes included metastatic-free survival and cause specific survival. RESULTS: A total of 1,275 patients were enrolled, and 1,043 had a minimum of 3 years of followup and were included in the analysis, of whom 425 were treated for localized prostate cancer. Patients noncompliant with the confirmatory biopsy had higher rates of recurrence after treatment (19% vs 12%, HR 1.64, 95% CI 1.19-2.26, p=0.003) and metastases (7% vs 2%, HR 3.56, 95% CI 1.8-7.0, p=0.0003) even after accounting for age, prostate specific antigen and Grade Group. Cause specific survival was not significantly different between the 2 groups. The results were consistent even in the subset of patients with Grade Group 1 disease at study entry. CONCLUSIONS: Noncompliance with a confirmatory biopsy compromises the control of prostate cancer in men followed on active surveillance. Patients and physicians should be aware of the importance of adhering to protocol for men on active surveillance.

Expression of Small Noncoding RNAs in Urinary Exosomes Classifies Prostate Cancer into Indolent and Aggressive Disease.

PURPOSE: This is the first report of the development and performance of a platform that interrogates small noncoding RNAs (sncRNA) isolated from urinary exosomes. The Sentinel™ PCa Test classifies patients with prostate cancer from subjects with no evidence of prostate cancer, the miR Sentinel CS Test stratifies patients with prostate cancer between those with low risk prostate cancer (Grade Group 1) from those with intermediate and high risk disease (Grade Group 2-5), and the miR Sentinel HG Test stratifies patients with prostate cancer between those with low and favorable intermediate risk prostate cancer (Grade Group 1 or 2) and those with high risk (Grade Group 3-5) disease. MATERIALS AND METHODS: sncRNAs were extracted from urinary exosomes of 235 participants and interrogated on miR 4.0 microarrays. Using proprietary selection and classification algorithms, informative sncRNAs were selected to customize an interrogation OpenArray™ platform that forms the basis of the tests. The tests were validated using a case-control sample of 1,436 subjects. RESULTS: The performance of the miR Sentinel PCa Test demonstrated a sensitivity of 94% and specificity of 92%. The Sentinel CS Test demonstrated a sensitivity of 93% and specificity of 90% for prediction of the presence of Grade Group 2 or greater cancer, and the Sentinel HG Test demonstrated a sensitivity of 94% and specificity of 96% for the prediction of the presence of Grade Group 3 or greater cancer. CONCLUSIONS: The Sentinel PCa, CS and HG Tests demonstrated high levels of sensitivity and specificity, highlighting the utility of interrogation of urinary exosomal sncRNAs for noninvasively diagnosing and classifying prostate cancer with high precision.

Extragonadal Steroids Contribute Significantly to Androgen Receptor Activity and Development of Castration Resistance in Recurrent Prostate Cancer after Primary Therapy.

PURPOSE: Beyond testosterone, several steroids contribute to the activation of the androgen receptor pathway, but their relative contributions to the activation of the androgen receptor signaling axis in patients with castrated prostate cancer remain unknown. MATERIALS AND METHODS: Serum levels of 9 steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (219) and from the PCA24 cohort (116). For each steroid standard curves for dose dependent prostate specific antigen promoter activation were built in castration sensitive (LAPC4) and resistant (VCaP) prostate cancer models. Standard curves were used to determine the androgen receptor activation potency for each steroid measurement from patients in these trials. RESULTS: In LAPC4 and VCaP cells testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol and androsterone stimulated androgen receptor only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total androgen receptor transcriptional activity found in castrated cases. The total androgen receptor transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR 2.17, 95% CI 1.12-4.23, p=0.02) in multivariate analysis using the castration sensitive model (LAPC4). Androgen receptor transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR 1.89, 95% CI 1.04-3.44, p=0.036). CONCLUSIONS: Extragonadal steroids contribute significantly to the androgen receptor axis activation at castration levels of testosterone in recurrent nonmetastatic prostate cancer and these sustain the development of castration resistance after primary local treatment.